MI20 • Michigan Nurses 2020

Table of Contents

MI20 • Michigan Nurses 2020

How to Receive Credit

NetCE 10 Hour Course #94130 • Neck Pain in Adults

94130 • Neck Pain in Adults

1. INTRODUCTION

2. EPIDEMIOLOGY

3. PATHOPHYSIOLOGY

4. ASSESSMENT AND DIAGNOSIS

5. TREATMENT OF NECK PAIN

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #38430 • Pathophysiology: The Immune System

38430 • Pathophysiology: The Immune System

1. INTRODUCTION

2. OVERVIEW OF IMMUNITY

3. IMMUNITY IN SPECIAL POPULATIONS

4. IMMUNE HYPERSENSITIVITY DISORDERS

5. RHEUMATIC DISORDERS

6. IMMUNE SYSTEM DISORDERS

7. CONCLUSION

8. CASE STUDIES

Works Cited

Evidence-Based Practice Recommendations Citations

MI20 • Michigan Nurses 2020

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

MI20 • Michigan Nurses 2020

Expiration Date: 09/30/2022

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

94130 • Neck Pain in Adults

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Acute neck pain can be minor and self-limiting or develop into chronic life-limiting pain. Neck pain is the fourth leading cause of disability in the United States, but its negative physical, psychologic, and socioeconomic impact on patients continues to be underappreciated. By combining the best available evidence from diverse sources, this course can greatly assist primary care clinicians in optimizing the care of patients with acute or chronic neck pain.

Table of Contents

94130 • Neck Pain in Adults

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

PERSONAL AND SOCIETAL IMPACT

SPECIFIC NECK PAIN CONDITIONS

CLINICAL COURSE AND PROGNOSIS

ASSOCIATED CONDITIONS

3. PATHOPHYSIOLOGY

CERVICAL SPINE STRUCTURE AND FUNCTION

CERVICAL SPINE PATHOPHYSIOLOGY

NECK PAIN PATHOPHYSIOLOGY

4. ASSESSMENT AND DIAGNOSIS

PATIENT HISTORY

ASSESSMENT OF PROGNOSTIC FACTORS

PHYSICAL EXAMINATION

DIAGNOSTIC IMAGING

LABORATORY TESTING

5. TREATMENT OF NECK PAIN

PATIENT EDUCATION

PHARMACOTHERAPIES

PHYSIOTHERAPIES

MECHANICAL AND MANUAL TRACTION

IMMOBILIZATION

PASSIVE ASSISTIVE DEVICES

THERMOTHERAPY

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION

PHYSICAL AND EXERCISE THERAPIES

PSYCHOSOCIAL INTERVENTIONS

ALTERNATIVE AND COMPLEMENTARY APPROACHES

INTERVENTIONAL AND SURGICAL THERAPIES

CHRONIC REFRACTORY NECK PAIN

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

94130 • Neck Pain in Adults

Education Category. Infection Control / Internal Medicine

Release Date. 10/01/2019

Expiration Date. 09/30/2022

Course Overview

Acute neck pain can be minor and self-limiting or develop into chronic life-limiting pain. Neck pain is the fourth leading cause of disability in the United States, but its negative physical, psychologic, and socioeconomic impact on patients continues to be underappreciated. By combining the best available evidence from diverse sources, this course can greatly assist primary care clinicians in optimizing the care of patients with acute or chronic neck pain.

Audience

This course is designed for all members of the interprofessional healthcare team involved in the care of patients with neck pain.

Course Objective

The purpose of this course is to provide primary care clinicians with the best available evidence on the clinical management of patients with acute or chronic neck pain.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline the prevalence of neck pain in the United States.

2. Review the personal and societal impact of various types of neck pain.

3. Identify risk factors for neck pain in the general public.

4. Describe the pathophysiology of various types of neck pain.

5. Evaluate key components of the assessment of patients with neck pain.

6. Analyze the role of diagnostic imaging in the evaluation of neck pain.

7. Describe the pharmacotherapeutic options for the clinical management of neck pain.

8. Discuss physiotherapies and traction approaches to the clinical management of neck pain.

9. Review the efficacy of physical and exercise therapies for neck pain.

10. Identify alternative and complementary modalities used in the management of neck pain.

11. Compare and contrast interventional modalities used in the management of neck pain.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Eli English, PT, DPT

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Acute neck pain can be minor and self-limiting or develop into chronic pain that adversely affects quality of life. Neck pain is the fourth leading cause of disability in the United States, but its negative physical, psychologic, and socioeconomic impact on patients continues to be underappreciated [1,2].

Primary care clinicians may find neck pain practice guidelines confusing, because recommended approaches are shaped by the training and specialty of guideline authors. This reflects the broader problem of failing to recognize pain medicine as a medical specialty, which has historically fragmented research and practice guidance and made standards of care elusive [3]. With pharmacotherapy studies in neck pain lacking, the focus of neck pain guidelines is nonpharmacologic treatment [4].

A subset of patients experience significant pain relief when structural tissue pathology is identified and treated. However, cervical spine pathology (e.g., disk bulges, degenerative changes) is common in asymptomatic persons, and the longstanding treatment focus on tissue pathology has contributed to poor pain outcomes in these patients. The diverse pain mechanisms produced by specific pathologies are suggested as a treatment focus in chronic neck pain.

By combining the best available evidence from diverse sources, this course can greatly assist healthcare providers in optimizing the care of patients with acute or chronic neck pain.

2. EPIDEMIOLOGY

Neck pain is very common in the general population, with an annual incidence of 10.4% to 21.3% and lifetime prevalence of 23%. Neck pain can occur repeatedly, and 50% of neck pain seen in primary care settings is in recurrent cases. More than 50% of the middle-aged population shows clinical or radiologic signs of cervical spine disease, which is often asymptomatic [5,6,7].

Neck pain encompasses a variety of associated disorders, including whiplash pain and associated disorders (WAD) and other non-traumatic, traumatic, and work-related neck pain [8]. Neck pain and associated disorders account for 10.2 million physician and hospital outpatient visits in the United States each year [8].

Neck pain prevalence is slightly higher in women in their fifth decade of life, and a higher incidence is found in office/computer workers, manual laborers, and healthcare workers. Chronic neck pain is associated with psychologic factors (e.g., anxiety, poor coping skills, somatization), sleep disorders, smoking, sedentary lifestyle, and genetics [9,10,11]. Common neck pain comorbidities include headache, back pain, arthralgias, and depression [2,9].

Higher body mass index increases risk of chronic neck and shoulder pain. Obese persons may be predisposed to neck pain due to systemic inflammation, deleterious structural changes, increased mechanical stress, diminished muscle strength, greater number of psychosocial factors, and greater kinesiophobia-related disability [2,12].

Treatments used in low back pain are considered applicable to neck pain. The presumptive similarity is generally true, but features of cervical anatomy and physiology make some neck pain conditions distinct from those of other spinal locations. WAD and some collision-related sports injuries (e.g., related to American football, rugby) are unique risk factors for neck pain [2,9].

In one study, risk of cervical spine injury was evaluated in roller-coaster riders [13]. In 656 neck and back injuries during roller-coaster riding, 72% considered significant were cervical disk injuries. Lumbar spine injuries also included disk herniation or vertebral compression fracture. Passenger testing showed that peak g-force for vertical or axial acceleration (4.5–5.0) and lateral acceleration (1.5) both occurred within 1/10 second (100 ms). The authors concluded a minimum threshold of significant spine injury is not established. Individual susceptibility largely explains the injuries from traumatic loading [13].

PERSONAL AND SOCIETAL IMPACT

As noted, neck pain is the fourth leading cause of disability in the United States (behind low back pain, depression, and arthritic disorders), and in some industries, it accounts for as much time off work as low back pain [1,2,14]. In many patients, neck pain becomes chronic, with life-impairing symptoms that severely decrease quality of life and restrict work productivity and daily activities [8].

However, neck pain has received a fraction of the research funding and attention directed to back pain. This reflects a wider underappreciation of its negative physical and psychologic impact, and of the associated high economic burden from medical visits, physiotherapy, pharmacologic and surgical treatments, lost work days, and compensation expenditure [2,4].

SPECIFIC NECK PAIN CONDITIONS

Whiplash Injury and Whiplash-Associated Disorders

WADs result from rapid acceleration/deceleration, typically involving rear-end or side-impact motor vehicle collisions, and represent 75% of all survivable motor vehicle collision injuries [15]. WAD can also occur from falls, diving, or collisions in contact sports. The "limit of harmlessness" with rear-end collision is 5 to 10 miles per hour (MPH); many whiplash injuries involve rear-end motor vehicle collision at speeds of 14 MPH or less [16,17,18,19]. WAD is associated with significant economic costs from lost work productivity, medical care, legal services, and other disability-related expenses, mostly incurred by patients with chronic symptoms [20].

The annual rate for acute whiplash symptoms is 1 to 6 cases per 1,000 population, and an estimated 1% of adults have chronic whiplash pain. In data from nine U.S. states, 45% of patients with chronic neck pain attributed their pain to a motor vehicle collision [16,21].

Women show higher rates of WAD, possibly due to less well-developed neck muscles than men. Pre-existing cervical spine pathology predisposes to spinal cord damage in whiplash injuries [19]. Head restraints have greatly reduced whiplash injury rates following rear-end collisions, but they increase whiplash injury risk when poorly fitted [16].

Cervical Radiculopathy

Cervical radiculopathy is cervical spine nerve root dysfunction that causes radiating neck or upper extremity pain or sensory abnormalities [22]. New cases are higher in men (107.3 per 100,000) than women (63.5 per 100,000) annually. Persons 50 to 54 years of age have the highest incidence by age. Overall, the prevalence is 3.5 cases per 1,000 population [22,23,24].

Risk factors include manual labor requiring lifting of more than 25 pounds, smoking, operating vibrating equipment, and previous spinal radiculopathy. Over-exertion or trauma antecedents are reported by 15% of patients with cervical radiculopathy [24].

CLINICAL COURSE AND PROGNOSIS

Acute Nonspecific (Idiopathic) Neck Pain

Outcomes for acute idiopathic neck pain are surprisingly poor. Resolution is often incomplete, and prognosis is markedly worse than commonly believed. Statistical pooling of published outcomes showed an average pain severity score (on a 0–100 scale) of 64 at onset, decreasing to 35 at 6.5 weeks, but increasing by 12 months to 42. Disability declined from an average score (0–100) of 30 at onset to 17 by 6.5 weeks, without further improvement at 12 months [25].

After the first 6.5 weeks, no further reduction in neck pain was found. The initial decreases in pain (45%) and disability (43%) are worthwhile to some patients, but the severity of persistent pain (35–42/100 up to one year) is sufficient to interfere with functioning and quality of life. Compared with low back pain one year after onset, neck pain intensity is twice as high and disability is comparable [25,26,27].

A comparison of 2,578 patients with WAD or nonspecific neck pain found substantially greater presence of dizziness and memory impairment at initial assessment. Between-group differences in pain and disability increased significantly over 12 months; patients with WAD had an average 2 points greater pain (on a 0–10 scale) and 17% more disability than those with nonspecific neck pain [28].

Acute Whiplash-Associated Disorders

Recovery rates from WAD have been unchanged for decades, with 50% of patients experiencing ongoing pain and disability [15]. Following acute whiplash injury, recovery is slow for pain intensity outcomes, which usually require six months or longer to decrease 20%. Recovery is no better for disability outcomes, with average scores failing to reach 20% improvement by 12 months [29]. Following acute traumatic neck pain (including WAD), patients follow one of three likely trajectories for pain and disability [29]:

- Mild problems with rapid recovery (45% of patients, depending on outcome)

- Moderate problems with incomplete recovery (40%)

- Severe problems with little or no recovery (15%)

Regardless of outcome, recovery is most rapid in the first 6 to 12 post-injury weeks, with considerable slowing after that and little recovery after 12 months [30].

Prognostic Factors in Acute WAD

During acute or subacute WAD, risk factors for persistent problems include [29]:

- High pain intensity

- High self-reported disability (as determined by Neck Disability Index [NDI] score)

- High post-traumatic stress symptoms

- Strong catastrophic beliefs

- Cold hyperalgesia

A meta-review of factors associated with long-term pain and disability after whiplash injury identified post-injury pain and disability, whiplash grade, and cold hyperalgesia as the strongest prognostic factors [31].

Factors unrelated to prognosis include those related to the collision (e.g., impact direction, stationary versus moving, seating position in car). Post-injury imaging findings or motor dysfunction has very weak association with pain/disability prognosis [29,31]. Compensation and early healthcare use were weakly positive prognostic factors, but equally plausible is reverse causality, whereby poor outcome is the cause of healthcare use and compensation-seeking [31].

Patients suffering from post-motor vehicle collision WAD often litigate to gain more comprehensive medical treatment and monetary compensation for their injury. A long-standing concern of treating physicians is that patients with whiplash may have barriers to recovery—believing they must remain "injured" to collect a settlement [16]. Compensation has been associated with incidence and prognosis, but literature indicates that litigation does not correlate with persistence of pain [32,33].

Risk factors for poor recovery from whiplash injury described in the medico-legal literature include [16,34]:

- High post-injury pain (>6/10) and disability (NDI >40%)

- Number and severity of injury-related symptoms (e.g., post-injury headache, low back pain, neuropathic pain, radicular symptoms)

- Psychologic distress (e.g., post-trauma stress symptoms, pain catastrophizing)

- Cervical spine cold hyperalgesia

- Failure to wear seatbelt

- Less than college education

Cervical Radiculopathy

Many patients with cervical radiculopathy secondary to acute disk herniation have a favorable clinical course. Symptom resolution occurs over weeks to months because 40% to 76% of herniated cervical disks spontaneously resorb independent of treatment. Acute neuropathic symptoms in spinal stenosis stabilize or improve in more than 50% of patients, but anatomic derangements do not generally improve without treatment [29,35,36].

However, patients with cervical radiculopathy and more severe acute pain or symptoms show higher risk of chronic pain. Higher pain scores and radicular symptoms are associated with chronicity and poor outcomes in both neck pain and low back pain [37,38].

Assessment of Prognostic Factors

With multiple studies showing that acute-phase risk factors can predict poor pain and disability outcomes, practice guidelines recommend that clinicians assess all patients during initial and follow-up contacts. Pain, disability, post-trauma symptoms, and pain catastrophizing are measured to quantify progress and to predict prognosis for recovery (discussed later) [39].

ASSOCIATED CONDITIONS

Vertigo

Many patients experience vertigo, dizziness, unsteadiness, and other proprioceptive abnormalities following whiplash trauma. Strains to facet joint capsules, paravertebral ligaments, or cervical musculature in WAD are thought to modify proprioceptive cervical balance to produce mild but chronic vertigo [40]. Dizziness may result from injury to facet joints supplied by proprioceptive fibers; when injured, these fibers can send confused vestibular and visual inputs to the brain [41].

Temporomandibular Joint Disorder

Temporomandibular joint disorder (TMD) is associated with whiplash injury, and TMD populations show an average 35% prevalence of whiplash trauma [42]. Chronic muscle pain in TMD is classified as localized or referred. Compared with patients with localized TMD, those with TMD and whiplash histories have greater jaw pain and dysfunction severities; more severe subjective, objective, and psychologic dysfunction; and poorer treatment outcomes. Some evidence suggests TMD pain after whiplash trauma differs pathophysiologically from localized TMD pain. Whiplash trauma is a common TMD comorbidity and probably an initiating or aggravating factor. Patients with TMD and whiplash require early evaluation and multidisciplinary management [43,44,45].

3. PATHOPHYSIOLOGY

This section discusses how neck pain develops and persists by examining pathologic processes in cervical spine and pain signaling structures. Discussion of normal function is presented first to assist in the understanding of pathology.

CERVICAL SPINE STRUCTURE AND FUNCTION

The top seven vertebrae (C1 to C7) make up the cervical spine, which provides mobility and stability to the head while connecting it to the relatively immobile thoracic spine [46]. The spine transfers force between the upper and lower extremities and generates force [47].

C1 and C2 are the upper cervical spine. C1 bears the head ("the globe") and is called the atlas. The atlas connects above with the occiput (the atlanto-occipital joint), where 50% of all neck flexion extension occurs. The atlas connects below with C2, termed the axis, forming the atlanto-axial joint, where 50% of all neck rotation occurs [46]. The lower (subaxial) cervical spine consists of vertebrae C3 to C7, connected by facet joints and intervertebral disks, unlike the complex ligament structures that connect C1 and C2 [48].

Facet joints, also called zygapophysial joints (z-joints), stabilize and limit excessive cervical spine flexion, extension, side-bending, and rotation [49]. The medial branch of the dorsal nerve innervates the facet joint. The joint contains a fibrous capsule, synovial membrane, articular cartilage, and menisci [50].

The intervertebral disk is a functional unit connecting two vertebral bodies of the spine. The disk absorbs shock, accommodates movement, provides support, and separates vertebral bodies to lend height. Disk units have a nucleus pulposus middle, annular fibers (annulus fibrosus) surrounding the nucleus pulposus, and two cartilage end plates that separate each segment level between the C2–T1 vertebrae [51]. Annular fibers are vulnerable to rotational force injury, and nociceptors innervate the middle and outer third [46].

Cervical spine nerve roots exit through small vertebral ports called the foraminal space, above their same-numbered vertebral body; the first cervical spine nerve exits above C1, and the eighth between C7 and T1 [46,48].

The longitudinal ligaments keep the seven vertebrae and atlanto-occipital joint behaving as a single unit. The ligamentum flavum connects annular fibers (laminae) of adjacent vertebrae and helps the vertebral column resume upright posture after flexion [46].

Nociceptors are sensory receptors of primary neurons in cervical spinal tissue. Nociceptors respond to harmful pressure, temperature, or biomechanical stress (noxious stimuli) by transmitting signals (nociception) to the spinal cord and brain.

CERVICAL SPINE PATHOPHYSIOLOGY

Neck pain can develop from chronic overuse or strain, injury, trauma, or degenerative processes involving bony, articular (disks, facets), nerve (root, spinal cord), or soft (ligament, tendon, muscle) tissues of the cervical spine. In this section, pathologic processes are described that can result in neck pain, starting with acute-onset conditions followed by chronic, degenerative conditions.

Facet-Mediated Pain

Facet joints and capsules are richly innervated by nociceptors sensitive to local stretch or compression. These neurons are activated by abnormal loading or excessive biomechanical stress from whiplash injury or fracture, and sensitized by inflammation and locally released inflammatory promoters (e.g., substance P, phospholipase A). Facet joint pain can develop from degenerative disk or facet joint changes; inflammatory cytokines are found at high levels in facet joint tissue when a degenerative disorder is present. Facet joints are covered by hyaline cartilage and enclosed by synovial capsules, features of other joints that make facet joints vulnerable to osteoarthritis (facet joint arthropathy) [50,52].

Facet joint pain accounts for 36% to 55% of neck pain and 60% of whiplash pain [50]. The C5–C6 facet joint is the most common origin of cervical, axial, and referred arm pain. Facet joints/capsules largely underlie chronic neck pain, and referred facet pain overlaps with myofascial and diskogenic pain patterns [41].

Cervicogenic Headache

Cervicogenic headache is defined as a unilateral, non-throbbing, non-lancinating head pain caused by referred cervical spine pain. Approximately 70% of cervicogenic headaches originate from the C2–C3 facet joint [53,54,55].

The lifetime prevalence of cervicogenic headache is as high as 4.1% in the general population, 17.5% in patients with severe headaches, and 53% in patients with post-whiplash headache [53]. Cervicogenic headache occurs at rates four times higher in women, and the average patient age is 43 years. Migraines often have a cervical pain component and can co-occur with cervicogenic headache [53].

Cervical Strain/Sprain

Cervical strain is injury to the muscle-tendon unit, while cervical sprain is injury to ligamentous structures. Cervical strain/sprain injuries involve flexion, extension, or rotation, with or without axial loading. Acute neck pain frequently involves injury to cervical muscle-tendon or ligamentous structures, which can expand into a range of secondary effects [47]. For instance, edema, hemorrhage, and inflammation can follow elongation and tearing of muscles or ligaments in cervical strain/sprain. Many cervical muscles do not terminate in tendons, but attach to the periosteum (membrane covering a bone surface). Muscles respond to injury by contracting, and recruit surrounding muscles to "splint" the injured muscle. This reflexive tightening (spasm) of paraspinal muscles can cause excruciating pain [56]. Chronic pain following cervical strains usually originates from facet joints, disks, or ligaments [41].

Cervical Myofascial Pain

Cervical myofascial pain also relates to overuse, injury, or trauma and originates from cervical muscles and their surrounding fascia that support the shoulders and neck [57]. Cervical myofascial pain may result as a secondary muscle tissue response to disk or facet-joint injury [41].

Myofascial pain is common in the general population, with 21% of patients in general orthopedic clinics and 85% to 93% of patients in specialty pain management centers having a myofascial pain component. Cervical myofascial pain incidence is disproportionately high in women and peaks in midlife and declines after middle age [57].

Trigger points—the hallmark feature of myofascial pain—are hyperirritable areas in palpable, taut bands of skeletal muscle fiber that elicit local or referred pain. Rapid palpation may elicit a local twitch response, a brisk contraction of muscle fibers around the taut band. Active trigger points generate spontaneous or movement-provoked pain; latent trigger points produce pain when compressed [57].

In cervical myofascial pain, other muscles in the functional unit compensate, promoting a more widespread, chronic problem. Chronicity and disability are strongly linked to pain duration. Recurrence decreases with early treatment initiation to prevent muscle compensation patterns. Migraine and muscle contraction headache frequently co-occur, and TMD can be myofascial in origin [57].

Cervical Disk Disorders

Disk disorders can develop acutely from neck injury or trauma, or through chronic degenerative processes. The C6–C7 disk is the most frequent herniation site [51]. More common cervical disk disorders include herniated nucleus pulposus, degenerative disk disease, and internal disk disruption.

Herniated Nucleus Pulposus

Herniated nucleus pulposus is localized displacement of the nucleus, cartilage, or fragmented annular tissue beyond the intervertebral disk space. Most cases of herniated nucleus pulposus involve the annulus fibrosus. The four herniated nucleus pulposus subtypes are [51]:

- Disk protrusion: The nucleus pulposus herniates through annular fibers but is confined within the annular margin.

- Disk extrusion: Nucleus pulposus herniation extends beyond the annular margin.

- Disk sequestration: A nucleus pulposus fragment separates from the extruded disk.

- Disk migration: Disk material displaces from the extrusion site.

Herniated nucleus pulposus results from repetitive cervical stress but seldom from a single traumatic incident. Increased risk may accrue with vibrational stress, heavy lifting, prolonged sedentary position, whiplash accidents, or frequent acceleration/deceleration [51]. Disk bulge, whereby disk margins extend past the margins of adjacent vertebral end plates, is not considered a true herniation [51].

Degenerative Disk Disease

Cervical degenerative disk disease involves degenerative annular tears, loss of disk height, and nucleus pulposus degradation. It is commonly age-related and affected by poor nutrition, smoking, atherosclerosis, job-related activities, and genetics. It is important to remember that degenerative disk changes seen by x-ray may reflect natural aging and not painful pathology [51].

Internal Disk Disruption

Internal disk disruption describes pathologic annular fissuring within the disk, without external disk deformation. Internal disk disruption can result from cervical trauma-related nucleus pulposus degradation, cervical flexion/rotation-induced annular injury, or whiplash [51].

Chemical Radiculitis

Herniated or degenerated nucleus pulposus releases inflammatory promoters (e.g., phospholipase A2, prostaglandin E2, proteoglycans, cytokines, tumor necrosis factors) and mediators (e.g., substance P, bradykinin, potassium, histamine). This inflammatory cascade can cause chemical radiculitis, characterized by intense chemical irritation of cervical spine nerve roots, radicular pain, and most herniated nucleus pulposus pain [24,51,58].

Cervical Radiculopathy

In cervical radiculopathy, compression or irritation of a cervical spine nerve root, typically by herniated disk material, chemical radiculitis, or stenosis, results in radiating pain, weakness, or numbness [22,23,58].

Most cervical radiculopathies involve C7 or C6 nerve root levels, but all root levels exhibit motor, sensory, and reflex abnormalities that follow specific dermatomal or myotomal distribution patterns in the neck and upper extremities (Table 1) [2,22,56].

Table 1: TYPICAL DISTRIBUTION OF SENSORY AND MOTOR WEAKNESS IN CERVICAL RADICULOPATHYa

Affected Nerve Root (Frequency)

Sensory Deficits/Pain Location

Muscle Weakness

Abnormal Reflexes

C4 (<10%)

Lower neck, cape-like distribution in upper shoulder

None

None

C5 (10%)

Lateral arm

Deltoid

Biceps

C6 (20% to 25%)

Radial forearm, radial two digits

Biceps, wrist extension

Brachioradialis

C7 (45% to 60%)

Middle finger

Triceps, wrist flexion

Triceps

C8 (10%)

Ulnar two digits

Finger flexors

Finger flexors

aPain referral patterns can vary among patients.

Source: [2,22,56]

Mechanical compression induces nerve deformation and malfunction when external pressure exceeds intraneuronal pressure. This results in conduction block, interruption of axonal flow, vascular sequelae (e.g., hypoxia), and accumulation of metabolic byproducts [22,58]. Nerve root compression alone may not be painful unless inflammation is present. Narrowing of the foraminal space (foraminal stenosis) encroaches on the exiting spinal nerve, and foraminal stenosis from disk or facet joint degeneration accounts for many cervical radiculopathy cases [51].

Cervical Spinal Stenosis

In the C3–C7 spinal canal, the normal anteroposterior diameter is 17–18 mm. The spinal cord requires 10–11 mm; an anteroposterior diameter <10 mm is absolute spinal canal stenosis, and 10–13 mm is relative stenosis [59,60].

In acquired cervical spinal stenosis, degenerative disk or facet disease pathologically narrows the canal in middle-aged and older patients. Cervical spondylosis (arthritis) may progress to stenosis, and stenosis to cervical spondylotic myelopathy, but this sequence is variable and difficult to predict. However, adults with asymptomatic stenosis show age-related increases in cervical spondylosis. Congenital cervical spinal stenosis occurs in younger, athletic patients when bony anomalies narrow the spinal canal diameter <13 mm [59,61].

Cervical Whiplash Injury

In cervical whiplash, diverse symptoms develop following a rapid sequence of injuries [16,19,62]. The first is cervical hyperextension injury. A driver/passenger is struck from behind, which throws the body forward, but the head lags to hyperextend the neck. When the head and neck reach maximum extension, the neck snaps into flexion. The head is then thrown forward, flexing the cervical spine and resulting in rapid deceleration injury. The chin truncates forward flexion, but it can remain sufficient to cause longitudinal distraction and neurologic damage. Hyperextension may occur in the subsequent recoil. Within 100 ms, the cervical spine is compressed from below; as lower segments extend with upper segments flexed, the cervical spine assumes an S-shaped curve. In a split-second, all cervical segments are forced backward into extension. Whiplash-like loads of combined shear, bending, and compression forces can injure facet joints/capsules, and facet injury is the most common source of chronic post-whiplash pain. Spinal bones, ligaments, muscles, tendons, and disks may also become injured [41,63,66].

The diverse constellation of post-whiplash symptoms, termed WAD, reflects the range of potentially injured tissue. Symptoms can include neck pain and stiffness, occipital headache, thoracic or lumbar pain, and referred pain or numbness to shoulders, arm, or scapula. Paraspinal muscle tightness and spasm, neck tenderness, and reduced range of movements are common. Patients may also experience headache, jaw pain, fatigue, dizziness, vertigo, blurred vision, or nausea. Insomnia, depression, and general anxiety or travel anxiety when in a car can follow acute whiplash. Symptoms can be severe, often without imaging abnormalities [16,19].

Degenerative Disorders of the Cervical Spine

As noted, x-rays show degenerative cervical spine abnormalities in many asymptomatic adults, making the boundary between normal aging and disease difficult to define. Even severe degenerative changes can be asymptomatic but can eventually lead to neck pain or neurologic complications [14]. Vertebral body, disk, and facet joint degeneration decreases foraminal and canal width, initiates inflammatory processes, and promotes nerve compression/irritation, chronic neck pain, and progressive radiculopathy symptoms [14,23,24,51,58,61,67,68].

Cervical Spondylosis

Cervical spondylosis is osteoarthritis, a chronic degenerative disorder that affects cervical vertebral bodies, intervertebral disks (as disk herniation and spur formation), and contents of the spinal canal (i.e., nerve roots and/or spinal cord). It may also affect the facet joints and longitudinal ligaments, but this is debated [67].

Cervical Facet Joint (Z-Joint) Arthropathy

Facet joint arthropathy describes osteoarthritis and degenerative changes in facet joints and usually follows the development of cervical degenerative disk disease. The degenerative changes resemble those of other joints, including osteophyte formation, osteosclerosis, thinning of articular cartilage, and hypertrophy (thickening) of the facet joint capsule, ligamentum flavum, and articular process. Facet joint hypertrophy distorts articular surfaces, leading to axial or referred pain [49].

Cervical Spondylotic Myelopathy

Cervical spinal cord compression causes cervical spondylotic myelopathy, the most serious degenerative disorder consequence. Reversible neurologic deficits occur with cord compression of 40% or greater [61]. Abnormal movement and cervical spondylotic myelopathy symptoms can develop from cervical spinal cord damage with traumatic compression or ischemia from arterial compression or cervical spondylosis [60,67]. In patients with cervical spondylotic myelopathy, co-occurring cervical radiculopathy is frequent and co-occurring stenosis is occasional [67].

NECK PAIN PATHOPHYSIOLOGY

In most patients with chronic neck pain, identifying and treating the pain mechanism(s), rather than spinal tissue pathology, is more effective. Pain from tissue injury or disease that resolves with tissue healing is a symptom of the tissue damage, and resolution typically occurs within three months of onset.

Pain becomes a disease entity (rather than a symptom) when it persists after healing or resolution of the original tissue insult [3]. Chronic (more than three months) neck pain can develop from acute pain of any cervical spine origin, but it is substantially more difficult to control and can be severely consequential to patients [2,69].

Normal Pain Processes

The somatosensory system enables the perception of pain, touch, pressure, temperature, position, movement, and vibration. This system begins with receptors of peripheral sensory neurons (nociceptors) in skin, muscles, joints, and fascia (peripheral tissue). In response to potentially harmful pressure, temperature, or biomechanical stress (noxious stimuli), nociceptor fibers send signals to the dorsal root ganglia (containing the cell bodies of sensory neurons), which are relayed to the dorsal horn of the spinal cord. In the dorsal horn, primary neurons synapse with second-order nociceptive neurons. The noxious stimuli signal is sent up ascending spinal pathways to the brain. The brain interprets pain signal intensity and location, assigns meaning, activates fear or anxiety, and initiates appropriate motor responses. The brain then signals back the spinal dorsal horn, via descending pathways, to inhibit or facilitate incoming nociceptive stimuli. Thus, pain transmission signals travel up the spinal cord for processing and interpretation in the brain, which responds by pain modulation signals down descending pathways to the spinal dorsal horn. This bi-directional feedback circuit balances signaling facilitation and inhibition; normal function is maintained.

Chronic Pain Pathophysiology

With normal somatosensory function, pain from tissue injury or damage resolves during or before tissue healing or resolution. In contrast, chronic pain develops as somatosensory function becomes pathologic [41,70,71,72,73]. Mechanical/inflammatory injury of peripheral sensory nerve fibers activates the function of their ion channels (e.g., sodium, calcium). This increases excitatory synaptic transmission in dorsal horn neurons and nociceptive circuits.

Intense nociceptive bombardment in the dorsal horn impacts synaptic activity, where primary neurons signal second-order neurons. The bombardment induces synaptic release of excitatory amino acids and neuropeptides (e.g., substance P, glutamate), which bind post-synaptic receptors of second-order neurons in the dorsal horn. In altered second-order spinal cord neurons, excessive N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling reflects a hyperexcitability state that amplifies sensory responses; central sensitization develops.

In this state, brainstem control of descending pain modulatory pathways becomes impaired; balance between descending inhibition and excitation is altered, and excitation dominates. Pain perception is facilitated by ascending pain pathway sensitization and disinhibited by impaired descending inhibitory. The brain now receives altered, abnormal sensory messages.

Pain Modulation

Nociceptor activation does not necessarily produce pain. Some persons with marked spinal pathology are asymptomatic, while others experience severe, chronic, disabling pain without apparent structural pathology. Patient responses to analgesic therapy also vary substantially. A key factor in this pain response variability is how the pain message is modulated in the central nervous system (CNS).

The pain signal can be augmented or diminished as it ascends from its dorsal horn entry point to the CNS and arrives in the cerebral cortex (which mediates awareness). An assumed correlation between peripheral tissue pathology and pain intensity is subject to modification and interference in the various pathways [71,74,75,76]. Without treatment, CNS pain modulation abnormalities persist and may become refractory to intervention [77,78].

Transitions in Chronic Whiplash Pain

Post-whiplash pain is the most-studied chronic neck pain condition, with cervical facet joints key pain contributors. Facet joint structure may pathologize as chronic post-whiplash pain develops [50].

Following acute tearing of the facet joint capsule or stretching beyond its limits, the joints fill with fluid and distend, causing pain and limiting cervical range of motion. In the subacute phase, inflammatory changes develop from vasodilation and invasion of inflammatory cytokines, promoting degeneration. Laxity from joint capsule hypertrophy and distention impinges a nerve root exiting the spinal canal or neuroforamen; radiating symptoms or radiculopathy develops. Chronic inflammation leads to central sensitization, with pain stimuli thresholds decreasing and pain signal firing rates increasing. Facet capsule fibrosis and osteophyte formation further restrict segmental motion.

Psychologic Factors in Chronic Neck Pain

Psychologic factors contribute to the development of chronic neck pain and disability in some patients. In the fear-avoidance model, key psychologic processes, including emotions, cognitions, attention, and behaviors, converge to form fear-avoidance beliefs and behaviors, which become drivers of pain-related disability. Fear develops in response to negative cognitions, exaggerating both the potential threat of pain and the negative interpretation of pain-related health information. Pain catastrophizing refers to this exaggerated set of pain-related cognitions, often appearing as anticipation of the worst possible outcome [79,80]. Fear focuses the attention on pain and related symptoms, leading to a hypervigilant state and avoidance of activities (e.g., occupational, social) and movements (e.g., walking, physical therapy) perceived to possibly worsen pain [81].

Evidence connects pain, stress response, and prognosis following whiplash. After whiplash injury, the presence of hyperalgesia (amplified pain sensitivity), stress-related symptoms, and pain catastrophizing is linked to higher initial pain and disability, and strongly predicts poor functional recovery [82]. Hyperalgesia is a consequence of inflammatory processes. Intense stress exposure (as with acute trauma) can release cytokines that signal infection or inflammation, and a relationship between catastrophizing and inflammation has been identified [83]. Hyperalgesia and stress-mediated responses/symptoms in whiplash-injured patients with poor prognosis suggests contribution of inflammatory processes [84,85].

Other evidence expands the understanding of how psychologic factors may influence pain. High levels of perceived injustice following whiplash injury have been associated with prolonged work disability at follow-up, suggesting a modifiable risk factor for psychologic intervention [86]. A study of whether social pain from rejection promoted social anxiety two days later identified a link between emotional and physical pain [87]. Participants rejected during an initial social situation had higher social anxiety before and during a second situation (versus those not rejected), fully mediated by initial social pain intensity. Next, all participants in a social situation were rejected, and randomized to acetaminophen or placebo before the next social situation. Acetaminophen lowered social anxiety before and during this exposure. Roughly 50% of this effect was mediated by, and specific to, reduction in social pain and not social anxiety [87].

Attachment insecurity (i.e., anxiety and/or discomfort in close relationships) is associated with physical symptoms, medically unexplained symptoms, and painful conditions. Medically unexplained chronic pain has been associated with attachment insecurity, after adjusting for depressive and anxiety disorders [88].

New Directions in Chronic Neck Pain Practice

Fewer than half of patients with chronic pain achieve at least 50% pain reduction with any single drug or their combinations, a consequence of [72,89,90]:

- Limitations of neuropathic pain definitions and the "nociceptive-neuropathic dichotomy" of chronic pain mechanisms

- Standard practice guidelines based on clinical trials that assess analgesic efficacy in patients with specific underlying pathologies, but not pain types

- Multiple pain mechanisms in most chronic pain, but most drugs target one pain mechanism

These flaws have prompted intensive efforts to overhaul chronic pain research and practice, leading to publications that expand and clarify chronic pain mechanisms to improve pain assessment and treatment. Many findings in chronic low back pain are relevant to chronic neck pain and are summarized here. Implementation in neck pain assessment and treatment is discussed in later sections.

Neuropathic pain definitions are often over-restrictive, with pain strictly tied to a lesion or disease in nerve structures, such as peripheral nerves (e.g., post-herpetic neuralgia, diabetic neuropathy) or spinal nerve roots (e.g., radiculopathy). In this model, without evidence of nerve lesion or disease, signs or symptoms are insufficient [91,92].

Current chronic low back pain guidelines class 85% to 90% of patients as nonspecific pain and a fraction as neuropathic pain, but many patients with chronic low back pain present with symptoms of a neuropathic component that goes undetected and untreated because nerve lesion or disease is absent [93,94,95,96]. Their misclassing as nociceptive or nonspecific pain may lead to poor treatment outcomes [95,96].

Neuropathic pain can develop when nerve fibers in any segment of the somatosensory system become dysfunctional or transmit signals inappropriately—without lesion or disease [97,98]. The painDETECT questionnaire (PDQ) was developed to identify neuropathic components in patients with chronic low back pain considered nociceptive [69,89,99]. This tool characterizes "altered nociception" as a distinct pain phenotype in chronic low back pain. In these patients, neuropathic-like signs and symptoms reflect maladaptive nervous system functioning and central rather than peripheral pain mechanisms [96,100].

Other advances are improving pain mechanism assessment. Sensory profile (pain-related sensory signs and symptoms) testing in 902 patients with diverse neuropathic pain etiologies identified distinct sensory profile subgroups: sensory loss (42%), thermal hyperalgesia (33%), and mechanical hyperalgesia (24%). All sensory profile subgroups occurred across etiologies, reflecting pain-related signs and symptoms that differ in neurobiologic mechanisms and treatment response [99].

With the nociceptive-neuropathic dichotomy of chronic pain mechanisms outdated, research has led to "altered nociception" as a proposed pain mechanism descriptor when chronic pain is neither nociceptive (tissue damage) or neuropathic (nerve pathology) [90,95,96]. Maladaptive CNS neuroplasticity in chronic pain has been recognized since the early 2000s as a disease process of its own right, and translation into clinical practice is overdue [101].

4. ASSESSMENT AND DIAGNOSIS

PATIENT HISTORY

Assessment of neck pain begins with a thorough history and physical exam. This information guides further diagnostics and clinical management. The top priority is to identify potentially serious underlying pathologies, termed "red flag" conditions (Table 2). While infrequently encountered, neck pain-related signs or symptoms that suggest serious disease require immediate investigation and intervention. "Red flags" should be assessed throughout the evaluation process, and imaging confirmation is necessary when clinician suspicion remains [7,102]. After obtaining basic patient demographics, a detailed history is taken [7,8,56,102,103].

Table 2: "RED FLAG" FEATURES IN NECK PAIN

Red Flag

Potential Conditions

Associated Signs and Symptoms

Trauma (fall, motor vehicle accident, whiplash injury)

Vertebral fractures, spinal cord injury/syrinx, ligamentous disruption

Loss of or alternating consciousness, cognitive deficits, traumatic brain injury, headaches, neurologic symptoms

Rheumatoid arthritis, Down syndrome, spondyloarthropathy

Atlantoaxial subluxation

Easily fatigued, gait abnormalities, limited neck mobility, torticollis, clumsiness, spasticity, sensory deficits, upper motor neuron signs

Constitutional symptoms

Metastases, infectious process, systemic rheumatologic disease

Weight loss, unexplained fevers, anorexia, family or personal history of malignant neoplasm, diffuse joint pain and stiffness, abnormal laboratory test results

Infectious symptoms

Epidural abscess, spondylodiskitis, meningitis

Fever, neck stiffness, photophobia, elevated white blood cell count

Upper motor neuron lesion

Spinal cord compression, demyelinating disease

Hoffmann sign, hyper-reflexia, Babinski sign, spasticity, incontinence, sexual dysfunction

Age younger than 20 years

Congenital abnormalities (cervical spina bifida, Scheuermann disease)

Birthmarks, overlying skin tags, patches of hair, family history, systemic disease (diabetes, epilepsy for spina bifida)

Conditions associated with substance abuse (e.g., infection)

Male sex, poor work or school performance, depression or other psychiatric morbidity

Concurrent chest pain, diaphoresis, or shortness of breath

Myocardial ischemia or infarction

Nausea, extension of pain into the left arm (especially medial upper arm)

Age older than 50 years

Metastases, vertebral fracture, carotid or vertebral artery dissection/bleeding

Family or personal history of malignant neoplasm, previous trauma

Arterial dissection: tearing sensation, headache, visual loss, or other neurologic sequelae

5 Ds And 3 Ns

Vertebrobasilar ischemia, carotid artery dissection

Diplopia, dizziness, drop attacks (syncope), dysarthria, dysphagia, ataxia of gait, nausea, numbness, and nystagmus

Source: [2]

To assess the history of the present illness, clinicians should inquire regarding:

- Pain details

- Quality

- Onset

- Duration

- Severity

- Location

- Time course

- Progression

- Modifying factors

- Rest/activity

- Changes in position

- Weight-bearing

- Time of day (e.g., at night, on awakening)

- Tolerance for neck flexion

- Associated symptoms

- Stiffness

- Numbness

- Paresthesia

- Weakness

- Urinary retention

- Constipation

- Urinary/fecal incontinence

- Primary/secondary complaints

- Primary neck pain

- Secondary arm pain

- Headaches

- Shoulder girdle complaints

- Radiating symptoms

- Presence and distribution of upper/lower extremity numbness, paresthesia, or weakness

- Percentage of axial versus peripheral pain (e.g., 90% neck versus 10% upper limb)

- Precipitated by coughing or sneezing, or alleviated by raising the affected arm over the head

- Initial treatment of present complaint

- Emergency department

- Acute care or clinic evaluation

- Imaging

- Analgesics given and symptom response

Spinal pain history should include information regarding:

- Known neck or back disorders (e.g., osteoporosis, osteoarthritis, disk disorders, recent or remote injury)

- Specific prior treatment, including surgery

- Chronic or recurrent symptoms

- Functional limitations

- History of motor vehicle collisions (if whiplash suspected)

- Risk factors for:

- Back disorders (e.g., cancer, osteoporosis)

- Aneurysm (e.g., smoking, hypertension)

- Infection (e.g., immunosuppression, IV drug use, recent surgery, hemodialysis, penetrating trauma)

- Extra-articular features of an underlying systemic disorder (e.g., diarrhea, abdominal pain, uveitis, psoriasis)

Patients should also be assessed regarding their medical history and a general review of systems. Any history of neoplasm, gout, arthritis, hypertension, or fractures should be noted. The review of systems will include current symptoms of systemic diseases:

- Infection (e.g., fever, sweats, chills)

- Cancer (e.g., weight loss, poor appetite)

- Multifactorial spinal pain (e.g., fatigue, depressive symptoms, headaches)

- Esophageal disorders (e.g., worsening neck pain during swallowing)

- Gastrointestinal (GI) disorders (e.g., anorexia, nausea, vomiting, changes in bowel function or stool)

- Urinary tract disorders (e.g., urinary symptoms, flank pain)

- Pulmonary disorders (e.g., cough, dyspnea, worsening pain during inspiration)

Medication use, smoking history, and diabetes risk should also be assessed.

ASSESSMENT OF PROGNOSTIC FACTORS

Clinicians should perform functional assessments during initial contact and all follow-ups and a psychosocial ("yellow flag") assessment during initial or follow-up visit to obtain important information about baseline status, trajectory, and prognosis of recovery. Both assessments are easily conducted using validated self-report questionnaires.

Functional Assessment

The Visual Analog Scale (VAS), the Numerical Pain Rating Scale (NRS), the NDI, the Pain Catastrophizing Scale (PCS), and the Impact of Events Scale-Revised (IES-R) measure clinical variables with significant prognostic value in acute neck pain; all may be used for the initial assessment and follow-up. Patients with high initial scores are at much greater risk of persistent pain and disability and may require treatment of greater intensity or focus. Clinical factors and cutoff scores for poorer prognosis [22,29,39,104]:

- Pain severity: High pain intensity (NRS or VAS score ≥6 on a 1–10 scale)

- Interference with daily activities: Evaluates pain impact on personal care, lifting, reading, concentration, work, driving, sleeping and recreation; pain intensity, and headaches. High self-reported disability is defined as an NDI score of ≥30%.

- Pain catastrophizing: Belief that pain is to be feared or may be severely disabling. High pain catastrophizing is defined as a PCS score of ≥20.

- Acute post-traumatic stress symptoms: The IES-R evaluates post-traumatic stress symptoms, not post-traumatic stress disorder (PTSD). High acute post-traumatic stress symptoms is defined as an IES-R score of ≥33.

"Yellow Flag" Assessment

The Tampa Scale of Kinesiophobia (TSK), the Fear Avoidance of Pain Scale (FAPS), the Patient Health Questionnaire-9 (PHQ-9), and the Hospital Anxiety and Depression Scale (HADS) measure "yellow flags," psychosocial conditions that may predispose the patient to a more complex clinical course, chronicity, or disability [8,19,103]. The following psychologic factors should be identified and measured using the associated tools:

- Pain catastrophizing: PCS

- Kinesiophobia, or avoiding activities due to fear of pain (fear-avoidance behavior): TSK or FAPS

- Passive coping: PCS

- Depressed mood or feelings of depression about pain: PHQ-9 or HADS

- Anxiety or fear about pain: TSK or FAPS

- Pessimism and poor recovery expectation: Ask the patient: Do you think that your injury will…

- Get better soon

- Get better slowly

- Never get better

- Don't know

- High levels of frustration or anger about pain. Ask the patient to quantify (on a 0–10 scale) how frustrated (angry) he or she feels about the pain.

Obtain during history:

- Past/current social or financial problems

- Past/current multiple medical diagnoses, unresolved musculoskeletal conditions

- Past/current history of physical abuse, emotional abuse, chronic pain

- Past/current active substance abuse

Sleep Assessment

Sleep quality and pain are intimately linked, making sleep important to assess. For every 1-point decrease in sleep quality (on a 0–3-point scale), pain intensity increased 2.08 points (on a 0–10-point scale) among 1,246 patients with acute low back pain [105]. This large effect of poor sleep on subsequent pain intensity was unrelated to depression or other common factors.

Among 1,016 patients with chronic low back pain or neck pain, 42.22% experienced sleep deprivation (less than six hours per night) and 19.88% experienced serious sleep impairment (less than four hours per night), even when using analgesics. Severity of sleep impairment strongly correlated with pain intensity score and pain chronification grade, but did not differ between low back pain and neck pain [106].

PHYSICAL EXAMINATION

The physical exam supports patient history findings, screens for serious pathology, informs further diagnostic work-up, and guides treatment selection. Neck pain origin is important to identify (when possible) and document, but underlying pathology of neck pain is seldom curable, and its treatment targeting has led to inadequate outcomes. Specific pathologies can generate different pain types, and the importance of pain type assessment and treatment is now stressed.

Characterizing neuropathic pain and identifying neuropathic components in chronic nociceptive neck pain are essential tasks during the physical exam. Sensory, motor, and reflex testing during the physical exam, assessment, and provocative tests assist in this task [2,19,29,41,96,103,107].

General Visual Inspection

Observe patient to identify nonverbal facial or behavioral pain expressions. Gait abnormalities can reflect spinal cord (myelopathy) or brain injury. Note traumatic or developmental abnormalities. Assess gait, posture, stance, rapid walking, balance, and visible deformities.

Palpation

Palpate the spine, facets, and paravertebral muscles for tenderness, muscle spasm, myofascial tightness, and trigger points. Painful facets can reflect osteoarthritis or post-traumatic irritation of the joint capsule.

Thoracic Spine and Shoulder

Examine shoulder for range of motion impingement and rotator cuff function.

Motor and Sensory Examination

Evaluate upper muscle groups with specific nerve root focus; assess sensation to light touch, pin prick, temperature, position, and vibration. A >2 cm difference in circumference of two upper extremities may indicate muscle atrophy; motor and sensory differences may implicate a specific nerve root.

Reflex Testing

Asymmetry of deep tendon reflexes may indicate pathology. Inverted reflexes (e.g., arm flexion or triceps tap) may indicate nerve root or spinal cord pathology at the tested level. Pathologic reflex tests include wrist clonus, grasp reflex, and Hoffman sign. In patients with suspected malingering or who report severe pain in the absence of pain-related behaviors, reflexes may be the only objective exam tool.

Cervical Range of Motion

During rotation, flexion, and extension, assess quality of motion and for presence of muscle spasm. Motion evaluation of specific joints may be indicated. Do not assess in acute trauma cases until fracture and instability are ruled out.

Cervical range of motion is often limited in all patients with neck pain, but aggravating and alleviating factors and specific exacerbating movements may provide clues to the pain origin and inform decisions to concerning further work-up. Pain-exacerbating movements and suggested pain origin include [2,14]:

- Turning or bending head ipsilateral to source: Radicular or facet pain

- Contralateral turning of head: Myofascial origin

- Arm pain aggravated by neck extension: Spinal stenosis

- Arm pain aggravated by neck flexion toward affected side: Foraminal stenosis and/or radiculopathy

- Forward flexion: Diskogenic origin

- Morning stiffness: Facet joint pain due to arthritis

- Severe unrelenting pain unaffected by rest or position changes: Assess for "red flags" (e.g., malignancy, primary neurologic disorder, infection)

Neuropathic Neck Pain

Cervical radiculopathy is the most common neuropathic neck pain. Distribution of abnormal sensations or pain can follow patterns specific to the innervated skin (dermatome) of the involved nerve root, and less commonly, other innervated structures that include muscles (myotome), joints, or ligaments (sclerotome) [22]. Symptom distribution with mechanical stimulation of nerve roots (dynatome) differs from dermatomal patterns (although they may overlap). Cervical disk herniation may induce thermal distributions (thermatome). Radiculopathy can occur without pain, and distribution patterns vary among patients [51].

Cervical radiculopathy can result from nerve root irritation (chemical radiculopathy) or compression (e.g., disk herniation, foraminal stenosis, cord compression in myelopathy) [2,29,51].

The origins of radiating neck pain/sensory disturbance are [7,107]:

- Cervical radiculopathy: Sensory, motor, and reflex abnormalities, with pain/sensory distribution from the affected nerve, weakness/tenderness of muscles innervated by the nerve, and hypoactive deep tendon reflexes of the same muscle.

- Radicular pain: Sharp, shooting, burning, or aching pain that radiates along the course of a nerve root—without neurologic abnormalities. Neck, upper trapezoid, or scapula tenderness is common.

- Referred pain: Pain radiates into the neck, head, upper trapezoid, scapula, or upper arm, but does not involve spinal nerve roots and is non-neuropathic (sensory, motor, reflex changes).

The Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale can help differentiate neuropathic from nociceptive pain [2,93,108].

Neuropathic Components in Neck Pain

Chronic non-radiculopathic neck pain may have a neuropathic component without apparent nerve root or spinal cord pathology, reflecting CNS alteration [96]. Assessment of a neuropathic component is performed by the physical exam and the PDQ tool [69,71,72,73]. The cardinal features are spontaneous pain (arising without stimuli), abnormal pain response to normally non-painful stimuli such as light touch or moderate heat/cold (allodynia), and exaggerated response to mildly painful stimuli (hyperalgesia). The spontaneous pain may be paroxysmal (e.g., shooting, stabbing, electric shock-like), dysesthetic (e.g., unpleasant abnormal sensations of touch, for example prickling, pins and needles, or crawling), or abnormal thermal sensations (e.g., burning, ice cold). These signs and symptoms can co-occur with loss of afferent sensation.

The PDQ is extensively used worldwide in research and clinical practice to identify neuropathic components in chronic spinal pain. A PDQ score greater than 18 indicates a significant neuropathic pain component, regardless of radiculopathy presence [96].

Provocative Tests in Neck Pain Assessment

Evidence Based Practice Recommendation

According to the Royal Dutch Society for Physical Therapy, the Spurling test and the traction/distraction test are considered to be valid as specific tests for ruling in cervical radiculopathy.

http://stoverpt.com/uploads/3/4/8/2/34823947/neeck_pain_guidelines.pdf

Last Accessed: September 17, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Some specialist and primary care practice guidelines recommend provocative tests (Table 3). They can be helpful adjuncts to history and physical exam findings in identifying potential neuropathic pain origins. These tests are not diagnostic alone, and clinicians should look for patterns in patient-reported, physical exam, and provocative test findings to rule in or rule out specific painful pathologies [29].

Table 3: PROVOCATIVE TESTS: DESCRIPTION AND DIAGNOSTIC USE

Test

Description

Cervical radiculopathy

Spurling

Radicular pain reproduced by lateral flexion and rotation to affected side with axial compression of the head

Shoulder abduction

Ipsilateral cervical radicular symptoms relieved by placing symptomatic arm on head (abduction)

Neck distraction test

Radicular symptom relief when examiner grasps patient's head under occiput and chin and applies 10–15 kg of axial traction force

Valsalva maneuver

Radicular pain reproduced by forced expiratory effort with mouth and nose closed

Jackson compression

Downward pressure on head with lateral flexion

Upper limb tension test 1 (median nerve bias)

Radicular pain reproduced with scapular depression; shoulder abduction; forearm supination, wrist and finger extension; shoulder external rotation; elbow extension; contralateral followed by ipsilateral cervical lateral flexion

Upper limb tension test 2A (median nerve bias)

Radicular pain reproduced with scapular depression; elbow extension; lateral rotation of the whole arm; wrist, finger, and thumb extension

Upper limb tension test 2B (radial nerve bias)

Radicular pain reproduced with scapular depression; elbow extension; medial rotation of the whole arm; wrist, finger, and thumb flexion

Upper limb tension test 3 (ulnar nerve bias)

Radicular pain reproduced with scapular depression; shoulder abduction; shoulder external rotation; wrist and finger extension; elbow flexion; shoulder abduction

Upper limb tension test (musculocutaneous)

Radicular pain reproduced with scapular depression; elbow extension; shoulder extension; ulnar deviation of the wrist with thumb flexion. Either medial or lateral rotation of the arm could further sensitize this nerve.

Cervical myelopathy

Lhermitte sign

Electrical-like sensations down spine or arms with passive flexion of neck

Hoffmann sign (also for spinal stenosis)

Reflex contraction of thumb and index finger from nipping of the middle finger

Babinski sign

Stimulation of the foot sole elicits dorsiflexion of hallux, or dorsiflexion and abduction of other toes

Hyper-reflexia

Over-reactive deep tendon reflexes

Clonus

More than two repetitive beats during wrist or ankle dorsiflexion movements

Facet joint pain

Paraspinal tenderness

Paraspinal > midline pain with palpation. The only test that identifies facet pain, distinguishes from diskogenic pain, and predicts treatment response.

Source: [2,29,49,51,56]

DIAGNOSTIC IMAGING

Diagnostic imaging has an essential role in some neck pain presentations. However, imaging findings of bulging disks or degenerative changes are common in asymptomatic persons and increase with age [14,103]. In some patients, the imaged abnormality is causing their neck pain. In most patients with acute neck pain, imaging fails to identify a pathologic cause or pathologic findings have uncertain relevance or do not change the course of treatment [29].

Imaging can produce false positive (abnormalities are inert) or false negative (pathology undetected) results. Clinicians should correlate imaging results with history and physical exam findings before deciding its relevance to patient symptoms [102].

Imaging results should be presented with patient education on prevalence, treatment, and prognosis. Patients may intensely want a clear-cut diagnosis of their neck pain. Neglecting this education increases the risk of patient fixation on the imaging abnormality (which may be inert), subsequent pursuit of "cure" for the assumed diagnosis, and with failed expectations, initiation into a chronic cycle that may have been prevented [102,103].

For these reasons, clinical practice guidelines state that patients with acute cervical spine injury, suspected "red flag" conditions, or suspected radiculopathy (and a few select presentations) should receive initial imaging, with imaging considered in other patients remaining symptomatic three to six weeks later [102,103].

Diagnostic Imaging Modalities

Imaging tests differ in accuracy for various pathologies, and no imaging test alone assures correct diagnosis. Information from patient history and physical exam should correlate with imaging results [103].

The indications in the following sections pertain to patients remaining symptomatic after four to six weeks of conservative therapy or with new onset or progression of neurologic symptoms at any follow-up time.

Plain Radiography

Evidence Based Practice Recommendation

According to the American College of Radiology (ACR), in absence of red flag symptoms, imaging may not be required at the time of initial presentation of the patient with neck pain, and the results rarely alter therapy. However, radiographs are widely accessible and useful to diagnose spondylosis, degenerative disk disease, malalignment, or spinal canal stenosis. As such, the ACR states that cervical spine x-ray is usually appropriate for initial imaging of patients with new or increasing nontraumatic cervical or neck pain with no red flags.

https://acsearch.acr.org/docs/69426/Narrative

Last Accessed: September 17, 2019

Level of Evidence: Expert Opinion/Consensus Statement

X-ray images are taken from different anatomic views to identify the following abnormalities [51]:

- Anteroposterior: Tumors, osteophytes, fractures

- Lateral: Stability, spondylosis (spurring, disk space narrowing)

- Odontoid: C1–C2 stability, odontoid process (bony projection of C2, prone to fracture)

- Bilateral oblique: Degenerative disk disease, foraminal encroachment by osteophytes

- Flexion-extension: Subluxations, cervical spine instability

A standard cervical spine x-ray series captures anteroposterior, lateral, and odontoid views [19]. All five views are used to evaluate the intervertebral foramen [41]. Radiographs of the lateral cervical spine may show straightening or reversal of the normal lordotic curve, which can represent spasm, guarding, or splinting of muscles that stabilize the neck [41].

Cervical spine x-ray is indicated for any significant trauma, pain, or cervical spine-related dysfunction; to rule out fracture; or screen for stenosis in symptomatic patients [16,41,59].

Magnetic Resonance Imaging

MRI is the imaging study of choice for most cervical spinal abnormalities. MRI can add important information about soft tissue injuries related to bony injuries seen on x-ray or CT or disk or ligamentous injuries suggested by x-ray, CT, or clinical findings [109]. It can also distinguish hematoma from edema. MRI is highly accurate in identifying disk injury and ligament injuries [19,110]. It is able to detect ligament disruption and subtle vertebral fracture, but is unreliable in depicting sources of cervical diskogenic pain because significant annular tears can escape MRI detection [16,41].

Indications for cervical spine MRI at four to six week follow-up include [22,41,47]:

- Persistent arm pain, neurologic deficits, or clinical signs of nerve root compression

- Cervical radiculopathy signs and symptoms

- Cervical disk injuries with any neurologic decline

- Failure of axial neck pain to resolve as expected

Patients with progressive neurologic deficit should receive MRI without delay.

MRI is contraindicated in patients with certain implanted devices, but MRI scanners compatible with pacemakers are now available. Some patients have panic reactions during MRI from claustrophobia and require mild sedation [103].

Computed Tomography

MRI is superior at imaging soft tissue abnormalities and potential neurologic compromise, while CT better delineates bony pathology by producing multiple 2- and 3-dimensional images of spinal segments [7]. CT alone has limited value in assessing cervical radiculopathy but is useful for visualizing degenerative spine and facet changes, spinal alignment, fractures, herniated disks, spinal and foraminal stenosis, and osteophyte formation, especially when not clearly shown on x-ray [23,24,50,58,103]. It is important to avoid unnecessary CT scanning to limit patient radiation exposure and associated carcinogenic risk [103].

CT Myelography

Myelogram followed by CT scan evaluates the spinal canal, its relationship to the spinal cord, and nerve root impingement from disk, spur, or foraminal encroachment. CT myelography is superior to MRI in detecting encroachment but is reserved for complex cases due to greater expense and morbidity or when MRI is unavailable, intolerable to the patient, or contraindicated [19,51].

Provocative Cervical Diskography

Provocative cervical diskography is the only procedure that can identify a disk as the pain generator. In this test, contrast dye is injected into the nucleus pulposus to visualize disk architecture and provoke a pain response. Discomfort and invasiveness make this procedure less desirable than cervical MRI, which provides much of the anatomic information. Possible complications include diskitis, epidural abscess, quadriplegia, stroke, pneumothorax, and nerve and spinal cord injury [51].

MRI often misses significant tears, which diskography can reveal as diskogenic source of cervical pain. As noted, while MRI can identify most painful disks, it has relatively high error rates [41].

Electrodiagnostic Tests

Electromyography and nerve conduction studies are the standard for evaluating cervical spine neurologic function and have advantages of limited cost and morbidity [51]. With persistent radicular symptoms, electromyography can help identify injuries to cervical nerve roots, brachial plexus, or peripheral nerves [16]. It may show nerve injury missed by imaging studies that only show structural injury [41].

Electromyography shows abnormalities with high specificity in cervical radiculopathy, diagnosed when two muscles innervated from the same nerve root are abnormal. Multiple muscles should be examined, including the paraspinals [11,12,22]. Nerve conduction studies are useful when extremity pain rather than cervical pain is more severe [7].

Initial Imaging

Initial imaging is recommended for some patients when they first present for medical attention with neck pain or symptom complaints.

Acute Cervical Spine Injury

The Canadian C-spine Rule identifies patient risk of cervical spine injury and appropriate diagnostic imaging. "Dangerous mechanism of injury" is defined as falling from a height greater than 3 feet or axial load to the head from diving, high-speed or rollover motor vehicle accident, ejection from a motor vehicle, accident involving motorized recreational vehicles or horse riding, or bicycle collision [111]. The Canadian C-spine Rule assesses high, low, or no patient risk of cervical spine injury (Table 4). Importantly, neck movement is unsafe to assess in high-risk patients [109,111].

Table 4: ASSESSMENT OF RISK LEVEL FOR CERVICAL SPINE INJURY

High Risk

One or more of the following factors:

Dangerous mechanism of injury

Age 65 years or older

Paresthesia in upper or lower limbs

Low Risk

Patients unable to rotate their neck 45° left and right and one or more of the following factors:

Involved in a minor rear-end motor vehicle accident

Comfortable in a sitting position

Ambulatory at any time since the injury

No midline cervical spine tenderness

Delayed onset of neck pain

No Risk

Patient has one low-risk factor and can rotate his/her neck 45° left and right.

Source: [111]

Cervical spine x-rays are indicated for all high-risk and low-risk patients [19,109,111]. CT and/or MRI is recommended for patients with one or more high risk factors, or one or more low-risk factors and inability to rotate neck 45° left and right. The Congress of Neurological Surgeons recommends CT and MRI for cervical spinal injury in patients with cervical spondylitis, even after minor trauma [112,113]. No-risk patients do not need imaging. Other indications for cervical spine MRI include [103,111]:

- Suspicion of cord compression

- Neurologic signs or symptoms, even if x-ray is negative

- Ligament or disk injuries suggested by x-ray, CT or clinical findings

- Suspected nerve root compression, disk herniation or cord contusion following neck injury

- Assessment of red-flag conditions

LABORATORY TESTING

Unless red flag conditions are suspected, laboratory tests are seldom needed in the evaluation of neck pain [103].

5. TREATMENT OF NECK PAIN

Practice guidelines for primary care are consistent in recommended management of acute neck pain [7,102,103,107]. After red flag causes and radiculopathy are ruled out, the neck pain condition is given a nonspecific diagnosis. Patients should then be instructed to take over-the-counter analgesics (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) if needed and to avoid bed rest and maintain activity. Patients should also be reassured their neck pain is benign, time-limited, and has an excellent prognosis. If pain worsens at any time, clinicians should consider specialist referral. If pain persists three to six weeks later, a brief psychosocial assessment is performed to assess "yellow flags," and patients are referred to physical therapy.

This standard guidance has merits of simplicity for clinicians, the benefits of remaining active, and the spontaneous resolution of acute neck pain in some patients. However, some assumptions may be inaccurate, such as the benign, self-limiting nature of most neck pain and patient access to, or availability of, specialist pain providers. Several systemic barriers interfere with patient access to pain therapy, including [114,115]:

- The acute nationwide shortage of pain specialist physicians

- The limited availability in some areas of trained physical, psychologic, or occupational therapy providers

- Insurance non-coverage of nonpharmacologic pain therapies, restrictive coverage that fragments and delays therapy continuity, and/or deductibles that are unaffordable

Poorly controlled acute pain can have negative consequences that include delayed recovery, disrupted sleep, and impaired physical and social functioning that diminishes the quality of life. Regardless of origin, poorly managed acute pain can transition to chronic pain [116]. Pain should be treated at once if it impairs functioning, and treatment options should be discussed clearly with the patient to prevent unrealistic expectations and possible disappointment [73].

The adverse impact of chronic pain on mortality captures the gravity of this state and importance to control. A study followed 1,528 patients with severe chronic pain over 12 years after they completed a multidisciplinary pain program. Among patients who died during follow-up (16%), the average age at death was 14 years younger than life expectancy. One year after the multidisciplinary pain program, pain and health-related quality of life scores were statistically and clinically worse among patients who died but significantly improved among patients who remained alive at last follow-up. These findings of significant premature mortality in patients with uncontrolled chronic pain raise questions of whether some deaths were preventable [117].

PATIENT EDUCATION

Evidence Based Practice Recommendation

For patients with acute neck pain with movement coordination impairments (including WAD), the American Physical Therapy Association recommends clinicians provide education to the patient to return to normal, non-provocative pre-accident activities as soon as possible; to minimize use of a cervical collar; and to perform postural and mobility exercises to decrease pain and increase range of motion. Patients should be reassured that recovery is expected to occur within the first two to three months.

https://www.jospt.org/doi/full/10.2519/jospt.2017.0302

Last Accessed: September 17, 2019

Strength of recommendation/Level of Evidence: B (Moderate recommendation based on one or more level II systematic reviews or a preponderance of level III systematic reviews or studies support the recommendation, providing evidence for a mild to moderate magnitude of effect)

As noted, acute neck pain guidelines recommend that clinicians educate and reassure patients of the typically benign nature and self-limited course of nonspecific neck pain and the importance of maintaining activity and movement. Education and counseling may also include spine anatomy and proper postures, pain perception neuroscience, pain coping strategies, and resumption of normal activities. Education interventions may add small benefits to physiotherapy but should not be used alone due to ineffectiveness [8,118].

For patients who are not proficient in English, it is important that information regarding the etiology of their pain and pain management resources be provided in their native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

PHARMACOTHERAPIES

Standard practice guidelines recommend the following analgesic options for acute/subacute neck pain [7,102,103,107]:

- Acetaminophen

- NSAIDs

- Muscle relaxants

- Opioid analgesics

Chronic neck pain management is more difficult and complex, but pharmacotherapy guidelines for chronic neck pain are non-existent, and general guidelines for the management of chronic pain may be unhelpful.

Practice guidelines recommend drug and non-drug therapies based on randomized controlled trials, considered the best study design to detect efficacy. Analgesic randomized controlled trials are usually placebo-controlled. Systematic reviews examine treatment efficacy by pooling the results of randomized controlled trials to measure differences in average response to treatment versus comparator/placebo [119].

Systematic reviews of guideline-recommended analgesics for neck pain have found acetaminophen ineffective and NSAIDs minimally effective, compared with placebo. Systematic reviews have also found minimal benefit in other analgesics considered effective. These results may reflect true ineffectiveness or possible limitations with randomized controlled trial evaluation of analgesics, including [120,121]:

- Rigid protocols that disallow dose adjustments when ineffective or intolerable

- Strict enrollment criteria, with outcomes of research subjects dissimilar to typical patients

- Increasing placebo-response rates that require larger studies to show relevant differences from placebo

In some cases, it is not the study design but the paradigm itself that limits usefulness. Randomized controlled trials have evaluated analgesic efficacy in patients with specific pathologies (e.g., disk herniation, degenerative processes). The efficacy of oral analgesics is mostly unrelated to underlying tissue pathology, which can produce diverse pain mechanisms. Pain mechanism targeting is now emphasized [71,72].

Central sensitization is recognized to underlie many chronic neck pain cases and is very difficult to treat. Optimized pain reduction can require combining medications that target peripheral inputs in the dorsal horn (bottom-up) and descending pain modulation pathways (top-down) with tapentadol (opioid and norepinephrine reuptake inhibitor) or opioids plus NSAIDs, norepinephrine reuptake inhibitors, or anticonvulsants. Adding topical analgesics can help decrease peripheral nociceptive input [71,98,122,123]. A 2017 practice guideline recommended combining analgesics in chronic pain treatment [124].

Assessment of Analgesic Response

Assessing treatment response to neck pain pharmacotherapy is very important. This requires the patient reaching and maintaining adherence to a target dose at which therapeutic effect is expected for at least two weeks. The most common errors are underdosing and insufficient treatment duration [73].

Assess treatment response using a 0–10 scale, and use the results to help guide treatment planning [73]. With a pain reduction to <3, continue monotherapy and consider indication for combination therapy, when appropriate. For a pain reduction by ≥30% but a pain intensity ≥4, combine the existing therapy with an additional first-line drug. If pain is reduced by <30% and the pain intensity ≥4, the drug should be considered ineffective and the patient should be switched to another first-line agent.

It is also important to check for side effects [73]. If intolerable side effects prevent effective dosing, switch to another drug. If the patient is taking a clinically effective dose but intolerable side effects continue, lower the dose before switching analgesics. Depending on the therapeutic and side effects after this is done, try switching the drug or starting combination therapy with a low dose of the original drug. If the pain relief remains inadequate, consult a pain specialist or refer the patient to a pain center.

Acetaminophen

Acetaminophen (paracetamol) is a nonsalicylate antipyretic analgesic recommended as first-line therapy in mild-to-moderate acute or chronic low back, spinal, and musculoskeletal pain [125,126,127]. Enduring assumptions of its efficacy and safety were first challenged by a randomized controlled trial of 1,649 patients with acute low back pain. Following 28 days of acetaminophen or placebo taken as regular dosing (three times per day) or as needed for pain, acetaminophen did not differ from placebo on any pain outcome, average time to recovery, or tablets consumed per day [126].

Reviews of placebo-controlled trials concluded that acetaminophen was ineffective in reducing pain and disability in low back pain and showed little evidence of efficacy in diverse chronic pain conditions. Even 4,000 mg/day for 1 to 12 weeks had no effect beyond placebo on pain, quality of life, function, or sleep quality in acute low back pain, and any effect in chronic low back pain was uncertain [125,127,128]. A caveat is that very few studies have evaluated acetaminophen in neck pain.

Acetaminophen shows a significant dose-response effect for increased risks of cardiovascular, renal, and GI adverse effects, suggesting considerable toxicity risk, especially at the upper end of standard analgesic dosing [129]. Acetaminophen may cause liver failure in acute overdose or chronic excessive exposure [130]. The universal endorsement and routine use of acetaminophen as first-choice analgesic in acute and chronic neck pain is questioned [125,126,127].

Muscle Relaxants

Appropriate for muscle spasm with pain, there is strong evidence that muscle relaxants can provide short-term pain relief in acute low back pain (and by extension, neck pain due to spasm). Clinicians should consider the side effects of drowsiness or dizziness. Carisoprodol is not recommended because its active metabolite, meprobamate, is a drug with abuse potential [103].

NSAIDs

NSAIDs are endorsed universally as first-line therapy for acute mild-to-moderate pain of any origin and broadly as first-line therapy for diverse chronic pain conditions, including neck pain. NSAIDs have similar pharmacology but diverse molecular structure. Patient response to specific NSAIDs varies, and several trials of different NSAIDs may be needed to identify an effective agent [103].

A meta-analysis evaluated 35 randomized controlled trials for NSAID efficacy in low back, neck, and sciatica pain. Pain and disability outcomes of NSAIDs or placebo were pooled and averaged, and differences were compared using a 0–10 scale. No study reported outcomes beyond 12 weeks. Only two neck pain studies were found, and the outcomes of these studies were for less than four weeks [131].

NSAIDs surpassed placebo in neck pain reduction by 1.6, a minimally important difference to patients in pain. NSAIDs surpassed placebo by 1.2 in disability reduction. Average differences between NSAIDs and placebo in low back pain/sciatica were lower than neck pain. In aggregate, six participants required treatment with NSAIDs, instead of placebo, for one additional participant to achieve clinically important pain reduction [131].

Another review of NSAIDs in spine pain found two neck pain studies. One involved intravenous NSAIDs, but the other study found greater pain reduction with indomethacin and piroxicam over placebo, and no difference between NSAIDs [47].

NSAIDs inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2), enzymes that convert arachidonic acid to pro-inflammatory prostanoids. COX-2 inhibition reduces inflammation and pain. Prostanoids also play key roles in maintaining normal physiologic processes; their inhibition accounts for the adverse effects of NSAIDs [132,133].

COX-1 inhibition suppresses prostaglandins that protect the gastric mucosa and thromboxanes that promote platelet aggregation. COX-2 inhibition suppresses prostacyclins in vascular endothelium that inhibit platelet aggregation [134]. Thus, serious or fatal GI, cardiovascular, or renal adverse effects can result from NSAIDs use [133].

In 1997, 16,500 deaths from upper GI bleeding/perforation were linked to NSAIDs [135,136]. This prompted introduction of COX-2-selective NSAIDs to reduce GI risks, which became linked to cardiovascular adverse effects. The view emerged that COX-2 selective NSAIDs had greater risk of cardiovascular toxicity and lower risk of GI toxicity than traditional NSAIDs. Greater accrual of patient outcomes demonstrated all NSAIDs carry GI and cardiovascular risks [132,137,138,139].

Celecoxib has the least GI toxicity but high, dose-related cardiovascular risk. Naproxen has the best cardiovascular safety, but greatest GI toxicity [139]. Concurrent NSAID and selective serotonin reuptake inhibitor (SSRI) use increases upper GI bleeding risks [140,141]. Adding a proton pump inhibitor or switching NSAIDs to celecoxib is recommended to mitigate upper GI risks [142]. Despite greater awareness, NSAIDs cause 7,000 to 10,000 GI hemorrhage fatalities annually [143].

All NSAIDs increase risks of fatal and non-fatal cardiovascular and cerebrovascular events and renal failure, especially in elderly patients. Serious adverse effects can occur within one month of regular therapy. Long-term NSAID use is not recommended, and NSAIDs should be used at the lowest effective dose for the shortest duration possible [103,134,144]. Given the risk profile, clinicians should reconsider using NSAIDs for pain and limit their use to pain with inflammation [145].

Antidepressants

Noradrenergic projections form a key component of descending pain inhibition pathways. Impaired descending pain inhibition can facilitate and maintain chronic pain. Drugs that inhibit norepinephrine reuptake can enhance spinal noradrenergic efficiency to reduce chronic pain, including some antidepressants and the opioids tramadol and tapentadol [71,123].

Tricyclic antidepressants (TCAs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) are recommended first-line options in chronic neuropathic pain disorders and in chronic pain with a neuropathic component [69,71,73].

Tricyclic Antidepressants

The first antidepressants used in pain treatment, TCAs may also produce analgesia by blocking NMDA-induced hyperalgesia, voltage-gated sodium channels, and delta-opioid receptor interaction [146,147,148]. Amitriptyline is the most studied, endorsed, and prescribed TCA in chronic pain, and some evidence suggests it may be the most effective analgesic antidepressant [70,72,73,81]. Other TCAs (e.g., nortriptyline, desipramine) are better tolerated but lack the evidence base of amitriptyline. Analgesic effects are independent of antidepressant effect, and analgesic dosing is 20% to 33% of antidepressant doses [148].

SNRIs

Duloxetine and venlafaxine are the most-studied SNRIs in chronic pain, with duloxetine the most widely endorsed agent [81]. SNRIs inhibit reuptake of serotonin and norepinephrine, but norepinephrine activity accounts for analgesic effects. In contrast, SSRI antidepressants have negligible norepinephrine activity and minimal analgesic efficacy.

Unlike TCAs, SNRIs require antidepressant doses for analgesia, especially venlafaxine, which only inhibits serotonin reuptake at lower doses (<175 mg/day) [148]. Duloxetine 60–120 mg/day is used for pain, with doses <60 mg/day ineffective [73].

Several placebo-controlled trials have evaluated duloxetine in chronic low back pain without radiculopathy or stenosis. Outcomes from four of these studies were pooled; 12 to 14 weeks of duloxetine led to pain reduction ≥30% in 60% (versus 48% with placebo) and ≥50% in 49% (versus 35% with placebo). Analgesic response to duloxetine surpassed placebo by 13% on both pain outcomes [149].

Another study of different doses found duloxetine 20 mg, 60 mg, and 120 mg no different from placebo at week 13, and noted a 24% dropout rate from side effects with duloxetine 120 mg [150].

With duloxetine in chronic pain, analgesic effects accounted for 91% of pain reduction in patients screened for depression, which shifted over time to antidepressant effects in patients with comorbid depression. The authors noted the mutually reinforcing relationship between pain and depression makes it plausible that alleviating depression can reduce pain symptoms [151].

Duloxetine was less effective in isolated chronic low back pain than in patients with two or more painful sites. Multiple pain sites may better reflect CNS alterations that amplify pain perception, and suggest duloxetine is more effective in centralized chronic pain [149].

Milnacipran, another SNRI, after six weeks was no different from placebo in pain reduction in chronic low back pain with a neuropathic component [152].

Antidepressant Adverse Effects

TCA side effects are intolerable for some patients, and low-dose (10 mg/day) initiation with gradual increase to 75 mg/day is suggested [73]. TCAs should be used cautiously in elderly patients due to greater risks of postural hypotension, impaired cognition, and falls and should be avoided in patients with a history of cardiovascular disease [70,148].

In placebo-controlled pain studies, desipramine and venlafaxine had the highest overall rates of adverse effects. Desipramine, milnacipran, venlafaxine, and duloxetine had highest dropout from side effects, suggesting greater severity and unpleasant perception. Adverse effects associated with duloxetine (e.g., nausea, constipation, dry mouth, hyperhidrosis) differed somewhat from amitriptyline (e.g., dry mouth, thirst, constipation, headache, weight gain, blurred vision, palpitations) [153].

Antiepileptic Drugs

Antiepileptic drugs are diverse, but pregabalin and gabapentin are the only widely studied agents in chronic low back pain. As with antidepressants, few neck pain studies are available and chronic low back pain outcomes are used to inform decisions.

Pregabalin and gabapentin are widely recommended first-line agents in neuropathic pain disorders, such as painful diabetic neuropathies and postherpetic neuralgia [72]. Analgesic, anxiolytic, and anticonvulsant effects arise from binding to alpha-2/delta-1 subunits of calcium channels, highly expressed in brainstem structures where descending pain modulatory pathways originate and a likely key analgesic target of pregabalin/gabapentin [70].

Pregabalin has greater binding affinity and greater analgesic potency in neuropathic pain than gabapentin. Pregabalin also has more rapid absorption, greater bioavailability, and a linear dose-response [70].

The dosage of pregabalin in pain treatment is 300–600 mg/day in divided doses. Gabapentin is used at 1,200–3,600 mg/day in three divided doses. Both can be initiated at 10% the maximum dose, increased every three to four days [73]. Pregabalin 600 mg/day has greater efficacy than 300 mg/day [72].

Pregabalin/gabapentin is generally well tolerated. The adverse effects most common with pregabalin are dizziness, somnolence, dry mouth, edema, and blurred vision; with gabapentin, common adverse effects include dizziness and somnolence (>20% of patients), confusion, and peripheral edema [70].

Adverse effects increase with pregabalin dose but do not appear to be age-related. In patients 65 years of age and older, titration to the lowest effective dose may help minimize adverse effects. Absence of known drug interactions with pregabalin/gabapentin increases safety in patients requiring polypharmacy [154].

Gabapentinoid efficacy in chronic spine-related pain is inconsistent. An uncontrolled study compared pregabalin monotherapy, pregabalin add-on therapy, and non-pregabalin therapy under "real-world" primary care conditions in 1,351 patients with chronic painful cervical (13%) or lumbosacral (87%) radiculopathy [155]. Pregabalin groups received 190 mg/day (mean). At 12 weeks, pain intensity reduction ≥50% was attained by 63%, 56%, and 33% of patients in pregabalin, pregabalin add-on, and non-pregabalin groups, respectively. Differences in pain reduction were significant by week 4. Improvements in sleep disturbances, depression, anxiety, and quality of life showed large effect sizes in pregabalin groups and moderate effect sizes in the non-pregabalin group [155]. The authors noted non-pregabalin patients received NSAIDs (67%) or acetaminophen (37%) rather than tramadol (19%), gabapentin (13%), or amitriptyline (5%), indicating inappropriate treatment with NSAIDs and acetaminophen, which are ineffective in chronic pain with a neuropathic component [155].

In contrast to these uncontrolled results, a review of pregabalin/gabapentin studies in nonspecific chronic low back pain found minimal pain improvement with gabapentin compared with placebo, and pregabalin inferior to active-drug control groups (with buprenorphine, tapentadol, or celecoxib). Studies comparing pregabalin to placebo were not found [156].

In a small trial, patients with chronic cervical or lumbar radicular pain had greater pain reduction with placebo than pregabalin after three weeks [157]. Pregabalin plus tapentadol did not improve tapentadol efficacy in severe chronic low back pain with a neuropathic component and significantly increased dizziness and somnolence [158].

An uncontrolled trial of pregabalin in cervical spondylosis pain found significant pain reduction after eight weeks, but intolerable somnolence and dropout by 27 of 50 patients. The authors suggest greater sensitivity to this side effect in the Asian study population [159].

Importantly, drug users who combine heroin (and possibly some patients receiving opioid therapy) with gabapentin or pregabalin potentially increase their risk of acute overdose death by reversing opioid tolerance or through additive effects on respiratory depression [160].

Opioid Analgesics

When severe pain requires powerful analgesic control, few options are as effective and widely available as opioids [161]. Non-opioid analgesics were examined for chronic pain efficacy in 271 randomized controlled trials. Many showed statistically significant effect sizes, but pain reduction sizes were usually not clinically relevant [162]. However, the current regulatory environment and concern regarding misuse inhibits opioid prescribing, placing clinicians with patients in severe pain in a double-bind [163].

Opioid prescribing is a complex issue that should be approached by balancing control (to prevent inappropriate use) with access (for appropriate patients). With focus on either, and neglect of the other, consequences follow [164]. Overemphasis on access has led to increased opioid prescriptions and related addiction, diversion, and overdose deaths. Opioid prescribing and related overdose deaths (16,917) appear to have peaked in 2011 [165,166,167].

Until improved analgesics are developed, opioids remain the only option for severe pain in many patients [161]. Clear evidence demonstrates that screening for substance use disorder before initiating opioid therapy in patients with chronic pain minimizes its development [98,168,169,170]. In addition, most fatalities involving prescription opioid analgesics occur with co-ingested benzodiazepines, alcohol, and other CNS/respiratory depressants. Prevention involves patient education and cautious or avoidance of co-prescribing CNS depressants [171,172,173].

In controlling severe acute neck pain, oxycodone, morphine, and hydromorphone are similarly effective. For chronic moderate-to-severe neck pain, the suggested options shift to several more recent opioid preparations with lower abuse potential, greater tolerability, and/or alternate drug delivery that increase safety in long-term use.

Opioid-induced constipation is a class-wide opioid adverse effect perceived by patients as the most distressing side effect [174]. A study of chronic pain patients with opioid-induced constipation from prior opioids found patient fear of constipation led to a number taking little or no study medication and inadequate pain control, despite the study drug being designed to reduce opioid-induced constipation [175].

Unlike other opioid side effects, opioid-induced constipation does not typically resolve with continued use, becoming chronic in 40% to 45% of patients on long-term opioids and adversely affecting patient quality of life and pain control [98,174]. Opioid-induced constipation should be anticipated and managed prophylactically. Several medications are approved by the U.S. Food and Drug Administration (FDA) for opioid-induced constipation, including naloxegol, methylnaltrexone, lubiprostone, and naldemedine.

Abuse-Deterrent Formulations

All extended-release oral opioids are available in abuse-deterrent formulations, designed to make nontherapeutic use more difficult, less attractive, or less rewarding. Abuse-deterrent formulations use physical barriers that resist crushing; chemical barriers that form into a viscous gel if mixed with liquid; and/or opioid antagonist sequestration that product tampering activates to neutralize the agonist. Some abuse-deterrent formulations use multiple deterrence mechanisms. While abuse-deterrent formulations can deter extended-release opioid tampering to defeat the slow-release mechanism for a rapid-onset, high-dose opioid effect, they cannot prevent abuse of intact pills. Abuse-deterrent formulations are one of several approaches to minimize prescription opioid abuse (Table 5), but insurance non-coverage is common, due to higher costs than standard opioid formulations [98,176,177].

Table 5: IDENTIFYING ADDICTION IN PATIENTS PRESCRIBED OPIOIDS

When implementing a neck pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function. Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Short attention span or inability to concentrate

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

- Use of the opioid to regress instead of re-engaging in life

- Lack of attention to hygiene and appearance

Information obtained by patient history, physical examination, and interview, from family members, a spouse, or state prescription drug monitoring database, and from the use of screening and assessment tools can help the clinician to stratify the patient according to level of risk for developing problematic opioid behavioral responses. A urine drug test should be performed prior to initiating opioid treatment.

Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations.

If substance abuse is active, in remission, or in the patient's history, one should consult an addiction specialist before starting opioids. In the setting of active substance abuse, opioids should not be prescribed until the patient is engaged in treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly those that are extended-release or long-acting), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental exposure by children.

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tool use to help determine patient risk level, most tools have not been extensively evaluated, validated, or compared to each other.

Source: [250,251,252,253,254,255]

Oxycodone/Naloxone

To reduce opioid-induced constipation during long-term therapy, the opioid antagonist naloxone was combined with oxycodone extended-release in a fixed-dose 2:1 ratio. Unlike short-acting naloxone, the extended-release formulation limits systemic exposure and does not block or reverse oxycodone analgesia [178]. Combination oxycodone/naloxone (Targin) was FDA-approved in 2014 [174]. Oxycodone/naloxone and oxycodone extended-release show similar efficacy in chronic pain. Oxycodone/naloxone reduces but does not eliminate constipation and seems more effective in new patients with opioid-induced constipation than in preventing constipation during treatment [178].

Buprenorphine

Buprenorphine differs from standard opioids as a partial mu-opioid receptor agonist. This produces a respiratory depression ceiling effect, making buprenorphine safer in overdose, and a euphoria ceiling effect that lowers drug "liking." Buprenorphine is a kappa-opioid receptor antagonist, producing an anti-hyperalgesic effect relevant to neuropathic pain that often contributes to chronic spine-related pain [179,180,181]. Transdermal buprenorphine is the primary form used in chronic pain treatment. The transdermal patch is effective for seven days, after which it is replaced [182]. A buccal formulation was FDA-approved in 2016 based on studies demonstrating efficacy in patients with moderate-to-severe chronic low back pain [183].

The lower abuse potential of transdermal buprenorphine also reflects its slow onset rate and difficulty extracting buprenorphine from the patch. Compared with fentanyl patches, extended-release opioids, and extended-release tramadol, transdermal buprenorphine has shown the lowest rates of abuse and diversion. Common side effects are constipation, dry mouth, nausea, vomiting, headache, dizziness, somnolence, and application site skin irritations [179,180,182].

In a study of transdermal buprenorphine therapy of 465 patients (median age: 67 years) with diverse chronic pain conditions, transdermal buprenorphine pain relief was rated effective/very effective by 69% after 3 months and 91% after at least 36 months [180]. Patient satisfaction with transdermal buprenorphine showed the same temporal pattern. Non-prescribed dose escalation (3%) was low, but patient motive (e.g., pain control, euphoria) was not analyzed. Dropout from ineffectiveness (4%) or adverse effects (12%, mostly skin irritation) exceeding similar trials [180].

Tramadol

Tramadol is a weak opioid that also inhibits serotonin and noradrenaline reuptake, and it is an established option in chronic low back pain. Opioid and non-opioid mechanisms both act to produce analgesia, and account for its low "likeability" by drug misusers, with lower abuse potential than other opioids. It may also have anti-inflammatory activity. Tramadol use with other serotonergic medications (e.g., most antidepressants) may result in serotonin syndrome and should be avoided [73,98,158].

Tapentadol

Tapentadol is a mu-opioid receptor agonist and norepinephrine reuptake inhibitor combined in a single molecule. Tapentadol extended-release was extensively investigated in Europe, with the finding that the formulation is effective in diverse chronic pain, with or without neuropathic pain component, in evaluations up to two years [184,185]. Researchers found function, health status, and quality of life improved during long-term treatment. The drug has a good safety profile, with GI tolerability more favorable than other opioids and a low risk of withdrawal after cessation. To date, analgesic tolerance has not been found in long-term data.

In studies, tapentadol was as effective as oxycodone in nociceptive and neuropathic chronic low back pain, with better GI tolerability and treatment adherence [73,186,187,188]. Earlier gains in function, health status, and quality of life maintained over one year in 1,154 patients receiving open-label tapentadol extended-release after completing randomized controlled trials, including average pain scores (3.9 start, 3.7 end) [189].

As noted, few studies have evaluated opioid therapy, and pharmacotherapy in general, in chronic neck pain. However, an uncontrolled trial evaluated tapentadol extended-release in 54 patients with moderate-to-severe chronic neck pain over 12 weeks [4]. Participants' reported pain-intensity scores (on 0–10 scale) were 1.7 resting (versus 6.8 at baseline) and 2.9 with movement (versus 8.8 at baseline). Approximately 89% of patients experienced ≥30% reduction in pain intensity on movement; 68% reported a ≥50% reduction. In addition, the average NDI score decreased from 55.6 at baseline to 19.7 after 12 weeks. Quality of sleep improved ≥30% in 79% of patients. Cervical range of motion was evaluated on flexion, extension, right and left lateral flexion, and rotation. Compared with baseline, patients with normal range of motion on flexion increased 13%; the other five measures increased 23% to 35% [4].

No patient dropped out from side effects, despite 90% being opioid-naïve on study entry. The average final dose was 204 mg/day, and tapentadol extended-release was well-tolerated in patients requiring 400 mg/day. Common side effects at 12 weeks were constipation and dizziness [4].

With further subject accrual, a second paper from this study compared tapentadol extended-release response in 94 patients with or without a neuropathic neck pain component. Both groups showed comparable reductions in neck pain intensity ≥30% (69% versus 70%) and in average pain scores from baseline (4.4 versus 4.8) at 4 weeks, and reduction in NDI scores from baseline to 12 weeks (46 to 13 versus 58 to 18) [190].

Despite the limitations of uncontrolled trials, this data, together with studies in chronic low back pain, suggest tapentadol extended-release may be effective and tolerable for patients with chronic moderate-to-severe neck pain.

The mu-opioid receptor binding affinity of tapentadol is 18-fold lower than morphine, suggesting lower abuse potential than standard opioids (confirmed by several studies) [98,191]. In 113,914 individuals assessed for substance abuse treatment, tapentadol abuse was lowest overall and significantly lower than other prescribed oral opioids. Adjusted for nationwide prescription volume, tapentadol abuse liability was the second lowest, after only tramadol [192]. Among 1.9 million messages posted by recreational drug users on online forums, the proportion of discussions and endorsements for abuse were substantially lower for tapentadol than comparator drugs [193].

Data from drug diversion databases and investigators and anonymous street drug pricing websites indicate illicit sales and use of tapentadol extended-release was rare. In the few cases of illicit sales, tapentadol extended-release was 10% the price of standard opioids [194].

Cebranopadol and NKTR-181

Two novel opioid analgesics designed to improve safety over standard opioids are in pre-approval evaluation. Cebranopadol is a mu-opioid receptor agonist and nociceptin/orphanin FQ peptide receptor agonist that may improve respiratory depression safety. A 14-week study in chronic low back pain found cebranopadol comparable to tapentadol in analgesic efficacy and sleep and functional improvements [195].

NKTR-181 is a long-acting mu-opioid receptor agonist with structural properties that alter its brain-entry kinetics and may limit abuse potential [176]. Initial studies involving patients with chronic low back pain have found improvements in pain score and sleep compared with placebo [196].

Topical Analgesics

Transdermal analgesic formulations are used for systemic drug delivery, absorption, and distribution. In contrast, topical analgesics are used for drug delivery to local tissue while avoiding systemic exposure.

Topical analgesics have evolved to gain acceptance as analgesic options and have the potential to reduce pain in some conditions while avoiding the side effects of systemic analgesics. Topical analgesics include FDA-approved and compounded formulations.

FDA-Approved Topical Analgesics

FDA-approved topical analgesics include NSAID gel or cream, 5% lidocaine patch or plaster, and 8% capsaicin patch [197].

Topical NSAIDs are increasingly favored in musculoskeletal conditions to avoid the systemic adverse effects of oral NSAIDs, with diclofenac and ketoprofen the most-studied topical NSAIDs. In acute pain, benefit in sprains or strains has good evidence, but the formulation used is critically important; this same consideration may also apply to chronic conditions. Use in chronic musculoskeletal conditions assessed over 6 to 12 weeks showed good pain relief beyond inert carrier in a minority of patients with knee osteoarthritis, limited benefit in hand osteoarthritis, and no evidence in other chronic painful conditions [198,199].

Emerging data suggest the capsaicin 8% patch and lidocaine 5% patch or medicated plaster may both be effective in the treatment of chronic low back pain (and by extension, chronic neck pain) with a neuropathic component [73]. Sodium channels expressed on nerve fibers become altered in neuropathic pain to enhance excitatory neurotransmission [71]. Lidocaine prevents the generation of pathologic nerve excitation by blocking sodium channels. Topical lidocaine may be beneficial when neuropathic pain is localized, because the maximum penetration depth is 8–10 mm. Lidocaine patches are applied to the painful area for 12 hours, followed by a patch-free interval of 12 hours [70].

An uncontrolled study evaluated 5% lidocaine plaster in 23 patients with cervical or lumbar disk herniation and peripheral neuropathic pain (radiculopathy). Compared with baseline, mean pain intensity scores following average treatment duration of eight months decreased from 8.3 to 3.1. Treatment was well-tolerated [200].

In neuropathic pain, transient receptor potential (TRP) channels induce and maintain spontaneous pain and thermal hyperalgesia. The TRPV1 agonist capsaicin activates TRP channels, and desensitization that follows can reduce neuropathic pain [72,73]. Capsaicin 8% patch was effective in painful radiculopathy when placed on involved spinal nerve dermatomes. Fifty patients with cervical or lumbar radiculopathy were evaluated 12 weeks after a single treatment. Among patients with pain duration 3 months, 24 months, or >24 months, 50%, 71%, and 39% achieved ≥30% pain reduction, respectively. Four patients experienced application site pain or pruritus [201].

Compounded Analgesic Formulations

Analgesic medications compounded for topical use are gaining popularity in chronic pain management. Compounded analgesic formulations have the potential advantages of FDA-approved topical analgesics, but with a broader range of options, including ketamine, clonidine, gabapentin, baclofen, and phenytoin [197]. Compounded analgesic formulations typically combine three or more analgesic drugs to achieve multiple complementary effects at lower doses of each drug [202].

Some evidence suggests greater pain reduction with compounded versus FDA-approved topical analgesics. In an uncontrolled study, 2,177 patients with chronic pain received one of three treatments [203]:

- Cream I: Flurbiprofen (20%), tramadol (5%), clonidine (0.2%), cyclobenzaprine (4%), and bupivacaine (3%)

- Cream II: Flurbiprofen (20%), baclofen (2%), clonidine (0.2%), gabapentin (10%), and lidocaine (5%)

- Voltaren gel: 1% diclofenac sodium (an FDA-approved NSAID formulation)

Pre-treatment chronic extremity, joint, musculoskeletal, or neuropathic pain intensity (0–10 scale) in all groups was severe (range: 7.9–8.4). Post-treatment pain intensity scores decreased 37% with cream I, 35% with cream II, and 19% with Voltaren gel. The compounded analgesic formulations did not differ in efficacy, and both were superior to Voltaren [203].

Many small uncontrolled trials show compounded analgesic formulations' efficacy, but this approach must balance local penetration against systemic exposure and potential toxicity. Compounding is not FDA-regulated; vehicle formulation and active drug concentration should be standardized for greater confidence in compounded analgesic formulations safety and efficacy [204].

Cannabinoids

Cannabinoids, which include plant Cannabis, cannabidiol extracts, and pharmaceutically synthesized molecular constituents of Cannabis, are increasingly available to patients with pain through state-level enactment of medical access. Cannabinoids are seldom considered first-choice therapeutic options but are used instead in patients for whom standard therapies are ineffective or intolerable, either as sole therapy or more typically as an add-on to the current regimen [205]. Cannabis has been safely co-administered with a wide range of other drug agents and acts synergistically with opioids to enhance analgesia and allow opioid dose reduction. Chronic pain treatment often requires multiple drug agents that target different pain mechanisms, and the novel mechanism and superior safety profile of cannabis versus opioids suggests that it can be a valuable addition to therapeutic options for chronic pain [206,207].

PHYSIOTHERAPIES

Physiotherapies broadly encompass passive interventions (i.e., without patient exertion or effort), such as massage and manipulation, and active interventions (i.e., requires patient exertion and effort), such as physical and exercise therapy. They are delivered by trained and licensed allied healthcare professionals manually to affected soft tissue or joints, or through instruction and supervision with active interventions. Physiotherapies may also include mechanical devices that patients with positive results can purchase for continued use at home but must be prescribed by their physician [41].

Soft Tissue Therapies

Massage

Massage therapy involves manual manipulation of soft tissue structures. Clinical (therapeutic) massage aims to accomplish specific goals, such as releasing muscle spasms. An example is myofascial trigger point therapy. Relaxation massage aims to relax muscles, move body fluids, and promote wellness [8].

Indications for massage include edema, muscle spasm, adhesions, and the need to improve peripheral circulation and range of motion or to increase muscle relaxation and flexibility prior to exercise. Massage can produce immediate pain reduction, and a frequency of one to two times per week for six to eight weeks is suggested [103]. Massage therapy (once-weekly for 10 weeks) can provide short-term relief for chronic cervical myofascial pain and reduce pain-related impairments [57].

A practice guideline concluded therapeutic massage can decrease pain and tenderness and improve range of motion in patients with subacute or chronic neck pain. Massage interventions are effective for relieving neck pain symptoms at post-treatment, but data on long-term effects are insufficient [208].

Soft Tissue Mobilization

Mobilization of soft tissue applies muscle energy, strain/counter strain, myofascial release, manual trigger point release, and other manual therapy techniques to improve or normalize movement patterns by reducing soft tissue pain and restrictions [103]. Mobilization applies gentle pressure within or at the limits of normal motion with the goal of increasing cervical range of motion [67].

Indications include muscle spasm around a joint, trigger points, adhesions, and neural compression. Mobilization should be accompanied by active therapy. The usual course of treatment is up to three times per week for four to six weeks [103].

Myofascial Release Therapy

In myofascial release therapy, after myofascial tissue with pain-generating trigger points is identified, focused manual pressure and stretching is applied to loosen restricted muscle and joint movements and reduce pain.

Pressure pain threshold is a validated measure of mechanical hyperalgesia and accurately discriminates chronic neck pain with neuropathic features from that without. Using an algometer (hand-held device), tissue pressure is increased until pain is evoked (the pressure pain threshold) [209].

Myofascial release therapy was compared with physical therapy for efficacy in reducing pressure pain threshold and neck pain in 41 patients randomized to myofascial release therapy (5 sessions) or multimodal physical therapy (10 sessions of ultrasound therapy, transcutaneous electrical nerve stimulation [TENS], and massage) over two weeks. At one-month follow-up, significant mean differences were found in pain scores and pressure pain threshold (trapezius, suboccipital) favoring myofascial release therapy. Better short-term improvement in neck pain with myofascial release therapy over physical therapy is suggested [209].

Joint-Directed Therapies

Joint-directed therapies include manipulation and joint mobilization. Spinal manipulation and mobilization may restore normal range of motion and decrease pain. The therapeutic mechanisms remain unknown, but facet joint adjustment may normalize afferent signaling from mechanoreceptors to the CNS, which may improve muscle tone, decrease muscle guarding, promote effective local tissue metabolism, and lead to pain and range of motion improvements [51].

Manipulation

Manipulative treatment applies manually guided force to reduce pain and improve physiologic function [103]. Manipulation is a broad term that includes high-velocity, low-amplitude thrusts to the cervical spine, and modalities such as myofascial release, counterstrain, and/or indirect or direct muscle energy techniques. Non-high-velocity, low-amplitude techniques may also be referred to as mobilization [16].

The most common chiropractic spinal manipulation is high-velocity, low-amplitude thrust to spinal segments, applied at or near the end of a joint's passive range of motion to increase articular mobility or realign the spine. Manual manipulation is also performed by osteopathic physicians trained in manipulative medicine [210].

Some evidence supports chiropractic treatment of WAD [16]. A 2015 Cochrane review of multiple manipulation treatment sessions in neck pain concluded combining laser therapy with manipulation may be superior to manipulation or laser alone for acute and chronic neck pain [211]. For acute and subacute neck pain, manipulation was more effective than muscle relaxants, NSAIDs, and acetaminophen in improving pain and function at immediate (same day) and long-term (around one year) follow-up, and function at intermediate (around six months) follow-up. For patients with acute neck pain, manipulation may be more effective in improving pain and function at short (three months) or intermediate (six months) follow-up. Manipulation may be more effective than massage in improving pain and function in patients with chronic cervical headache at short/intermediate follow-up, and may be favored over TENS for pain reduction at short-term.

The recommended frequency of manipulation therapy is one to two times per week for the first two weeks, and one treatment per week for the next six to eight weeks. At week 8, patients should be re-evaluated [103].

Contraindications include myelopathy, severe degenerative changes, fracture or dislocation, infection, malignancy, ligamentous instability, and vertebrobasilar insufficiency [67]. Relative contraindications include stenosis, spondylosis, and disk herniation [103].

Vertebral artery dissection caused by high-velocity, low-amplitude thrusting is a rare but recognized outcome. Vascular accidents following extension and rotation of the neck beyond the physiologic range lead to a cascade of events including thrombosis, stroke, and death [212]. More than 400 cases following cervical manipulation have described arterial dissection, brain stem injury, cerebellar injury, spinal cord injury, thrombosis, locked-in syndrome, joint dislocation, and death. Risk of these rare but catastrophic events can be minimized by avoiding extension-based high-velocity, low-amplitude thrust [16].

Joint Mobilization

Joint mobilization techniques incorporate a low-velocity and small- or large-amplitude oscillatory movement, within a joint's passive range of motion [8]. A mobilization treatment consists of passive movement involving oscillatory motions to the vertebral segment(s). The passive mobility is performed in a graded manner (I, II, III, IV, or V), which depicts the speed and depth of joint motion during the maneuver. Mobilization may include skilled manual joint tissue stretching [103]. Other modalities include myofascial releases, counterstrain, and indirect or direct muscle energy techniques [16]. Indications include the need to improve joint play, segmental alignment, or intracapsular arthrokinematics or to reduce pain associated with tissue impingement. Mobilization should be accompanied by active therapy [103].

A 2015 Cochrane review of mobilization therapy in neck pain noted anterior-posterior mobilization may favor pain reduction over rotatory or transverse mobilizations at immediate follow-up in patients with acute and subacute neck pain [211]. For those with subacute and chronic neck pain, cervical mobilization alone may not be different from ultrasound, TENS, acupuncture, and massage in improving pain, function, quality of life, and participant satisfaction at immediate and intermediate follow-up. Multiple sessions of TMD manual therapy may be more effective than cervical mobilization in improving pain/function at immediate and intermediate follow-up for patients with chronic cervical headache and TMD.

For grade V mobilization, contraindications include joint instability, fracture, severe osteoporosis, infection, metastatic cancer, active inflammatory arthritides, and signs of progressive neurologic deficits, myelopathy, vertebrobasilar insufficiency, or carotid artery disease. Relative contraindications include stenosis, spondylosis, and disk herniation [103].

Manipulation and Joint Mobilization Co-Therapy

Manipulation and mobilization show similar results on most outcomes. In acute and chronic neck pain, manipulation and cervical mobilization produced similar changes in pain, function, quality of life, global perceived effect, and patient satisfaction at immediate-, short-, and intermediate-term follow-up [211].

Outcomes with gentle mobilization were superior to physical therapy and comparable to high-velocity, low-amplitude thrust [211]. For mechanical neck disorders, manipulation or mobilization were more beneficial combined with exercise than as monotherapy [16]. Short-term improvement is documented in acute whiplash pain, cervicogenic headache, and radiculopathy secondary to disk herniation, but others conclude that mobilization or manipulation in patients with radicular findings has insufficient evidential support [16,51]. No evidence exists that manipulation confers long-term benefit, improves chronic conditions, or alters the natural course of a neck pain disorder [16].

MECHANICAL AND MANUAL TRACTION

Manual or mechanically assisted traction applies an intermittent or continuous distractive force to the cervical spine. Distraction refers to gentle pulling of the head upward to relieve pressure and compression of joints or nerve roots in the cervical spine [8].

Traction is initiated manually by a physiotherapist or as a component of manipulation or mobilization treatment. The usual course of treatment is two to three times per week for four weeks. Patients who benefit from manual traction should continue with a home cervical traction unit [103].

Traction regimens may be heavy weight-intermittent or light weight-continuous. The neck is flexed 15–20 degrees (i.e., not extended) during traction. In the cervical spine, 10 pounds of force is necessary to counter gravity and 25 pounds of force is needed to achieve separation of posterior vertebral segments. Light weight-continuous home traction is cost-effective and provides greater autonomy to the patient. Pneumatic traction devices afford greater patient comfort, which can increase treatment adherence [51].

Traction is popular among patients with cervical radiculopathy, but it is contraindicated with tumor, infection, fracture, or dislocation [103]. Mechanical traction is widely used to promote cervical immobilization and widen the foraminal openings. Cervical traction may relieve radicular pain from nerve root compression, but it does not improve pain from soft-tissue injury. Hot packs, massage, or electrical stimulation should be applied before traction to relieve pain and relax muscles [67].

IMMOBILIZATION

Immobilization limits neck motion to reduce nerve or soft tissue irritation, and soft cervical collars are the most widely used device. For acute soft-tissue neck injuries, cervical collar use should not exceed three to four consecutive days to avoid risks of losing cervical range of motion and neck strength from muscle disuse and atrophy [51].

In radiculopathy caused by foraminal stenosis, the wide part of the collar is placed posteriorly, with the thin part placed anteriorly to promote neck flexion, discourage extension, and open the intervertebral foramina. Cervical collars can be worn during sleep or distance-driving [51].

In severe cervical spondylosis with evidence of myelopathy, cervical spine immobilization is the mainstay of conservative treatment. Soft cervical collars do not sufficiently limit cervical spine motion and should only be used in daytime. More rigid orthoses adequately immobilize the cervical spine; isometric cervical exercises may help limit loss of muscle tone [67].

PASSIVE ASSISTIVE DEVICES

Passive assistive devices inhibit or prevent movement [8]. Molded cervical pillows can better align the spine during sleep and provide symptom relief for some patients [67].

THERMOTHERAPY

Thermotherapy applies heat or cold to superficial or deep tissue. Superficial thermotherapy applies heat or cold to raise or lower skin tissue temperatures. This approach is indicated for reducing acute pain, edema, muscle spasm, and inflammation, or for promoting stretching/flexibility. Heat packs or hydrotherapy can apply heat, while cold packs or vapocoolant spray can apply cold. Cold and heat packs can be used at home [8,103].

Deep tissue thermotherapy is applied to affect structures beneath the skin surface and includes low-level laser, electrical muscle stimulation, pulsed electromagnetic therapy, and ultrasonic heat [8]. Electrical muscle stimulation is indicated for muscle spasm or atrophy with varying frequencies, from twice daily to once weekly. A home unit should be purchased, if effective. Short-wave diathermy applies an electromagnetic field to soft tissues to reduce muscle guarding, inflammation, or edema, typically two to three times per week for three to five weeks [103].

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION

Evidence Based Practice Recommendation

For patients with chronic neck pain with movement coordination impairments (including WAD), the American Physical Therapy Association asserts that appropriate treatment options are education, TENS, and cervical mobilization plus individualized progressive exercise.

https://www.jospt.org/doi/full/10.2519/jospt.2017.0302

Last Accessed: September 17, 2019

Strength of recommendation/Level of Evidence: C (Weak recommendation based on one or more level III systematic reviews or a preponderance of level IV evidence supports the recommendation, providing minimal evidence of effect)

Indications for TENS therapy in patients with neck pain include muscle spasm, atrophy, and decreased circulation and pain control. Minimal TENS unit parameters should include pulse rate, pulse width, and amplitude modulation. In patients with pain relief using TENS, also consider functional improvement before prescribing for purchase of a home unit [103].

PHYSICAL AND EXERCISE THERAPIES

Functional Restoration Programs

Functional restoration programs assist patients disabled by chronic cervical pain to overcome obstacles to recovery, such as deconditioning, secondary gain, poor motivation, and psychopathology. Patients should receive education on cervical anatomy, biomechanics, pathology, and ergonomics, and develop preventive strategies that protect against further injury during daily activities. These medically directed interdisciplinary programs have been successful in helping workers' compensation patients return to work and in reducing recurrent injury, new surgeries, and healthcare use in patients with chronic cervical pain who successfully complete a program [51].

The McKenzie Approach

For most cervical disk disorders, studies support conservative treatment, such as the McKenzie approach or cervicothoracic stabilization programs combined with aerobic conditioning. The McKenzie system identifies three mechanical syndromes that cause pain and compromise function [51]:

- The postural syndrome: Provokes pain when normal soft tissues are loaded statically at end-range of motion. Treatment aims to correct posture.

- The dysfunction syndrome: Produces pain when the patient attempting full movement mechanically deforms contracted scarred soft tissue. Therapy involves stretching and remodeling of such contracted tissue.

- The derangement syndrome: Produces intermittent pain with certain movements or postures from activity-dependent displacement of intradiskal material. Therapy attempts to correct derangement by promoting activity that centralizes pain.

The McKenzie theory recognizes that patients may demonstrate similar signs and symptoms, but one movement (i.e., cervical extension) may help some patients and aggravate symptoms in others. In McKenzie therapy, treatment individualization plays a key role [51].

Cervicothoracic Stabilization Programs

Cervicothoracic stabilization programs reduce pain, maximize function, and prevent further injury through cervical spine flexibility, postural training, and strengthening [51,103]. Flexibility restoration prevents further repetitive microtrauma resulting from poor movement patterning. Soft tissue or joint restriction that inhibits range of motion is treated, and range of motion is restored through spine and soft-tissue mobilization, passive range of motion, self-stretching, and correct posturing.

Postural training in spinal stabilization uses mirrors and therapist feedback to maintain neutral spine and correct posture during daily activities. Patients learn whole-body movements while maintaining a stabilized spine, and progress to controlled movement of the spine that approximates normal biomechanical motions without creating undue vertebral stress.

Cervicothoracic stabilization requires strengthening and coordination of neck, shoulder, and scapular muscles, as well as training of the lumbar spine and lower extremities to provide a foundation for the cervicothoracic spine. Stabilization exercises proceed systematically from simple to complex. Isometric and isotonic resistive exercises employ elastic bands, weight machines, and free weights. Such conditioning distributes forces away from the cervical spine. Exercise repetition ultimately encodes an engram that commands immediate, automatic cervicothoracic stabilization during everyday activity. Proprioceptive skills are used during strengthening exercises to facilitate stable, safe, and pain-free cervical posture during strenuous activity.

Neuromuscular Re-Education

Neuromuscular re-education and movement training involves stabilizing and mobilizing muscles, proper sequencing, and optimal biomechanical motion patterns for daily tasks and activities. Tasks are broken down into their component single-joint movement patterns and perfected with proper alignment, breathing, and muscle stabilization in non-weight-bearing postures using manual or mechanical assistance. After single-joint patterns are mastered without symptoms, the training complexity increases, with multi-joint movement, non-linear motion (circular or diagonal), weight-bearing postures, proprioceptive challenges (e.g., eyes closed, unstable surfaces), progressive resistance, and/or variable speeds and durations. The end goal is to transition the patient from movement incompetence to a state of automatic movement competence [213]. Directional exercises are used in pain-generators that show "directional preference" to apply beneficial mechanical loads that correct the abnormality and avoid loading in the direction of vulnerability [213].

In cervical myofascial pain, the goal of physical therapy is to restore balance between muscles working as a functional unit, accomplished using cervical stretch and stabilization, myofascial release techniques, massage, and postural retraining [57].

Strengthening Exercise

General exercise is defined as purposeful physical activity involving repetitive exercises that incorporate multiple muscle groups [214]. In contrast, therapeutic exercise programs should be specific to the injury and address general functional deficits as identified in the diagnosis and clinical assessment. Common specific approaches include strengthening, stretching/range of motion, and flexibility training [8].

Many patients with spine-related symptoms and functional deficits lose strength in specific muscles or muscle groups from neurologic compromise, disuse, and deconditioning. Strength training rehabilitation is used for restoring muscle loss and reversing changes, and for easing recurrent spine-related symptoms in patients with pre-episode deficits. This process can take many months of effort. In the early phases, most gains are in learning and neuromuscular adaptation, which lead to better efficiency and economy of movement [213].

Strengthening is initiated under trained supervision and is later self-directed. Strength training is performed two to five days per week, with any number of movement patterns performed 8 to 20 times over two to four sets. The loads, intensity, volume, and duration used for desired outcomes vary greatly. Equipment that can assist in strengthening includes barbells and dumbbells, exercise machines, medicine balls, and elastic cords [213].

Stretching

Lack of flexibility in certain muscle groups is linked to spine-related symptoms. A causal relationship is not established, but improving the flexibility of muscle, tendon, and connective tissue elements may enhance recovery and reduce focal areas of tension and stress. Stretching involves techniques ranging from static, passive, low-load, long-duration strategies applied by a therapist, to contract-relax tactics that enhance muscle reception to stretching [213].

Patients should continue exercise and stretching therapies at home as an extension of the treatment process to maintain improvement levels. Follow-up visits to reinforce and monitor progress and proper technique are recommended. Home exercise can include exercise with or without mechanical assistance or resistance and functional activities with assistive devices [103].

Evidence of Efficacy

Strengthening tailored to individual patients with neck pain is superior to generalized strengthening [213]. A 2016 practice guideline stated that supervised qigong, Iyengar yoga, and programs that combined strengthening, range of motion, and flexibility were effective in persistent neck pain; exercise alone had minimal benefit [215].

Exercise combined with any blend of manipulation, mobilization, muscle energy, and stretching is more effective in reducing neck pain and disability than any single approach used alone [103]. A systematic review of exercise efficacy in neck pain disorders concluded that use of strengthening and endurance exercises for the cervico-scapulothoracic region and shoulder may be beneficial in reducing pain and improving function; and that stretching exercises alone are not beneficial [216]. In acute radiculopathy, cervical stretch, strengthening, and stabilization exercises show a small benefit in pain reduction. For chronic neck pain, the authors identified five modalities with some evidence of efficacy for neck pain [216]:

- Cervico-scapulothoracic and upper extremity strength training: Moderate to large improvements in pain at short-term follow-up

- Scapulothoracic and upper extremity endurance training: Smaller beneficial effect on pain at short-term follow-up

- Combined cervical, shoulder, and scapulothoracic strengthening and stretching exercises: Smaller to large-magnitude benefit on pain from post-treatment to long-term follow-up, and a medium magnitude of effect on improved function at short-term follow-up

- Cervico-scapulothoracic strengthening/stabilization exercises: Improved pain and function at intermediate-term follow-up

- Mindfulness exercises and qigong: Minimally improved function at short term

The study also determined that weak evidence suggested minimal-to-no short-term benefit on pain or function with breathing exercises, general fitness training, stretching alone, and feedback exercises with pattern synchronization. Very weak evidence suggests neuromuscular eye-neck coordination and proprioceptive exercises may improve pain and function short-term [216].

In patients with chronic cervicogenic headache, static-dynamic cervico-scapulothoracic strengthening/endurance exercises (including pressure biofeedback) were found to improve pain, function, and global perceived effect at post-treatment and probably at long-term follow-up [216]. Low-grade evidence supports sustained natural apophyseal glide exercises in this patient population.

Two randomized controlled trials compared the outcomes of patients with chronic nonspecific neck pain after four weeks of stabilization exercises alone or combined with a manual therapy. In the first trial, patients receiving cervical and scapulothoracic stabilization exercises plus manual therapy showed significantly greater improvements in pressure pain threshold, disability, pain intensity at night, cervical rotation motion, and quality of life than patients receiving exercises alone [217].

The second trial compared cervical and scapulothoracic stabilization exercises alone or plus connective tissue massage. Both decreased pain intensity and anxiety levels, but combination therapy led to significantly greater improvements in pain intensity at night, pressure pain threshold, state anxiety, and mental health than exercises alone [218]. At six-month follow-up, patients with chronic nonspecific neck pain showed significantly greater reductions in pain and disability from global postural re-education than manual therapy (nine 1-hour sessions for both) [219].

The Alexander technique is an educational approach to modify dysfunctional posture, movement, and thinking patterns associated with musculoskeletal disorders. In patients with chronic nonspecific neck pain, the Alexander technique did not differ from local heat application in pain reduction after both were delivered weekly for five weeks [220].

Consensus indicates that exercise therapy is beneficial for chronic pain, but the lack of endogenous analgesia in some chronic pain disorders should not be ignored and clinicians should account for this when treating patients with chronic pain [221]. General exercise is frequently recommended for WADs. In contrast to other musculoskeletal pain conditions, a review of high-quality studies concluded general exercise does not reduce pain or disability in patients with WAD [214].

Exercise-induced hypoalgesia describes the desired effect of reduced pain sensitivity following exercise. The effect of acute exercise on pain sensitivity in chronic pain conditions is controversial, because hypoalgesia, unchanged pain sensitivity, and hyperalgesia (impaired exercise-induced hypoalgesia) have all been reported. Evidence suggests impaired exercise-induced hypoalgesia is evident in WAD following aerobic exercise [222].

In patients with chronic WAD, exercise-induced hypoalgesia responses to isometric (3 minute wall squat) or aerobic (30 minute bicycling) exercise were compared by recording neck and leg pressure pain thresholds before and after exercises. Pressure pain threshold increases were found at both areas after isometric, but not aerobic, exercise. Isometric exercises directed at non-painful muscles may reduce local and remote pain sensitivity in patients with chronic WAD and mild-to-moderate neck pain and disability [223].

In patients with chronic neck pain, exercise-induced hypoalgesia after isometric exercises seems less dependent on exercise intensity than aerobic exercises, which may increase adherence. Isometric exercise has potential as a rehabilitation component to target central mechanisms of pain [222].

PSYCHOSOCIAL INTERVENTIONS

People with chronic pain are not passive; they actively attempt to change the causes of pain and their behavior in response to pain. For many patients, such change without therapeutic help is unachievable, and repeated misdirected efforts to resolve their pain problem can drive a cycle of pain, depression, and disability. Psychologic interventions are designed to promote adaptive pain management and reduce the consequences [224]. As such, psychosocial interventions are used in select patients with acute or chronic pain. Examples include cognitive-behavioral therapy (CBT), relaxation training, mindfulness training, and sleep hygiene training.

Cognitive-Behavioral Therapy

CBT is widely used in the treatment of pain-related functional impairments and disabilities. In general, CBT is a skills-training intervention that emphasizes identifying and changing maladaptive cognitions, emotions, and behaviors, and can be delivered in individual or group-based sessions [81].

In fear-avoidance, CBT targets pain catastrophizing and avoidant beliefs (maladaptive cognitions), fear (a maladaptive emotion), and avoidant (maladaptive) behaviors by helping the patient develop and apply coping strategies that enhance problem-solving for successfully confronting and self-managing health-related threats posed by pain. Core elements of this approach are [81,225]:

- Graded homework assignments

- Cognitive restructuring (i.e., learning how to challenge maladaptive cognitions)

- Relaxation training (e.g., diaphragmatic breathing, progressive muscle relaxation, imagery)

- Time-based activity pacing (paced by time and not task completion)

- Extinguishing pain behaviors (i.e., verbal and nonverbal expressions of pain)

Other strategies taught to patients include distraction (diverting attention away from pain), reinterpretation (changing thoughts about pain), dissociation (separating pain from other sensations), coping self-statements (affirming self-messages), and emotional disclosure (expressive writing) [225].

CBT is widely endorsed for patients with subacute or chronic spinal pain and comorbid psychosocial conditions. CBT can lead to long-term improvements in pain intensity, disability, quality of life, pain-related coping, depressed mood, and health care-seeking behaviors. The favorable effects of CBT on pain outcomes are supported by functional imaging studies [81,226].

Two systematic reviews found inconsistent evidence of pain reduction with CBT. In chronic neck pain, changes in pain and disability were only found when CBT was compared with no treatment, and no effects on kinesiophobia were found. In subacute neck pain, CBT showed benefit in pain relief but not disability compared with other interventions, but the size of these effects was not clinically meaningful. These conclusions were stated as based on low-quality evidence, which might change with new data [227].

A broader review of psychologic interventions evaluated recent-onset and persistent neck pain separately [228]. In persistent (three to six months) neck pain with or without radiculopathy, researchers found no clear evidence supporting CBT or relaxation training for reducing pain intensity or disability; however, they did find that Jyoti (candle or light) meditation may help reduce neck pain intensity and bothersomeness. In persistent post-whiplash pain, evidence to support the efficacy of biofeedback or relaxation training was not found, and evidence for using CBT was conflicting. Adding progressive goal attainment to functional restoration physiotherapy may benefit these patients.

In recent-onset (less than three months) neck or post-whiplash pain, there was no evidence for or against using psychologic interventions. The limited evidence support for psychologic interventions may reflect interventions that are ineffective or poorly conceptualized or implemented [228].

In another study, a physiotherapist-led cognitive-behavioral intervention was effective in modifying cognitive risk factors in patients with chronic neck pain. These patients showed larger increases in functional self-efficacy, greater reductions in pain intensity and pain-related fear, and a greater proportion attained clinically meaningful reductions in pain and disability compared with patients randomized to a progressive neck exercise program. Both were delivered in group format [229].

ALTERNATIVE AND COMPLEMENTARY APPROACHES

Acupuncture

Acupuncture therapy is one of most popular complementary approaches and has become a widely accepted treatment for diverse pain-related conditions [230]. Acupuncture therapy involves insertion of needles into the skin and underlying tissues at specific sites, known as acupoints, to reduce pain or induce anesthesia. Needles may be manipulated manually or through electrical stimulation [2,8].

The persistence of therapeutic effects following a course of acupuncture was evaluated in a meta-analysis of 29 randomized controlled trials of diverse chronic pain. Depending on the control group (no-acupuncture versus sham acupuncture), 50% to 90% of acupuncture benefit was sustained 12 months after treatment and did not seem to decrease importantly in chronic pain [231]. Patients can generally be reassured that treatment effects persist. Questions of acupuncture cost-effectiveness can take these findings into account.

Acupuncture is not without risks. Deaths and serious nonfatal complications of acupuncture are reported, with pneumothorax the most frequent fatal and non-fatal cause. All deaths were avoidable with proper acupuncture technique and sufficient anatomic knowledge. Most reports originated in East Asia, but some came from the United States and Western Europe [212].

Yoga, Qigong, and Tai Chi

Iyengar yoga involves a range of classical yoga poses adapted to patients with neck pain with the use of supportive props. Emphasis is placed on muscle strengthening, stretching, joint mobility, and proper posture [8]. A systematic review found evidence for significant short-term benefits in neck pain intensity, neck pain-related disability, quality of life, and mood, suggesting that yoga might be a good treatment option in chronic nonspecific neck pain [232].

With origins in traditional Chinese medicine, qigong and tai chi are gentle, focused exercises for the mind and body that aim to increase and restore the flow of qi energy and encourage healing [8]. In one study, patients with chronic nonspecific neck pain were randomized to 12 weeks of group tai chi, sessions of conventional neck exercises, or to a wait-list control group. Tai chi and exercise intervention did not differ, and both significantly improved pain on movement, functional disability, and quality of life compared with the wait-list group [233].

Of 89 patients with chronic neck pain randomized to 8 weeks of jyoti meditation or self-care exercise program, meditation training significantly reduced pain and pain-related bothersomeness compared with the exercise group. Researchers suggest that mediation may support patients with chronic pain in pain reduction and pain coping [234].

INTERVENTIONAL AND SURGICAL THERAPIES

Interventional modalities involve injection or ablation approaches in the treatment of spinal pain. They are considered minimally invasive, in contrast to spinal surgery, which is invasive. Cervical epidural, spinal nerve root, facet joint, and sympathetic injections serve diagnostic and therapeutic roles. These procedures can be instrumental in identifying the anatomic pain generator (e.g., nerve root, facet joint) and providing aggressive treatment [51].

Cervical Epidural Injections

For cervical radiculopathy, epidural steroid injections place a corticosteroid and anesthetic (lidocaine or bupivacaine) into the epidural space (interlaminar) or along the nerve root (transforaminal) under radiographic guidance. Epidural steroid injections are thought to reduce pain by interrupting the inflammatory cascade, blocking C-fiber transmission, increasing microcirculation around ischemic areas, and/or modulating pain transmission in the dorsal horn [235,236].

Rare but catastrophic neurovascular complications following cervical transforaminal steroid injections have resulted from particulate matter in corticosteroid preparations. Only the nonparticulate steroid dexamethasone should be used in cervical transforaminal injections. All epidural steroid injections should be performed under radiographic guidance to avoid serious CNS injuries [237].

Epidural steroid injections can induce dose-dependent suppression of the hypothalamic-pituitary-adrenal axis lasting one to three months. Steroids provide no additional benefit to local anesthetic (bupivacaine) alone in pain, function, or disability. Considering local and systemic risks versus negligible benefit, adding a corticosteroid to local anesthetic is not recommended. Aside from cervical radiculopathy, epidural injections are not indicated for other neck pain conditions [2,238,239].

Cervical Facet Joint Interventions

Facet joint interventions identify and treat facet-mediated pain. To identify facet joints as the pain source, inter-articular injections of local anesthetic are placed into facet joints or along their innervating nerve fibers (sensory medial branch). A separate comparative block is performed on a different date to confirm the level of involvement and reduce placebo response. Pain relief from both medial branch nerve blocks confirms facet origin, and radiofrequency ablation is indicated for extended pain control [50,240].

Radiofrequency neurotomy applies a radiofrequency current with heat sufficient to ablate the afferent nerve supply of the facet joint. Denervating these joints is effective in relieving pain and restoring function in these patients. Nerve regeneration occurs 9 to 12 months post-radiofrequency neurotomy, but repeat radiofrequency neurotomy is usually successful and longer-lasting [103,241]. Continuous radiofrequency neurotomy is the preferred method; pulsed radiofrequency neurotomy should not be used, as it may result in incomplete denervation [50]. Precise positioning of the radiofrequency probe with fluoroscopic guidance is required [103].

A systematic review of cervical medial branch thermal radiofrequency neurotomy found most patients were pain-free at six months and more than 33% reported being free of pain at one year [242]. The evidence of effectiveness was rated as high quality. Side effects were reported in 12 studies; most were minor and temporary. Adhering to International Spine Intervention Society guidelines on fluoroscopic-guided cervical medial branch thermal radiofrequency neurotomy was stressed; when performed as described, cervical medial branch thermal radiofrequency neurotomy is effective for resolving chronic facet joint pain and carries only minor risks [242]. Repeat procedures may lead to atrophy of supportive spinal musculature from denervation of sensory and motor nerve inputs. Focused physical therapy may mitigate this risk [103].

Trigger Point Injections

Trigger point injection with a local anesthetic (with or without corticosteroid) is widely used in treating myofascial pain. With trigger point injection, the trigger point in the taut muscle band is palpated, slightly stretched to prevent it from moving, and injected. The needle is redirected in the area to ensure injectate distribution. The fast-in/fast-out method is the most successful in eliciting a local twitch response (which helps confirm diagnosis) and reducing myofascial pain [57]. Sedation is not needed for trigger point injection [103]. The efficacy of this approach is enhanced when immediately followed by a myofascial intervention [57,103].

There are two main approaches to trigger point injection. The first is the stretch and spray technique, in which areas around the trigger point and referred pain are stretched using parallel strokes in the same direction, and a vapocoolant spray is applied. A variant involves spraying first, then stretching, and repeating the spraying. The second is ischemic compression (myotherapy). With this approach, the affected muscle is placed in a fully stretched position and sustained pressure by thumb press is applied on the trigger point, with pressure gradually increased as the pain lessens. Specific soft tissue mobilization or physical modalities may be used with either approach.

Rare trigger point injection complications include infection, pneumothorax, anaphylaxis, neurapraxia, and neuropathy. Corticosteroid injection carries a risk of local myopathy. Severe pain on trigger point injection suggests an intraneural injection, and the needle should be immediately repositioned [103].

Intradiskal Interventions

A variety of different approaches have been used to address diskogenic pain. In the treatment of cervical diskogenic pain, thermal annuloplasty applies heat along the annulus fibrosus to denervate the annulus and/or reconfigure the collagen structure of the disk [243]. Coblation nucleoplasty applies bipolar radiofrequency current to decrease the volume of disk tissue. Intradiskal electrothermal therapy places an electrode or catheter into the annulus of the disk and applies electrothermal energy to denervate the annulus. Percutaneous intradiskal radiofrequency places an electrode or catheter into a disk to apply alternating radiofrequency current.

Diskography is used for identifying the disk as the axial pain source by placing contrast dye into the intervertebral disk under fluoroscopy before CT imaging. The validity of diskography remains controversial, and there is concern that the procedure may accelerate disk degeneration [244].

Disk Decompression

In treating radicular pain secondary to intervertebral disk herniation, percutaneous disk decompression is used to remove a portion of disk material in order to reduce intradiskal pressure and decompress the involved nerve [245].

Vertebroplasty consists of injecting polymethyl methacrylate cement into the vertebral body. Kyphoplasty involves inflating a balloon within the vertebral body before polymethyl methacrylate is injected. The proposed mechanism is the combination of thermal necrosis and chemotoxicity of intraosseous pain receptors [246]. Vertebroplasty did not show benefit over sham or placebo interventions in two large randomized trials [247].

Botulinum Toxin A Injections

Botulinum toxin A reduces muscular contractions and spasm by inhibiting acetylcholine release into the neuromuscular junction. Compared with placebo, trigger point injections of botulinum toxin A into painful muscles significantly improved pain scores, reduced headaches per week, and improved general activity and sleep after 12 weeks in patients with severe shoulder girdle and chronic cervical myofascial pain [248]. Trigger point injections with botulinum toxin A for chronic cervical myofascial pain are now considered supported by the available evidence [64,249]. Side effects with cervical botulinum toxin A injection include transient dysphagia, neck weakness, dry mouth, and vocal hoarseness [103].

Botulinum toxin A may also be effective in relieving primary headache disorders, trigeminal neuralgia, chronic neuropathic pain, and nociceptive and osteoarticular pain. The favorable side effect profile and long-lasting pain relief after a single injection, when effective, makes botulinum toxin A an attractive treatment option. As neck pain therapy, optimal dosing and patient selection need clarification [65].

Cervical Spine Surgery

Cervical spine surgery is indicated when natural history and prognosis with surgical treatment is better than with non-operative treatment. Indications include progressive neurologic deficits, compression of the cervical nerve root and/or spinal cord, or intractable pain. Cervical spine surgical outcomes are most favorable for radicular pain, spinal instability, progressive myelopathy, or upper extremity weakness [51,67,103]. Detailed discussion of cervical spine surgeries is beyond the scope of this course.

CHRONIC REFRACTORY NECK PAIN

In patients with chronic neck pain refractory to standard therapies, established therapeutic options include stimulation of spinal dorsal horn columns to block spinal pain transmission, or intrathecal drug delivery systems to deliver opioids, with or without other medications, to maximize effectiveness and reduce systemic side effects [244].

6. CONCLUSION

A significant proportion of acute neck pain resolves with conservative management. However, chronic neck pain is substantially more difficult to treat and can develop from an acute neck injury or insidiously over time. Long-term changes in the CNS maintain chronic pain. Anatomic, biochemical, and functional abnormalities develop in the brain and spinal cord that amplify pain perception and perpetuate pain.

Pharmacologic and nonpharmacologic therapies have shown disappointing long-term outcomes in chronic pain. Pharmacotherapy focusing on tissue pathology has contributed to inadequate pain reduction. As such, pain mechanism identification and targeting is increasingly stressed, and combining pharmacotherapies that target different pain mechanisms is also emphasized. A substantial volume of new research is changing chronic pain assessment and treatment, and its uptake into clinical practice brings optimism for improving pain and functioning of patients with chronic neck pain in the near future.

Works Cited

1. Murray CJ, Atkinson C, Bhalla K, et al. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310(6):591-608.

2. Cohen SP. Epidemiology, diagnosis, and treatment of neck pain. Mayo Clin Proc. 2015;90(2):284-299.

3. Webster LR. Pills, policies, and predicaments: the unintended consequences of a health care system's policy towards opioids. Pain Med. 2013;14(10):1439-1440.

4. Billeci D, Coluzzi F. Tapentadol extended release for the management of chronic neck pain. J Pain Res. 2017;10:495-505.

5. Hoy DG, Protani M, De R, Buchbinder R. The epidemiology of neck pain. Best Pract Res Clin Rheumatol. 2010;24(6):783-792.

6. Hill J, Lewis M, Papageorgiou AC, Dziedzic K, Croft P. Predicting persistent neck pain: a 1-year follow-up of a population cohort. Spine. 2004;29(15):1648-1654.

7. Teichtahl AJ, McColl G. An approach to neck pain for the family physician. Aust Fam Physician. 2013;42(11):774-777.

8. Côté P, Wong JJ, Sutton D, et al. Management of neck pain and associated disorders: a clinical practice guideline from the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Eur Spine J. 2016;25(7):2000-2022.

9. Côté P, van der Velde G, Cassidy JD, et al. The burden and determinants of neck pain in workers: results of the bone and joint decade 2000–2010 task force on neck pain and its associated disorders. Spine. 2008;33(4):S60-74.

10. Nilsen TI, Holtermann A, Mork PJ. Physical exercise, body mass index, and risk of chronic pain in the low back and neck/shoulders: longitudinal date from the Nord-Trondelag health study. Am J Epidemiol. 2011;174(3):267-273.

11. Kääriä S, Laaksonen M, Rahkonen O, Lahelma E, Leino-Arjas P. Risk factors of chronic neck pain: a prospective study among middle-aged employees. Eur J Pain. 2012;16(6):911-920.

12. Vincent HK, Adams MC, Vincent KR, Hurley RW. Musculoskeletal pain, fear avoidance behaviors, and functional decline in obesity: potential interventions to manage pain and maintain function. Reg Anesth Pain Med. 2013;38(6):481-491.

13. Freeman MD, Croft AC, Nicodemus CN, Centeno CJ, Elkins WL. Significant spinal injury resulting from low-level accelerations: a case series of roller coaster injuries. Arch Phys Med Rehabil. 2005;86(11):2126-2130.

14. Binder AI. Cervical spondylosis and neck pain. BMJ. 2007;334(7592):527-531.

15. Ritchie C, Ehrlich C, Sterling M. Living with ongoing whiplash associated disorders: a qualitative study of individual perceptions and experiences. BMC Musculoskelet Disord. 2017;18(1):531.

16. American Academy of Physical Medicine and Rehabilitation. Cervical Whiplash. Available at https://www.aapmr.org/about-physiatry/conditions-treatments/musculoskeletal-medicine/cervical-whiplash. Last accessed September 16, 2019.

17. Castro WH, Schilgen M, Meyer S, Weber M, Peuker C, Wortler K. Do "whiplash injuries" occur in low-speed rear impacts?Eur Spine J. 1997;6(6):366-375.

18. Bunketorp OB, Elisson LK. Cervical status after neck sprains in frontal and rear-end car impacts. Injury. 2012;43(4):423-430.

19. Patient Platform Limited. Whiplash and Cervical Spine Injury. Available at https://patient.info/doctor/whiplash-and-cervical-spine-injury. Last accessed September 16, 2019.

20. Teasell RW, McClure JA, Walton D, et al. A research synthesis of therapeutic interventions for whiplash-associated disorder (WAD): part 2—interventions for acute WAD. Pain Res Manag. 2010;15(5):295-304.

21. Freeman MD, Croft AC, Rossignol AM, Centeno CJ, Elkins WL. Chronic neck pain and whiplash: a case-control study of the relationship between acute whiplash injuries and chronic neck pain. Pain Res Manag. 2006;11(2):79-83.

22. American Academy of Physical Medicine and Rehabilitation. Cervical Radiculopathy. Available at https://www.aapmr.org/about-physiatry/conditions-treatments/musculoskeletal-medicine/cervical-radiculopathy. Last accessed September 16, 2019.

23. Polston DW. Cervical radiculopathy. Neurol Clin. 2007;25(2):373-385.

24. Carette S, Phil M, Fehlings MG. Cervical radiculopathy. N Engl J Med. 2005;353:392-399.

25. Hush JM, Lin CC, Michaleff ZA, Verhagen A, Refshauge KM. Prognosis of acute idiopathic neck pain is poor: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2011;92(5):824-829.

26. Pengel LH, Herbert RD, Maher CG, Refshauge KM. Acute low back pain: systematic review of its prognosis. BMJ. 2003;327(7410):323.

27. Henschke N, Maher CG, Refshauge KM, et al. Prognosis in patients with recent onset low back pain in Australian primary care: inception cohort study. BMJ. 2008;337:a171.

28. Anstey R, Kongsted A, Kamper S, Hancock MJ. Are people with whiplash-associated neck pain different from people with nonspecific neck pain? J Orthrop Sports Phys Ther. 2016;46(10):894-901.

29. Blanpied PR, Gross AR, Elliott JM, et al. Neck pain: revision 2017. J Orthop Sports Phys Ther. 2017;47(7):A1-A83.

30. Sterling M, Hendrikz J, Kenardy J. Compensation claim lodgement and health outcome developmental trajectories following whiplash injury: a prospective study. Pain. 2010;150(1):22-28.

31. Sarrami P, Armstrong E, Naylor JM, Harris IA. Factors predicting outcome in whiplash injury: a systematic meta-review of prognostic factors. J Orthop Traumatol. 2017;18(1):9-16.

32. McLean SA, Ulirsch JC, Slade GD, et al. Incidence and predictors of neck and widespread pain after motor vehicle collision among US litigants and nonlitigants. Pain. 2014;155(2):309-321.

33. Spearing NM, Connelly LB, Nghiem HS, Pobereskin L. Research on injury compensation and health outcomes: ignoring the problem of reverse causality led to a biased conclusion. J Clin Epidemiol. 2012;65(11):1219-1226.

34. Worsfold C. When range of motion is not enough: towards an evidence-based approach to medico-legal reporting in whiplash injury. J Forensic Leg Med. 2014;25:95-99.

35. Minamide A, Yoshida M, Maio K. The natural clinical course of lumbar spinal stenosis: a longitudinal cohort study over a minimum of 10 years. J Orthop Sci. 2013;18(5):693-698.

36. Micankova Adamova B, Vohanka S, Dusek L, Jarkovsky J, Bednarik J. Prediction of long-term clinical outcome in patients with lumbar spinal stenosis. Eur Spine J. 2012;21(12):2611-2619.

37. Hsu E, Atanelov L, Plunkett AR, Chai N, Chen Y, Cohen SP. Epidural lysis of adhesions for failed back surgery and spinal stenosis: factors associated with treatment outcome. Anesth Analg. 2014;118(1):215-224.

38. Costa Lda C, Maher CG, McAuley JH, et al. Prognosis for patients with chronic low back pain: inception cohort study. BMJ. 2009;339:b3829.

39. Chiarotto A, Fortunato S, Falla D. Predictors of outcome following a short multimodal rehabilitation program for patients with whiplash associated disorders. Eur J Phys Rehabil Med. 2015;51(2):133-141.

40. Li Y, Peng B. Pathogenesis, diagnosis, and treatment of cervical vertigo. Pain Physician. 2015;18(4):E583-E595.

41. Freeman MD. Cervical Sprain and Strain. Available at https://emedicine.medscape.com/article/306176-overview. Last accessed September 16, 2019.

42. Abboud WA, Hassin-Baer S, Joachim M, Givol N, Yahalom R. Localized myofascial pain responds better than referring myofascial pain to botulinum toxin injections. Int J Oral Maxillofac Surg. 2017;46(11):1417-1423.

43. Häggman-Henrikson B, Rezvani M, List T. Prevalence of whiplash trauma in TMD patients: a systematic review. J Oral Rehabil. 2014;41(1):59-68.

44. Häggman-Henrikson B, List T, Westergren HT, Axelsson SH. Temporomandibular disorder pain after whiplash trauma: a systematic review. J Orofac Pain. 2013;27(3):217-226.

45. Landzberg G, El-Rabbany M, Klasser GD, Epstein JB. Temporomandibular disorders and whiplash injury: a narrative review. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;124(2):e37-e46.

46. Windsor RE. Cervical Spine Anatomy. Available at https://emedicine.medscape.com/article/1948797-overview. Last accessed September 16, 2019.

47. Wong JJ, Côté P, Ameis A, et al. Are non-steroidal anti-inflammatory drugs effective for the management of neck pain and associated disorders, whiplash-associated disorders, or non-specific low back pain? A systematic review of systematic reviews by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Eur Spine J. 2016;25(1):34-61.

48. Bokshan SL, DePasse JM, Eltorai AE, Paxton SE, Green A, Daniels AH. An evidence-based approach to differentiating the cause of shoulder and cervical spine pain. Am J Med. 2016;129(9):913-918.

49. Everett C, Bauernfeind M, Essaff D. Cervical and Thoracic Zygapophyseal Joint Arthropathy. Available at https://now.aapmr.org/cervical-and-thoracic-zygapophsial-joint-arthropathy. Last accessed September 16, 2019.

50. Nance PW, Adcock EM. Facet Mediated Pain. Available at https://now.aapmr.org/facet-mediated-pain. Last accessed September 16, 2019.

51. Furman MB. Cervical Disc Disease. Available at https://emedicine.medscape.com/article/305720-overview. Last accessed September 16, 2019.

52. Czervionke LF, Fenton DS. Fat-saturated MR imaging in the detection of inflammatory facet arthropathy (facet synovitis) in the lumbar spine. Pain Med. 2008;9(4):400-406.

53. Mehnert MJ, Freedman MK, Surrey DE. Cervicogenic Headache. Available at https://now.aapmr.org/cervicogenic-headache. Last accessed September 16, 2019.

54. Bogduk N, Govind J. Cervicogenic headache: an assessment of the evidence on clinical diagnosis, invasive tests, and treatment. Lancet Neurol. 2009;8(10):959-968.

55. Sjaastad O, Fredriksen TA, Pfaffenrath V. Cervicogenic headache: diagnostic criteria. The Cervicogenic Headache International Study Group. Headache. 1998;38(6):442-445.

56. Moley PJ. Evaluation of Neck and Back Pain. Available at https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/neck-and-back-pain/evaluation-of-neck-and-back-pain. Last accessed September 16, 2019.

57. Cooper G. Cervical Myofascial Pain. Available at https://emedicine.medscape.com/article/305937-overview. Last accessed September 16, 2019.

58. Rhee JM, Yoon T, Riew KD. Cervical radiculopathy. J Am Acad Orthop Surg. 2007;15(8):486-494.

59. American Academy of Physical Medicine and Rehabilitation. Cervical Stenosis. Available at https://www.aapmr.org/about-physiatry/conditions-treatments/musculoskeletal-medicine/cervical-stenosis. Last accessed September 16, 2019.

60. American Academy of Physical Medicine and Rehabilitation. Cervical Spondylotic Myelopathy. Available at https://www.aapmr.org/about-physiatry/conditions-treatments/rehabilitation-of-central-nervous-system-disorders/cervical-spondylotic-myelopathy. Last accessed September 16, 2019.

61. Hirpara KM, Butler JS, Dolan RT, O'Byrne JM, Poynton AR. Nonoperative modalities to treat symptomatic cervical spondylosis. Adv Orthop. 2012;2012:294857.

62. State Insurance Regulatory Authority. Guidelines for the Management of Acute Whiplash Associated Disorders for Health Professionals. Available at https://www.sira.nsw.gov.au/resources-library/motor-accident-resources/publications/for-professionals/whiplash-resources/SIRA08104-Whiplash-Guidelines-1117-396479.pdf. Last accessed September 16, 2019.

63. Kaneoka K, Ono K, Inami S, Hayashi K. Motion analysis of cervical vertebrae during whiplash loading. Spine. 1999;24(8):763-769.

64. Zhou JY, Wang D. An update on botulinum toxin A injections of trigger points for myofascial pain. Curr Pain Headache Rep. 2014;18(1):386.

65. Sandrini G, De Icco R, Tassorelli C, Smania N, Tamburin S. Botulinum neurotoxin type A for the treatment of pain: not just in migraine and trigeminal neuralgia. J Headache Pain. 2017;18(1):38.

66. Barnsley L, Lord SM, Wallis BJ, Bogduk N. The prevalence of chronic cervical zygapophysial joint pain after whiplash. Spine. 1995;20(1):20-25.

67. Al-Shatoury HAH. Cervical Spondylosis. Available at https://emedicine.medscape.com/article/306036-overview. Last accessed September 16, 2019.

68. Rubin M. Cervical Spondylosis and Spondylotic Cervical Myelopathy. Available at https://www.merckmanuals.com/professional/neurologic-disorders/spinal-cord-disorders/cervical-spondylosis-and-spondylotic-cervical-myelopathy. Last accessed September 16, 2019.

69. Baron R, Binder A, Attal N, Casale R, Dickenson AH, Treede RD. Neuropathic low back pain in clinical practice. Eur J Pain. 2016;20(6):861-873.

70. Fornasari D. Pharmacotherapy for neuropathic pain: a review. Pain Ther. 2017;6(1):25-33.

71. Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002.

72. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations. Lancet Neurol. 2015;14(2):162-173.

73. Binder A, Baron R. The pharmacological therapy of chronic neuropathic pain. Dtsch Arztebl Int. 2016;113(37):616-625.

74. Baron R, Hans G, Dickenson AH. Peripheral input and its importance for central sensitization. Ann Neurol. 2013;74(5):630-636.

75. Bannister K, Dickenson AH. What the brain tells the spinal cord. Pain. 2016;157(10):2148-2151.

76. Yarnitsky D. Role of endogenous pain modulation in chronic pain mechanisms and treatment. Pain. 2015;156(Suppl 1):S24-S31.

77. Davis CG. Mechanisms of chronic pain from whiplash injury. J Forensic Leg Med. 2013;20(2):74-85.

78. Worley SL. New directions in the treatment of chronic pain. PT. 2016;41(2):107-114.

79. Vlaeyen JW, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain. 2000;85(3):317-332.

80. Linton SJ, Shaw WS. Impact of psychological factors in the experience of pain. Phys Ther. 2011;91(5):700-711.

81. Hooten WM. Chronic pain and mental health disorders: shared neural mechanisms, epidemiology, and treatment. Mayo Clin Proc. 2016;91(7):955-970.

82. Sterling M, Hendrikz J, Kenardy J, et al. Assessment and validation of prognostic models for poor functional recovery 12 months after whiplash injury: a multicenter inception cohort study. Pain. 2012;153(8):1727-1734.

83. Baker DG, Nievergelt CM, C'Connor DT. Biomarkers of PTSD: neuropeptides and immune signaling. Neuropharmacology. 2012;62(2):663-673.

84. Edwards RR, Kronfli T, Haythornthwaite JA, Smith MT, McGuire L, Page GG. Association of catastrophizing with interleukin-6 responses to acute pain. Pain. 2008;140(1):135-144.

85. Sterling M, Elliott JM, Cabot PJ. The course of serum inflammatory biomarkers following whiplash injury and their relationship to sensory and muscle measures: a longitudinal cohort study. PLoS One. 2013;8(10):e77903.

86. Carriere JS, Thibault P, Adams H, Milioto M, Ditto B, Sullivan MJL. Expectancies mediate the relationship between perceived injustice and return to work following whiplash injury: a 1-year prospective study. Eur J Pain. 2017;21(7):1234-1242.

87. Fung K, Alden LE. Once hurt, twice shy: social pain contributes to social anxiety. Emotion. 2017;17(2):231-239.

88. McWilliams LA. Adult attachment insecurity is positively associated with medically unexplained chronic pain. Eur J Pain. 2017;21(8):1378-1383.

89. Cruccu G, Truini A. Neuropathic pain: the scope of the problem. Pain Ther. 2017;6(1):1-3.

90. Kosek E, Cohan M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain. 2016;157(7):1382-1386.

91. Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Washington, DC: International Association for the Study of Pain; 1994.

92. Jensen TS, Baron R, Haanpaa M, et al. A new definition of neuropathic pain. Pain. 2011;152(10):2204-2205.

93. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22(10):1911-1920.

94. Attal N, Perrot S, Fermanian J, Bouhassira D. The neuropathic components of chronic low back pain: a prospective multicenter study using the DN4 questionnaire. J Pain. 2011;12(10):1080-1087.

95. Förster M, Mahn F, Gockel U, et al. Axial low back pain: one painful area—many perceptions and mechanisms. PLoS One. 2013;8(7):e68273.

96. Spahr N, Hodkinson D, Jolly K, Williams S, Howard M, Thacker M. Distinguishing between nociceptive and neuropathic components in chronic low back pain using behavioral evaluation and sensory examination. Musculoskelet Sci Pract. 2017;27:40-48.

97. Fornasari D. Pain mechanisms in patients with chronic pain. Clin Drug Investig. 2012;32(1):45-52.

98. Pergolizzi JV, LeQuang JA, Berger GK, Raffa RB. The basic pharmacology of opioids informs the opioid discourse about misuse and abuse: a review. Pain Ther. 2017;6(1):1-16.

99. Baron R, Maier C, Attal N, et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain. 2017;158(2):261-272.

100. Freynhagen R, Tolle TR, Gockel U, Baron R. The PainDETECT Project: far more than a screening tool on neuropathic pain.Curr Med Res Opin. 2016;32(6):1033-1057.

101. Woolf CJ, American College of Physicians, American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441-451.

102. Glass LS, Harris JS. Cervical and thoracic spine disorders. In: Occupational Medicine Practice Guidelines: Evaluation and Management of Common Health Problems and Functional Recovery of Workers. 2nd ed. Elk Grove, IL: American College of Occupational and Environmental Medicine; 2003: 1-711.

103. Colorado Department of Labor and Employment. Cervical Spine Injury Medical Treatment Guidelines. Available at https://www.colorado.gov/pacific/sites/default/files/Rule_17_Exhibit_8_prior_to_2011.pdf. Last accessed September 16, 2019.

104. Guzman J, Haldeman S, Carroll LJ, et al. Clinical practice implications of the bone and joint decade 2000–2010 task force on neck pain and its associated disorders: from concepts and findings to recommendations. Spine. 2008;33(4):199-213.

105. Alsaadi SM, McAuley JH, Hush JM, et al. Poor sleep quality is strongly associated with subsequent pain intensity in patients with acute low back pain. Arthritis Rheumatol. 2014;66(5):1388-1394.

106. Artner J, Cakir B, Spiekermann JA, et al. Prevalence of sleep deprivation in patients with chronic neck and back pain: a retrospective evaluation of 1016 patients. J Pain Res. 2013;6:1-6.

107. Intermountain Healthcare. Primary Care Management of Neck Pain. Available at https://intermountainhealthcare.org/ext/Dcmnt?ncid=526837557. Last accessed September 16, 2019.

108. Giamberardino MA, Affaitati G, Fabrizio A, Costantini R. Myofascial pain syndromes and their evaluation. Best Pract Res Clin Rheumatol. 2011;25(2):185-198.

109. National Institute for Health and Care Excellence. Head Injury: Assessment and Early Management. Available at https://www.nice.org.uk/guidance/cg176. Last accessed September 16, 2019.

110. Wee B, Reynolds JH, Bleetman A. Imaging after trauma to the neck. BMJ. 2008;336(7636):154-157.

111. National Institute for Health and Care Excellence. Spinal Injury: Assessment and Initial Management. Available at https://www.nice.org.uk/guidance/ng41. Last accessed September 16, 2019.

112. Hadley MN, Walters BC, Aarabi B, et al. Clinical assessment following acute cervical spinal cord injury. Neurosurgery. 2013;72(2):40-53.

113. Hadley MN, Walters BC. Introduction to the guidelines for the management of acute cervical spine and spinal cord injuries. Neurosurgery. 2013;72(2):5-16.

114. Schneider JP, Jay GW, Goldstein L, Pinzon EG. CDC issues final guidelines for opioid prescribing: PPM editorial board responds. Practical Pain Management. 2019;16(3):1-6.

115. Chaverneff F. CDC Guidelines on Opioids: Reaction from the American Academy of Pain Management. Available at https://www.psychiatryadvisor.com/home/news/cdc-guidelines-on-opioids-reaction-from-the-american-academy-of-pain-management. Last accessed September 16, 2019.

116. Polomano RC, Jungquist CR. Foreword. Am J Nurs. 2017;117(3 Suppl 1):S3.

117. Vartiainen P, Heiskanen T, Sintonen H, et al. Mortality of Chronic Pain Patients, Presentation: 10th Congress of the European Pain Federation. Available at https://www.efic2017.kenes.com/Documents/EFIC%202017%20Website%20Program.pdf. Last accessed September 16, 2019.

118. Yu H, Côté P, Southerst D, et al. Does structured patient education improve the recovery and clinical outcomes of patients with neck pain? A systematic review from the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Spine J. 2016;16(12):1524-1540.

119. Moore RA, Eccleston C, Derry S, et al. "Evidence" in chronic pain: establishing best practice in the reporting of systematic reviews. Pain. 2010;150(3):386-389.

120. Moore RA, Straube S, Derry S, McQuay HJ. Chronic low back pain analgesic studies: a methodological minefield. Pain. 2010;149(3):431-434.

121. Tuttle AH, Tohyama S, Ramsay T, et al. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain. 2015;156(12):2616-2626.

122. Nijs J, Malfliet A, Ickmans K, Baert I, Meeus M. Treatment of central sensitization in patients with "unexplained" chronic pain: an update. Expert Opin Pharmacother. 2014;15(12):1671-1683.

123. Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care. 2014;8(2):143-151.

124. Holbech JV, Jung A, Jonsson T, Wanning M, Bredahl C, Bach FW. Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process. J Pain Res. 2017;10:1467-1475.

125. Ennis ZN, Dideriksen D, Vaegter HB, Handberg G, Pottegard A. Acetaminophen for chronic pain: a systematic review on efficacy. Basic Clin Pharmacol Toxicol. 2016;118(3):184-189.

126. Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol for acute low-back pain: a double-blind, randomized controlled trial. Lancet. 2014;384(9954):1586-1596.

127. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomized placebo controlled trials. BMJ. 2015;350:h1225.

128. Saragiotto BT, Machado GC, Ferreira ML, et al. Paracetamol for low back pain. Cochrane Database Syst Rev. 2016;(6):CD012230.

129. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552-559.

130. Nalamachu S. An overview of pain management: the clinical efficacy and value of treatment. Am J Manag Care. 2013;19(14):s261-s266.

131. Machado GC, Maher CG, Ferreira PH, Day RO, Pinheiro MB, Ferreira ML. Nonsteroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis. Ann Rheum Dis. 2017;76(7):1269-1278.

132. Bozimowski G. A review of nonsteroidal anti-inflammatory drugs. AANA J. 2015;83(6):425-433.

133. Fanelli A, Ghisi D, Aprile PL, Lapi F. Cardiovascular and cerebrovascular risk with nonsteroidal anti-inflammatory drugs and cyclooxygenase 2 inhibitors: latest evidence and clinical implications. Ther Adv Drug Saf. 2017;8(6):173-182.

134. The Medical Letter. Celecoxib safety revisited. Med Lett Drugs Ther. 2016;58:159.

135. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998;105(1B):31S-38S.

136. Slater D, Kunnathil S, McBride J, Koppala R. Pharmacology of nonsteroidal anti-inflammatory drugs and opioids. Semin Intervent Radiol. 2010;27(4):400-411.

137. Walker C, Biasucci LM. Cardiovascular safety of non-steroidal anti-inflammatory drugs revisited. Postgrad Med. 2018;130(1):55-71.

138. Speed C, Wolfarth B. Challenges of pain masking in the management of soft tissue disorders: optimizing patient outcomes with a multi-targeted approach. Curr Med Res Opin. 2014;30(5):953-959.

139. Quan M. Hot topics in primary care: the cardiovascular safety of nonsteroidal anti-inflammatory drugs: putting the evidence in perspective. J Fam Pract. 2017;66(4):S52-S57.

140. Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis.Am J Gastroenterol. 2014;109(6):811-819.

141. Laporte S, Chapelle C, Caillet P, et al. Vleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res. 2017;118:19-32.

142. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152(4):706-715.

143. Lanza FL, Chan FK, Quigley EM. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104(3):728-738.

144. Guerrero F, Bolier R, Van Cleave JH, Reid MC. Pharmacological approaches for the management of persistent pain in older adults: what nurses need to know. J Gerontol Nurs. 2016;42(12):49-57.

145. Hunt RH, Choquette D, Craig BN, et al. Approach to managing musculoskeletal pain: acetaminophen, cyclooxygenase-2 inhibitors, or traditional NSAIDs? Can Fam Physician. 2007;53(7):1177-1184.

146. Dick IE, Brochu RM, Purohit Y, Kaczorowski GJ, Martin WJ, Priest BT. Sodium channel blockade may contribute to the analgesic efficacy of antidepressants. J Pain. 2007;8(4):315-324.

147. Benbouzid M, Gaveriaux-Ruff C, Yalcin I, et al. Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia. Biol Psychiatry. 2008;63(6):633-636.

148. Mu A, Weinberg E, Moulin DE, Clarke H. Pharmacologic management of chronic neuropathic pain: review of the Canadian Pain Society consensus statement. Can Fam Physician. 2017;63(11):844-852.

149. Alev L, Fujikoshi S, Yoshikawa A, et al. Duloxetine 60 mg for chronic low back pain: post hoc responder analysis of double-blind placebo-controlled trials. J Pain Res. 2017;10:1723-1731.

150. Skljarevski V, Ossanna M, Liu-Seifert H, et al. A double-blind, randomized trial of duloxeting versus placebo in the management of chronic low back pain. Eur J Neurol. 2009;16(9):1041-1018.

151. Enomoto H, Fujikoshi S, Funai J, et al. Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies. J Pain Res. 2017;10:1357-1368.

152. Derry S, Phillips T, Moore RA, Wiffen PJ. Milnacipran for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(7):CD011789.

153. Riediger C, Schuster T, Barlinn K, Maier S, Weitz J, Siepmann T. Adverse effects of antidepressants for chronic pain: a systematic review and mate-analysis. Front Neurol. 2017;8:307.

154. Semel D, Murphy TK, Zlateva G, Cheung R, Emir B. Evaluation of the safety and efficacy of pregabalin in older patients with neuropathic pain: results from a pooled analysis of 11 clinical studies. BMC Fam Pract. 2010;11:85.

155. Saldaña MT, Navarro A, Perez C, Masramon X, Rejas J. Patient-reported-outcomes in subjects with painful lumbar or cervical radiculopathy treated with pregabalin: evidence from medical practice in primary care settings. Rheumatol Int. 2010;30(8):1005-1015.

156. Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2017;14(8):e1002369.

157. Malik KM, Nelson AM, Avram MJ, Robak SL, Benzon HT. Efficacy of pregabalin in the treatment of radicular pain: results of a controlled trial. Anesth Pain Med. 2015;5(4):e28110.

158. Baron R, Martin-Mola E, Muller M, Dubois C, Falke D, Steigerwald I. Effectiveness and safety of tapentadol prolonged release (PR) versus a combination of tapentadol PR and pregabalin for the management of severe, chronic low back pain with a neuropathic component: a randomized, double-blind, phase 3b study. Pain Pract. 2015;15(5):455-470.

159. Lo YL, Cheong PWT, George JM, et al. Pregabalin and radicular pain study (PARPS) for cervical spondylosis in a multiracial Asian population. J Clin Med Res. 2014;6(1):66-71.

160. Lyndon A, Audrey S, Wells C, et al. Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction. 2017;112(9):1580-1589.

161. Wallwork RS, Chipidza FE, Stern TA. Obstacles to the prescription and use of opioids. Prim Care Companion CNS Disord. 2016;18(1).

162. Nicol AL, Hurley RW, Benzon HT. Alternatives to opioids in the pharmacologic management of chronic pain syndromes: a narrative review of randomized, controlled, and blinded clinical trials. Anesth Analg. 2017;125(5):1682-1703.

163. Rose ME. Are prescription opioids driving the opioid crisis? Assumptions vs facts. Pain Medicine. 2018;19(4):793-807.

164. Ciccone TG. Responses and Criticisms Over New CDC Opioid Prescribing Guidelines. Available at https://www.practicalpainmanagement.com/resources/news-and-research/responses-criticisms-over-new-cdc-opioid-prescribing-guidelines. Last accessed September 16, 2019.

165. Hedegaard H, Chen LH, Warner M. Drug-poisoning deaths involving heroin: United States, 2000–2013. NCHS Data Brief. 2015;(190):1-8.

166. Centers for Disease Control and Prevention. Provisional Drug Overdose Death Counts. Available at https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm. Last accessed September 16, 2019.

167. Socías ME, Wood E. Epidemic of deaths from fentanyl overdose. BMJ. 2017;358:j4355.

168. Cheatle MD, Gallagher RM, O'Brien CP. Low risk of producing an opioid use disorder in primary care by prescribing opioids to prescreened patients with chronic noncancer pain. Pain Med. 2018;19(4):764-773.

169. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;(1):CD006605.

170. Minozzi S, Amato L, Davoli M. Development of dependence following treatment with opioid analgesics for pain relief: a systematic review. Addiction. 2013;108(4):688-698.

171. Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S. Cohort study of the impact of high-dose opioid analgesics on overdose mortality. Pain Med. 2016;17(1):85-98.

172. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171(7):686-691.

173. Warner M, Trinidad JP, Bastian BA, Minino AM, Hedegaard H. Drugs most frequently involved in drug overdose deaths: United States, 2010–2014. Natl Vital Stat Rep. 2016;65(10):1-15.

174. Ueberall MA, Mueller-Schwefe GHH. Efficacy and tolerability balance of oxycodone/naloxone and tapentadol in chronic low back pain with a neuropathic component: a blinded end point analysis of randomly selected routine data from 12-week prospective open-label observations. J Pain Res. 2016;9:1001-1020.

175. Jones GP, Tripathi SS. Oxycodone and naloxone combination: a 12-week follow-up in 20 patients shows effective analgesia with opioid-induced bowel dysfunction. Pain Ther. 2016;5(1):107-113.

176. Miyazaki T, Choi IY, Rubas W, et al. NKTR-181: a novel mu-opioid analgesic with inherently low abuse potential. J Pharmacol Exp Ther. 2017;363(1):104-113.

177. The Medical Letter. Abuse-deterrent opioids. Med Lett Drugs Ther. 2017;59:95-96.

178. DePriest AZ, Miller K. Oxycodone/naloxone: role in chronic pain management, opioid-induced constipation, and abuse deterrence. Pain Ther. 2014;3(1):1-15.

179. Lee YH, Brown DL, Chen HY. Current impact and application of abuse-deterrent opioid formulations in clinical practice. Pain Physician. 2017;20(7):E1003-E1023.

180. Serpell M, Tripathi S, Scherzinger S, Rojas-Farreras S, Oksche A, Wilson M. Assessment of transdermal buprenorphine patches for the treatment of chronic pain in a UK observational study. Patient. 2016;9(1):35-46.

181. Parkin-Smith GF, Amorin-Woods LG, Davies SJ, Losco BE, Adams J. Spinal pain: current understanding, trends, and the future of care. J Pain Res. 2015;8:741-752.

182. Plosker GL. Buprenorphine 5, 10, and 20 µg/h transdermal patch: a review of its use in the management of chronic non-malignant pain. Drugs. 2011;71(18):2491-2509.

183. The Medical Letter. Buprenorphine buccal film (Belbuca) for chronic pain. Med Lett Drugs Ther. 2016;58:47-48.

184. Baron R, Eberhart L, Kern KU, et al. Tapentadol prolonged release for chronic pain: a review of clinical trials and 5 years of routine clinical practice data. Pain Pract. 2017;17(5):678-700.

185. Sánchez Del Águila MJ, Schenk M, Kern KU, Drost T, Steigerwald I. Practical considerations for the use of tapentadol prolonged release for the management of severe chronic pain. Clin Ther. 2015;37(1):94-113.

186. Steigerwald I, Muller M, Davies A, et al. Effectiveness and safety of tapentadol prolonged release for severe, chronic low back pain with or without a neuropathic pain component: results of an open-label, phase 3b study. Curr Med Res Opin. 2012;28(6):911-936.

187. Galvez R, Schafer M, Hans G, Falke D, Steigerwald I. Tapentadol prolonged release versus strong opioids for severe, chronic low back pain: results of an open-label, phase 3b study. Adv Ther. 2013;30(3):229-259.

188. Pergolizzi J, Alon E, Baron R, et al. Tapentadol in the management of chronic low back pain: a novel approach to a complex condition? J Pain Res. 2011;4:203-210.

189. Buynak R, Rappaport SA, Rod K, et al. Long-term safety and efficacy of tapentadol extended release following up to 2 years of treatment in patients with moderate to severe, chronic pain: results of an open-label extension trial. Clin Ther. 2015;37(11):2420-2438.

190. Billeci D, Coluzzi F. Tapentadol extended release for the management of chronic neck pain. J Pain Res. 2017;10:495-505.

191. Safeer S, Cleary J, Fudin J. A perspective on tapentadol therapy. Practical Pain Management. 2016;16(7).

192. Butler SF, McNaughton EC, Black RA. Tapentadol abuse potential: a postmarketing evaluation using a sample of individuals evaluated for substance abuse treatment. Pain Med. 2015;16(1):119-130.

193. McNaughton EC, Black RA, Weber SE, Butler SF. Assessing abuse potential of new analgesic medications following market release: an evaluation of internet discussion of tapentadol abuse. Pain Med. 2015;16(1):131-140.

194. Dart RC, Surratt HL, Le Lait MC, et al. Diversion and illicit sale of extended-release tapentadol in the United States. Pain Med. 2016;17(8):1490-1496.

195. Christoph A, Eerdekens MH, Kok M, Volkers G, Freynhagen R. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. Pain. 2017;158(9):1813-1824.

196. Markman J, Gudin J, Rauck R, et al. SUMMIT-07: a randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain. Pain. 2019;160(6):1374-1382.

197. Knezevic NN, Tverdohleb T, Nikibin F, Knezevic I, Candido KD. Management of chronic neuropathic pain with single and compounded topical analgesics. Pain Manag. 2017;7(6):537-558.

198. Derry S, Conaghan P, Da Silva JA, et al. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2016;4:CD007400.

199. Derry S, Wiffen PJ, Kalso EA, et al. Topical analgesics for acute and chronic pain in adults: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017;5:CD008609.

200. Likar R, Kager I, Obmann M, Pipam W, Sittl R. Treatment of localized neuropathic pain after disk herniation with 5% lidocaine medicated plaster. Int J Gen Med. 2012;5:689-692.

201. Baron R, Treede RD, Birklein F, et al. Treatment of painful radiculopathies with capsaicin 8% cutaneous patch. Curr Med Res Opin. 2017;33(8):1401-1411.

202. Cline AE, Turrentine JE. Compounded topical analgesics for chronic pain. Dermatitis. 2016;27(5):263-271.

203. Somberg JC, Molnar J. Retrospective evaluation on the analgesic activities of 2 compounded topical creams and Voltaren gel in chronic noncancer pain. Am J Ther. 2015;22(5):342-349.

204. Hesselink JMK. Topical analgesics: critical issues related to formulation and concentration. J Pain Relief. 2016;5:274.

205. Kalant H. Marihuana: medicine, addictive substance, or both? A common-sense approach to the place of cannabis in medicine. CMAJ. 2013;4(3):4-9.

206. Berlach DM, Shir Y, Ware MA. Experience with the synthetic cannabinoid nabilone in chronic noncancer pain. Pain Med. 2006;7(1):25-29.

207. Burns TL, Ineck JR. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain. Ann Pharmacother. 2006;40(2):251-260.

208. Brosseau L, Wells GA, Tugwell P, et al. Ottawa panel evidence-based clinical practice guidelines on therapeutic massage for neck pain. J Bodyw Mov Ther. 2012;16(3):300-325.

209. Lopez-de-Uralde-Villanueva I, Beltran-Alacreu H, Fernandez-Carnero J, Kindelan-Calvo P, La Touche R. Widespread pressure pain hyperalgesia in chronic nonspecific neck pain with neuropathic features: a descriptive cross-sectional study. Pain Physician. 2016;19(2):77-88.

210. Cugalj AP, McManus K. Manual Treatments. Available at https://now.aapmr.org/manual-treatments. Last accessed September 16, 2019.

211. Gross A, Langevin P, Burnie SJ, et al. Manipulation and mobilization for neck pain contrasted against an inactive control or another active treatment. Cochrane Database Syst Rev. 2015;(9):CD004249.

212. Ernst E. Fatalities after CAM: an overview. Br J Gen Pract. 2011;61(587):404-405.

213. Reed ML. Physical Therapy. Available at https://www.spine.org/KnowYourBack/Treatments/Nonsurgical-Treatments/Physical-Therapy. Last accessed September 16, 2019.

214. Griffin A, Leaver A, Moloney N. General exercise does not improve long-term pain and disability in individuals with whiplash-associated disorders: a systematic review. J Orthop Sports Phys Ther. 2017;47(7):472-480.

215. Southerst D, Nordin MC, Côté P, et al. Is exercise effective for the management of neck pain and associated disorders or whiplash-associated disorders? A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.Spine J. 2016;16(12):1503-1523.

216. Gross A, Kay TM, Paquin JP, et al. Exercises for mechanical neck disorders. Cochrane Database Syst Rev. 2015;1:CD004250.

217. Celenay ST, Akbayrak T, Kaya DO. A comparison of the effects of stabilization exercises plus manual therapy to those of stabilization exercises alone in patients with nonspecific mechanical neck pain: a randomized clinical trial. J Orthop Sports Phys Ther. 2016;46(2):44-55.

218. Celenay ST, Kaya DO, Akbayrak T. Cervical and scapulothoracic stabilization exercises with and without connective tissue massage for chronic mechanical neck pain: a prospective, randomized controlled trial. Man Ther. 2016;21:144-150.

219. Pillastrini P, de Lima E Sa Resende F, Banchelli F. Effectiveness of global postural re-education in patients with chronic nonspecific neck pain: randomized controlled trial. Phys Ther. 2016;96(9):1408-1416.

220. Lauche R, Schuth M, Schwickert M, et al. Efficacy of the Alexander technique in treating chronic non-specific neck pain: a randomized controlled trial. Clin Rehabil. 2016;30(3):247-258.

221. Daenen L, Varkey E, Kellmann M, Nijs J. Exercise, not to exercise, or how to exercise in patients with chronic pain? Applying science to practice. Clin J Pain. 2015;31(2):108-114.

222. Vaegter HB. Exercising non-painful muscles can induce hypoalgesia in individuals with chronic pain. Scand J Pain. 2017;15:60-61.

223. Smith A, Rirchie C, Pedler A, McCamley K, Roberts K, Sterling M. Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders. Scand J Pain. 2017;15:14-21.

224. Eccleston C, Crombez G. Worry and chronic pain: a misdirected problem solving model. Pain. 2007;132(3):233-236.

225. Richmond H, Hall AM, Copsey B, et al. The effectiveness of cognitive behavioral treatment for non-specific low back pain: a systematic review and meta-analysis. PLoS One. 2015;10(8):e0134192.

226. Butler AC, Chapman JE, Forman EM, Beck AT. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin Psychol Rev. 2006;26(1):17-31.

227. Monticone M, Ambrosini E, Cedraschi C, et al. Cognitive-behavioral treatment for subacute and chronic neck pain: a Cochrane review. Spine. 2015;40(19):1495-1504.

228. Shearer HM, Carroll LJ, Wong JJ, et al. Are psychological interventions effective for the management of neck pain and whiplash-associated disorders? A systematic review by the Ontatio Protocol for Traffic Injury Management (OPTIMa) Collaboration. Sping J. 2016;16(12):1566-1581.

229. Thompson DP, Oldham JA, Woby SR. Does adding cognitive-behavioral physiotherapy to exercise improve outcome in patients with chronic neck pain? A randomized controlled trial. Physiotherapy. 2016;102(2):170-177.

230. Moon TW, Posadzki P, Choi TY, et al. Acupuncture for treating whiplash associated disorder: a systematic review of randomized clinical trials. Evidence-Based Complementary and Alternative Medicine. 2014:870271.

231. MacPherson H, Vertosick EA, Foster NE, et al. The persistence of the effects of acupuncture after a course of treatment: a meta-analysis of patients with chronic pain. Pain. 2017;158(5):784-793.

232. Cramer H, Klose P, Brinkhaus B, et al. Effects of yoga on chronic neck pain: a systematic review and meta-analysis. Clin Rehabil. 2017;31(11):1457-1465.

233. Lauche R, Stumpe C, Fehr J, et al. The effects of tai chi and neck exercises in the treatment of chronic nonspecific neck pain: a randomized controlled trial. J Pain. 2016;17(9):1013-1027.

234. Jeitler M, Brunnhuber S, Meier L, et al. Effectiveness of jyoti meditation for patients with chronic neck pain and psychological distress: a randomized controlled clinical trial. J Pain. 2015;16(1):77-86.

235. Stout A. Epidural steroid injections for cervical radiculopathy. Phys Med Rehabil Clin N Am. 2011;22(1):149-159.

236. Stout A. Epidural steroid injections for low back pain. Phys Med Rehabil Clin N Am. 2010;21(4):825-834.

237. Rathmell JP, Benzon HT, Dreyfuss P. Safeguards to prevent neurologic complications after epidural steroid injections: consensus opinions from a multidisciplinary working group and national organizations. Anesthesiology. 2015;122(5):974-984.

238. Gross AR, Peloso PM, Galway E, et al. Physician-delivered injection therapies for mechanical neck disorders: a systematic review update (non-oral, non-intravenous pharmacological interventions for neck pain). Open Orthop J. 2013;7:562-581.

239. Bicket MC, Gupta A, Brown CH, Cohen SP. Epidural injections for spinal pain: a systematic review and meta-analysis evaluating the "control" injections in randomized controlled trials. Anesthesiology. 2013;119(4):907-931.

240. Kennedy DJ, Shokat M, Visco CJ. Sacroiliac joint and lumbar zygapophysial joint corticosteroid injections. Phys Med Rehabil Clin N Am. 2010;21(4):835-842.

241. Mazin DA, Sullivan JP. Lumbar and sacral radiofrequency neurotomy. Phys Med Rehabil Clin N Am. 2010;21(4):843-850.

242. Engel A, Rappard G, King W, Kennedy DJ, SIS. The effectiveness and risks of fluoroscopically-guided cervical medial branch thermal radiofrequency neurotomy: a systematic review with comprehensive analysis of the published data. Pain Med. 2016;17(4):658-669.

243. Helm li S, Simopoulos TT, Stojanovic M, Abdi S, El Terany MA. Effectiveness of thermal annular procedures in treating discogenic low back pain. Pain Physician. 2017;20(6):447-470.

244. Oken J, Foorsov V. Spinal Procedures. Available at https://now.aapmr.org/spinal-procedures. Last accessed September 16, 2019.

245. Singh V, Benyamin RM, Datta S, Falco FJ, Helm S, Manchikanti L. Systematic review of percutaneous lumbar mechanical disc decompression utilizing decompressor. Pain Physician. 2009;12(3):589-599.

246. Lavelle W, Carl A, Lavelle ED, Khaleel MA. Vertebroplasty and kyphoplasty. Anesthesiol Clin. 2007;25(4):913-928.

247. Friedly J, Standaert C, Chan L. Epidemiology of spine care: the back pain dilemma. Phys Med Rehabil Clin N Am. 2010;21(4):659-677.

248. Nicol AL, Wu II, Ferrante FM. Botulinum toxin type A injections for cervical and shoulder girdle myofascial pain using an enriched protocol design. Anesth Analg. 2014;118(6):1326-1335.

249. Canadian Agency for Drugs and Technologies in Health. Botulinum Toxin A for Myofascial Pain Syndrome: A Review of the Clinical Effectiveness. Available at https://www.cadth.ca/botulinum-toxin-myofascial-pain-syndrome-review-clinical-effectiveness-1. Last accessed September 16, 2019.

250. Federation of State Medical Boards. Model Policy for the Use of Opioid Analgesics in the Treatment of Chronic Pain. Washington, DC: The Federation of State Medical Boards; 2013.

251. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR. 2016;65(1):1-49.

252. U.S. Food and Drug Administration. Medication Guides: Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS). Available at https://www.fda.gov/media/79776/download. Last accessed December 18, 2019.

253. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116.

254. Strickland JM, Huskey A, Brushwood DB. Pharmacist-physician collaboration in pain management practice. J Opioid Manag. 2007;3:295-301.

255. Sundwall DN, Utah Department of Health. Utah Clinical Guidelines on Prescribing Opioids for Treatment of Pain. Salt Lake City, UT: Utah Department of Health; 2009.

Evidence-Based Practice Recommendations Citations

1. Bier JD, Scholten-Peeters WGM, Staal JB, et al. Clinical practice guideline for physical therapy assessment and treatment in patients with nonspecific neck pain. Phys Ther. 2018;98(3):162-171. Available at http://stoverpt.com/uploads/3/4/8/2/34823947/neeck_pain_guidelines.pdf. Last accessed September 17, 2019.

2. American College of Radiology. ACR Appropriateness Criteria: Cervical Neck Pain or Cervical Radiculopathy. Available at https://acsearch.acr.org/docs/69426/Narrative. Last accessed September 17, 2019.

3. Blanpied PR, Gross AR, Elliott JM, et al. Neck pain: revision 2017. J Orthop Sports Phys Ther. 2017;47(7):A1-A83. Available at https://www.jospt.org/doi/full/10.2519/jospt.2017.0302. Last accessed September 17, 2019.

38430 • Pathophysiology: The Immune System

Jane C. Norman, RN, MSN, CNE, PhD

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

The human body is constantly exposed to potentially deleterious micro-organisms and foreign substances. Therefore, it has evolved as a complete system composed of complementary and inter-related mechanisms to defend against invasion by bacteria, viruses, and other foreign substances. This course will cover immunity and the immune system, including a discussion of innate and adaptive immunity. Concepts related to key cellular functions, recognition systems, and effector responses integral to the immune system are also presented. In addition, developmental aspects of the immune system are discussed.

Table of Contents

38430 • Pathophysiology: The Immune System

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. OVERVIEW OF IMMUNITY

ACTIVE VERSUS PASSIVE IMMUNITY

CYTOKINES AND THEIR ROLE IN IMMUNITY

PATHOGEN RECOGNITION

INNATE IMMUNITY

ADAPTIVE IMMUNITY

3. IMMUNITY IN SPECIAL POPULATIONS

TRANSFER OF IMMUNITY FROM MOTHER TO INFANT

IMMUNE RESPONSE IN THE OLDER ADULT

4. IMMUNE HYPERSENSITIVITY DISORDERS

ALLERGIES

ASTHMA

5. RHEUMATIC DISORDERS

RHEUMATOID ARTHRITIS

SYSTEMIC LUPUS ERYTHEMATOSUS

SJÖGREN SYNDROME

SCLERODERMA

SPONDYLOARTHROPATHIES

IDIOPATHIC INFLAMMATORY MYOPATHY

VASCULITIS

LYME DISEASE

6. IMMUNE SYSTEM DISORDERS

ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)

PRIMARY IMMUNE DEFICIENCY DISEASES

SEPSIS

7. CONCLUSION

8. CASE STUDIES

SYSTEMIC LUPUS ERYTHEMATOSUS

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

IMMUNE THROMBOCYTOPENIC PURPURA

Works Cited

Evidence-Based Practice Recommendations Citations

38430 • Pathophysiology: The Immune System

Education Category. Infection Control / Internal Medicine

Release Date. 11/01/2019

Expiration Date. 10/31/2022

Course Overview

The human body is constantly exposed to potentially deleterious micro-organisms and foreign substances. Therefore, it has evolved as a complete system composed of complementary and inter-related mechanisms to defend against invasion by bacteria, viruses, and other foreign substances. This course will cover immunity and the immune system, including a discussion of innate and adaptive immunity. Concepts related to key cellular functions, recognition systems, and effector responses integral to the immune system are also presented. In addition, developmental aspects of the immune system are discussed.

Audience

This course is designed for nurses working in critical care and general and specialty medical-surgical units in which patients with multiple organ system problems are found.

Course Objective

As health care becomes more complex, it is essential that the theoretical concepts of the basis of illness (pathophysiology) be well understood. The purpose of this course is to reinforce the scientific rationales for the interventions nurses perform and the decisions nurses make as patients move through the ever-changing management of their autoimmune or immune system disorder.

Learning Objectives

Upon completion of this course, you should be able to:

1. Review the general characteristics of active and passive immunity.

2. Describe the role of cytokines in human immunity.

3. Identify the cells of the innate immune system and their functions.

4. Discuss the cells of the adaptive immune system and their functions.

5. Analyze features of immunity in special populations.

6. Evaluate the manifestation, diagnosis, and treatment of allergic conditions, including allergic rhinitis.

7. Outline the clinical manifestations and management of anaphylaxis.

8. Identify signs and symptoms of food allergy.

9. Review the diagnosis and management of asthma in various patient populations.

10. Describe the presentation and medical management of rheumatoid arthritis.

11. Discuss key points in the recognition and management of systemic lupus erythematosus.

12. Compare and contrast features of various other autoimmune rheumatic disorders, including Sjögren syndrome, spondyloarthropathies, and vasculitis.

13. Analyze tools available to diagnose and treat Lyme disease.

14. Describe the manifestations of acquired immune deficiency syndrome (AIDS) and available treatment options.

15. Evaluate other immune system disorders, including sepsis.

Faculty

Jane C. Norman, RN, MSN, CNE, PhD, received her undergraduate education at the University of Tennessee, Knoxville campus. There she completed a double major in Sociology and English. She completed an Associate of Science in Nursing at the University of Tennessee, Nashville campus and began her nursing career at Vanderbilt University Medical Center. Jane received her Masters in Medical-Surgical Nursing from Vanderbilt University. In 1978, she took her first faculty position and served as program director for an associate degree program. In 1982, she received her PhD in Higher Education Administration from Peabody College of Vanderbilt University. In 1988, Dr. Norman took a position at Tennessee State University. There she has achieved tenure and full professor status. She is a member of Sigma Theta Tau National Nursing Honors Society. In 2005, she began her current position as Director of the Masters of Science in Nursing Program.

Faculty Disclosure

Contributing faculty, Jane C. Norman, RN, MSN, CNE, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Sharon Cannon, RN, EdD, ANEF

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

The human body is constantly exposed to potentially deleterious micro-organisms and foreign substances. Therefore, it has evolved a complete system composed of complementary and inter-related mechanisms to defend against invasion by bacteria, viruses, parasites, and other foreign substances. Through recognition of molecular patterns, the body's immune system is able to distinguish itself from these foreign substances and discriminate potentially harmful from non-harmful agents. In addition, it can defend against abnormal cells and molecules that periodically develop. The skin and its epithelial layers, in conjunction with the body's normal inflammatory processes, make up the first line of the body's defense and confer innate or natural immunity to the host. After these protective barriers have been crossed, the body relies on a second line of defense known as the adaptive immune response to eradicate infection by invading organisms. The adaptive immune response evolves slowly over time but results in the development of antibodies capable of targeting specific micro-organisms and foreign substances should a second exposure occur [1,2].

This course will cover immunity and the immune system, including a discussion of innate and adaptive immunity. Concepts related to key cellular functions, recognition systems, and effector responses integral to the immune system are also presented. In addition, developmental aspects of the immune system are discussed.

2. OVERVIEW OF IMMUNITY

Immunity can be defined as the body's ability to defend against specific pathogens and/or foreign substances in the initiation of disease processes. The multidimensional response initiated by the body's various defense systems is known as the immune response. Some of these responses become active almost immediately, while others develop slowly over time. It is the coordinated interaction of these mechanisms that allows the body to maintain normal internal homeostasis. However, when these mechanisms are either depressed or overactive, they become responsible for many of the pathophysiologic processes encountered in health care [1,2].

In order for a host organism to remain healthy, the immune system must function properly. A weakened immune response may lead to immunodeficiency, but an inappropriate or excessive response can cause allergic/hypersensitivity reactions or autoimmune diseases. Therefore, the immune system must be capable of regulating itself. The process by which this regulation occurs is poorly understood but involves all aspects of the innate and adaptive immune responses.

Intact innate immune mechanisms are essential for the initiation of the adaptive immune response, and therefore, a successful immune response depends upon cooperation between the two systems. Dendritic cells are an essential component of both innate and adaptive responses and act through the release of dendritic cell-derived substances, such as cytokines and chemokines. Innate immune cells are capable of communicating important information regarding key characteristics of the invading micro-organism or foreign substance to the B and T lymphocytes involved in adaptive immunity. The adaptive immune response is also capable of increasing its efficiency by recruitment and activation of additional phagocytes and molecules of the innate immune system. Each system is thus essential for an effective immune response and occurs in concert in the fight against infection [1,2].

Each exposure to an antigen elicits a predictable response from the immune system. After activation, the response is amplified until it peaks and eventually subsides. This occurs because the body's normal immune responses are self-limiting. After the antigen is destroyed and the action of chemical mediators terminated, the immune response ceases. It is believed that anti-inflammatory cytokines and regulatory T lymphocytes play a role in this process [4].

Tolerance, or the ability of the immune system to react to foreign antigens but remain nonreactive to self-antigens, also plays a role in the self-regulation of the immune response. Tolerance to self-antigens protects the body from harmful autoimmune responses. This is exquisitely important in vital organs such as the brain, testes, ovaries, and eyes, where immunologic damage could be lethal [4].

ACTIVE VERSUS PASSIVE IMMUNITY

The goal of the immune system is to protect the host against invasion by potentially dangerous pathogens, foreign substances, and other sources of harmful antigens. Adaptive immune responses accomplish this goal though the activation of cell-mediated and humoral responses. This type of protection can be induced in one of two ways [3]:

- After exposure to the offending substance and activation of B and T lymphocytes (active immunity)

- Through the transfer of antibodies against an antigen directly to the host (passive immunity)

Active immunity is acquired when the host mounts an immune response to an antigen, either through the process of vaccination or from environmental exposure. It is called active immunity because it requires the host's own immune system to develop an immunologic response, including the development of memory. Active immunity is usually long-lasting but requires a few days to weeks after first exposure to sufficiently develop an appropriate immunologic response that culminates in the destruction of the presenting antigen. With subsequent exposures, the immune system rapidly becomes fully activated because of the presence of memory B and T lymphocytes and circulating antibodies. The process by which active immunity is acquired through the administration of a vaccine is termed immunization. An acquired immune response can improve on repeated exposures to an injected antigen (booster vaccines) or natural infections [3].

Passive immunity is immunity transferred from another source. The most common form is immunity conferred from mother to fetus. During fetal development, maternal immunoglobulin G (IgG) antibodies are transferred to the fetus via the placenta. After birth, the neonate also receives IgG antibodies from the mother in breast milk or colostrum. Therefore, infants are provided with some degree of protection from infection for approximately three to six months, giving their own immune system time to mature. Some protection against infectious diseases can also be provided by the administration of immunoglobulins pooled from human or animal sources. Passive immunity produces only short-term protection that lasts weeks to months [3].

CYTOKINES AND THEIR ROLE IN IMMUNITY

The ability of the cells of both the innate and adaptive immune systems to communicate critical information with each other and initiate end effector responses is dependent upon the secretion of short-acting, biologically active, soluble molecules called cytokines. Cytokines are an essential component of host defense mechanisms and the primary means by which cells of innate and adaptive immunity interact. Chemokines are a subset of cytokines that consist of small-protein molecules involved in both immune and inflammatory responses. They are responsible for directing leukocyte migration to areas of injury and to locations where primary immune responses are initiated, such as lymph nodes, the spleen, Peyer patches, and the tonsils [6].

General Properties of Cytokines

Cytokines are low-molecular-weight, regulatory, pro- or anti-inflammatory proteins that are produced by cells of the innate and adaptive immune systems and that mediate many of the actions of these cells. The majority of the functionally important cytokines are interleukins, interferons, and tumor necrosis factor-alpha (TNF-α). Cytokines generate their responses by binding to specific receptors on their target cells and activating G-protein-coupled receptors [6,7].

Interleukins are produced by macrophages and lymphocytes in response to the presence of an invading micro-organism or activation of the inflammatory process. Their primary function is to enhance the acquired immune response through alteration of molecular expression, induction of leukocyte maturation, enhanced leukocyte chemotaxis, and general suppression or enhancement of the inflammatory process [1,6,7].

Interferons are cytokines that primarily protect the host against viral infections and play a role in the modulation of the inflammatory response. Interferons are cell-type specific, with IFN-α and IFN-β produced primarily by macrophages and IFN-γ produced primarily by T lymphocytes.

TNF-α, a cytokine in a class by itself, is one of the most important mediators of the inflammatory response and is produced by macrophages when surface toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) on the surface of micro-organisms. TNF-α acts as an endogenous pyrogen (i.e., fever producer) and induces synthesis of preinflammatory substances in the liver. With prolonged exposure, it has the ability to cause intravascular coagulation and subsequent thrombosis production [1,6,7].

Despite the diverse functions of the cytokines, they all share certain important properties. All cytokines are secreted in a brief, self-limited manner. They are rarely stored as preformed molecules but rather are synthesized through transcription as a result of cellular activation. The actions of cytokines are often pleiotropic, meaning that a single cytokine has the ability to act on a variety of different cell types. For example, the interleukin IL-17 is produced by T-helper 17 (T_17H) cells and acts on several cell types, including leukocytes, epithelial cells, mesothelial cells, vascular endothelial cells, and fibroblasts. As a result, T_17H cells play a critical role in host defense against pathogens that infiltrate the mucosal barrier. Although pleiotropic action allows cytokines to mediate diverse effects, it greatly limits their use for therapeutic purposes. Because of this redundancy, antagonists against a single cytokine may not have functional consequences; other cytokines may compensate. Redundancy refers to the ability of different cytokines to stimulate the same or overlapping biologic functions [1,6,7].

In addition to being pleiotropic and redundant, cytokines can have broad activity. Several different cell types are capable of producing a single cytokine. For example, IL-1 is a preinflammatory cytokine that is primarily produced by macrophages but can be produced by virtually all leukocytes, endothelial cells, and fibroblasts.

Cytokines also function to initiate cascade functions, with one cytokine influencing the synthesis and actions of other cytokines. Often, the second and third cytokines will mediate the biologic effects of the first cytokine. These effects may be localized, acting on a single cell or group of cells in the area surrounding the effector cell, or systematic, with the cytokines secreted into the bloodstream and transported to their site of action. TNF-α is an example of a cytokine with wide-reaching systemic effects. Cytokines may also serve as antagonists to inhibit the action of another cytokine and as a result act as anti-inflammatory cytokines. For example, IL-10 is an anti-inflammatory cytokine that down-regulates the inflammatory and adaptive immune response [1,6,7].

Chemokines

As noted, chemokines are small-protein molecules (consisting of 70 to 130 amino acids) that are involved in immune and inflammatory cellular responses and function to control the migration of leukocytes to their primary site of action in the immune response. There are four distinct classes of chemokines (C, CC, CXC, and CX3C), each named for the number and location of cysteine residing on the terminal amino acid of the protein. Currently, 47 distinct chemokine molecules have been identified within the four different classes. The vast majority of these are classified as either CC or CXC chemokines. The CC chemokines have the first two cysteine molecules adjacent to each other, while these molecules are separated by an amino acid in the CXC chemokines. The CC chemokines attract monocytes, lymphocytes, and eosinophils to sites of chronic inflammation. The CXC chemokines attract neutrophils to sites of acute inflammation [8,9].

Functionally, chemokines may be categorized as either homeostatic or inflammatory. Homeostatic chemokines are produced in relatively constant amounts (constitutively) regardless of cellular environmental conditions, while inflammatory chemokines are produced in response to proinflammatory stimuli. However, there is some overlap in the actions of specific chemokines.

Colony-Stimulating Factors

Colony-stimulating factors (CSFs) are a subset of cytokines that participate in hematopoiesis by stimulating bone marrow pluripotent stem cells and progenitor or precursor cells to produce large numbers of mature platelets, erythrocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and dendritic cells. The CSFs are named according to the type of target cell on which they act. Macrophages, endothelial cells, and fibroblasts produce granulocyte colony-stimulating factor (G-CSF) during times of stress or inflammation, and this factor promotes growth and maturation of neutrophils. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the mononuclear phagocyte progenitor. While CSFs are necessary for normal blood cell production and maturation, excess production has been implicated in several disease processes and in the development of corticosteroid-resistant chronic obstructive pulmonary disease (COPD). Impaired macrophage function and subsequent impairment of G-CSF activity have been associated with the development of neutrophilia in animal studies [8]. In clinical practice, recombinant CSF is being used to increase the success rates of bone marrow transplantation and to treat chemotherapy-induced neutropenia and myelosuppression. The availability of recombinant CSFs and other cytokines offers the possibility of clinical therapy in which stimulation or inhibition of the immune response or cell production is desirable [8,9].

PATHOGEN RECOGNITION

The innate immune response plays a crucial role in the proinflammatory response to infection and relies on the ability of host defenses to differentiate self from non-self, so only invading organisms are targeted. The leukocytes involved in this response recognize certain evolutionarily retained patterns present on the surface of pathogens and in response bind to the membrane and destroy the invading organism through the process of phagocytosis [3].

Invading pathogens contain conserved structures in their cell membranes termed PAMPs, which are recognized by the cells of the innate immune system because they possess a limited number of germline-encoded pattern-recognition receptors (PRRs). Upon PAMP recognition, PRRs come in contact with the cell surface and/or send intracellular signals to the host that trigger proinflammatory and antimicrobial responses, including the synthesis and release of cytokines, chemokines, and cell-adhesion molecules. The PAMPs recognized by host PRRs are made up of a combination of sugars, lipid molecules, proteins, and/or patterns of modified nucleic acids. Because PAMPs are essential for the functioning and infectivity of the micro-organism, mutation cannot help it avoid immune recognition. The human complement of PRRs is extensive (approximately 1,000), so the classes of pathogens recognized are diverse. Pathogens of very different biochemical composition are recognized by relatively similar mechanisms by host PRRs, and no single class of pathogens is sensed by only one type of PRR; the host genetic code allows for the unique receptors involved in both innate and adaptive immunity to recognize fine details of molecular structure [3].

The ability of the innate immune response to limit microbes early in the infectious process results from the binding of pathogens to the PRRs on leukocytes, which in turn initiates the signaling events that lead to complement activation, phagocytosis, and autophagy. Once initiated, white blood cells, neutrophils, and monocytes migrate from the blood to the tissues, along with other body fluids, causing peripheral edema. Blood monocytes mature into macrophages as they traverse the tissues and join the macrophages already present in the tissues. PRRs present on these cells become activated, which amplifies the inflammatory response through enhanced secretion of all chemical mediators, including cytokines and complements [3].

INNATE IMMUNITY

The innate immune system is comprised of two separate but inter-related lines of defense: the epithelial layer, which acts as a physical barrier to invading substances and organisms, and the inflammatory response. The innate immune response utilizes the body's natural epithelial barriers along with phagocytic cells (mainly neutrophils and macrophages), natural killer (NK) cells, and several plasma proteins, including kinins, clotting factors, and those of the complement system, to maintain internal homeostasis. The response of the innate immune system is rapid, usually within minutes to hours, and prevents the establishment of infection and deeper tissue penetration of micro-organisms. The innate immune response is effective against most pathogens. However, when the innate response is overwhelmed or ineffective, adaptive immune responses become activated as the final line of defense against invading organisms. Innate immune mechanisms are always present in the body and are rapidly activated, so the body's defenses have responded before the adaptive immune response is triggered. The innate immune system also interacts with and directs adaptive immune responses [9,10].

Under normal conditions, the innate immune response is essential to the continued health and well-being of the body. However, during times of hyper-responsiveness or hyporesponsiveness, the innate immune system plays a role in the pathogenesis of disease. One of the main functions of the innate immune system is the initiation of the inflammatory response, which involves activation of a complex cascade of events and chemical mediators. However, inflammation plays a key role in the genesis of many common pathophysiologic states, including atherosclerosis and coronary artery diseases, bronchial asthma, diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus [9].

Epithelial Barriers

Physical, mechanical, and biochemical barriers against microbial invasion are found in all common portals of entry into the body, including the skin and the respiratory, gastrointestinal, and urogenital tracts. The intact skin is by far the most formidable physical barrier available because of its design. It is comprised of closely packed cells that are organized in multiple layers that are continuously shed. In addition, a protective layer of protein, known as keratin, covers the skin. The skin has simple chemicals that create a nonspecific, acidic environment (acid mantle) and antibacterial proteins, such as the enzyme lysozyme, that inhibit the colonization of micro-organisms and aid in their destruction. The complexity of the skin becomes evident in cases of contact dermatitis, whereby increased susceptibility to cutaneous infection occurs as the result of abnormalities of the innate immune response, including defects in the epithelial layer itself and defects in both signaling and expressing of innate responses [3].

Sheets of tightly packed epithelial cells also line and protect the gastrointestinal, respiratory, and urogenital tracts and physically prevent micro-organisms from entering the body. These cells destroy invading organisms by secreting antimicrobial enzymes, proteins, and peptides. Specialized cells in the lining, such as goblet cells in the gastrointestinal tract, secrete a viscous material comprised of high-molecular-weight glycoproteins known as mucins, which form mucus when hydrated. Mucins bind to pathogens, trapping them and washing away potential invaders. In the lower respiratory tract, hair-like mobile structures called cilia protrude through the epithelial cells and move microbes trapped in the mucus up the tracheobronchial tree and toward the throat. The physiologic responses of coughing and sneezing further aid in their removal from the body [3,4].

Micro-organisms that are trapped by mucus are also subjected to various chemical defenses present throughout the body. For example, lysozyme is a hydrolytic enzyme found in tears, saliva, and breast milk capable of cleaving the walls of bacterial cells by hydrolyzing the 1,4 beta-lineages between residues in peptidoglycan.

In the stomach and intestines, microbes may be eliminated by the action of digestive enzymes, acid conditions, and secretions of defensins, small cationic peptides that kill both gram-positive and gram-negative micro-organisms within minutes by disrupting the microbial membrane [3,4].

When pathogens overcome the epithelial defenses, the adaptive immune response is initiated by the body's leukocytes via the recognition of common surface receptors present on the invading micro-organisms [6,11].

Cells of Innate Immunity

The cells of innate immunity are capable of recognizing microbes that share common surface receptor characteristics. In response, they initiate a broad spectrum of responses that target the invading micro-organisms. The key cells of innate immunity include neutrophils, macrophages, dendritic cells, NK cells, and intraepithelial lymphocytes [4].

Neutrophils and Macrophages

The leukocytes (white blood cells) involved in the innate immune response are derived from myeloid stem cells and subdivided into two distinct groups based on the presence or absence of specific staining granules in their cytoplasm. Leukocytes that contain granules are classified as granulocytes and include neutrophils, eosinophils, and basophils. Cells that lack granules are classified as lymphocytes or monocytes [4].

Neutrophils, which are named for their neutral-staining granules, are the most abundant granulocytes found in the blood and make up approximately 55% of all white blood cells. They are also known as polymorphonuclear neutrophils. Neutrophils are phagocytic cells capable of amoeboid-like movement and function as early responder cells in innate immunity. They are rare in the tissues and in body cavities and lay predominantly dormant in the blood and bone marrow until they are needed in the immune response.

Eosinophils have large, coarse granules and normally comprise only 1% to 4% of the total white cell count. In contrast to neutrophils, these cells ingest antigen-antibody complexes and viruses rather than cellular debris. They frequently become active in parasitic infections and allergic responses.

Basophils make up less than 1% of the total white cell count and contain granules that release a multitude of substances, including histamine and proteolytic enzymes. Their function is not completely understood, but they are believed to play a role in allergy and parasitic infection as well [4].

Monocytes are the largest in size of all the white blood cells but make up only 3% to 7% of the total leukocyte count. They are released from the bone marrow into the bloodstream, where they migrate into tissues and mature into macrophages and dendritic cells. These cells participate in the inflammatory response and phagocytize foreign substances and cellular debris. Macrophages have a long life span, reside in the tissues, and are the first phagocyte that invading organisms encounter upon entering the body. Neutrophils and macrophages work in concert with each other and are crucial to the host's defense against all intracellular and extracellular pathogens [4].

Macrophages are essential for the clearance of bacteria that reach the epithelial barrier in the intestine and other organ systems. They also have remarkable plasticity that allows them to efficiently respond to environmental signals and change their functional characteristics. This makes them more efficient than the more abundant neutrophils. Once activated, macrophages engulf and digest microbes that attach to their cell membrane. The ability of these cells to initiate this response is dependent upon recognition of pathogenic surface structures (i.e., PAMPs or PRRs), of which the toll-like receptors have been the most extensively studied. Phagocytosis of invading micro-organisms helps to limit the spread of infection until adaptive immune responses can become fully activated [4,5].

In addition to phagocytosis, macrophages process and present antigens, acting as major initiators of the adaptive immune response. These cells secrete substances that initiate and coordinate the inflammatory response on active lymphocytes. Macrophages can also remove antigen-antibody aggregates or, under the influence of T cells, can destroy malignant host or virus-infected cells [5].

Dendritic Cells

Dendritic cells are specialized, bone marrow-derived leukocytes found in lymphoid tissue and are the bridge between the innate and adaptive immune systems. These cells take their name from the dendrites within the central nervous system (CNS), because they have surface projections that give them a similar appearance. Dendritic cells are relatively rare and are found mainly in tissues exposed to external environments, such as the respiratory and gastrointestinal systems. They are present primarily in an immature form that is available to directly sense pathogens, capture foreign agents, and transport them to secondary lymphoid tissues. Once activated, dendritic cells undergo a complex maturation process in order to function as key antigen-presenting cells capable of initiating adaptive immunity. As noted, dendritic cells are responsible for the processing and presenting of foreign antigens to the lymphocytes and, like macrophages, also release several communication molecules that direct the nature of adaptive immune responses [4,5].

Natural Killer Cells and Intraepithelial Lymphocytes

NK cells and intraepithelial cells are other cell types involved in the innate immune response. NK cells are so named because of their ability to spontaneously kill target organisms. Both types of cells rely on the recognition of specific PAMPs associated with the micro-organism cell type [5].

NK cells are a heterogeneous population of innate lymphocytes that mediate spontaneous cytotoxicity against infected cells. They resemble large granular lymphocytes and are capable of killing some types of tumor and/or infectious cells without previous exposure to surface antigens. NK cells have been shown to play an equally important role in limiting the spread of infection and assisting in the development of adaptive immune responses through the production of cytokines. NK cells assist in dendritic cell maturation and innate immune control of viral infections. These cells are capable of directly killing host cells infected with intracellular (viral) or bacterial pathogenic organisms. They comprise approximately 10% to15% of peripheral blood lymphocytes but do not bear T-cell receptors (TCRs) or cell surface immunoglobulins. Two cell surface molecules have been identified—CD16 and CD56—and are widely used to identify NK cell activity. CD16 serves as a receptor for the IgG molecule, which provides NK cells with the ability to lyse IgG-coated target cells [5].

NK cells can be divided into two main subsets based upon their ability to excrete proinflammatory cytokines. In addition, they differ in their expression of inhibitor versus activating receptors. Cells that express activating receptors (NKG2D) are induced in response to pathogen-infected or stressed cells, whereas the inhibitor receptors on NK cells recognize patterns (e.g., major histocompatibility complex [MHC]-1, lectins) on normal host cells and function to inhibit the action of the cells. This assures that only "foreign" cells are destroyed. In addition to their role as phagocytes, NK cells assist in T-cell polarization, dendritic cell maturation, and innate immune control of viral infection through the secretion of immune modulators and antiviral cytokines. Investigations of the potential role of these properties for the development of vaccines that can modulate and direct the immune response though enhanced cytokine activity are ongoing [5].

Complement System

The complement system is a primary effector system that functions as part of both the innate and adaptive immune responses. It is comprised of a group of proteins that are activated by three distinct but convergent pathways: the classical, the lecithin, and the alternative pathways. The primary function of the complement system is the promotion of inflammation and the destruction of microbes [10].

The complement system is found in the blood and is essential for the activity of antibodies. It is comprised of 20 different proteins, many of which act as precursors of enzymes. An antigen-antibody complex initiates this system. Activation of the complement system increases bacteria aggregation, which renders them more susceptible to phagocytosis through activation of mast cells and basophils through the direct release of C3 and C5 from dendritic cells.

ADAPTIVE IMMUNITY

The adaptive immune response involves a complex series of interactions between components of the immune system and the antigens of a foreign pathogen. It is the final line of defense against infection and is activated after the innate immune response initiates the inflammatory process. In contrast to innate immunity, the adaptive immune response is capable of targeting specific cells or organisms that it recognizes as foreign to the body through activation of various lymphocytes and their products, including antibodies. The lymphocytes involved in adaptive immunity have the unique ability to remember specific pathogens and mount a heightened immune response during repeat exposures. Each exposure results in a more rapid and aggressive response. Substances present on the surface of pathogens are called antigens [10,12].

Adaptive immunity is comprised of two distinct but inter-related processes: cell-mediated and humoral immunity. Together, they respond to foreign antigens, amplify and sustain immunologic responses, distinguish self-from non-self, and confer "memory" so a heightened response can be initiated on subsequent exposures to an organism. Antigens are usually a substance foreign to the host that can stimulate an immune response. They possess specific antigenic binding sites (epitopes) for the cells of the immune system. Epitopes allow the adaptive immune system to distinguish foreign antigens from normal cellular substances whose destruction would be detrimental to the organism [5].

Humoral immunity is mediated by B-lymphocyte activation and subsequent antibody production. It is the primary defense against extracellular microbes and toxins. In contrast, cell-mediated immunity involves the activation of specific T lymphocytes (i.e., T-helper and T-cytotoxic lymphocytes), which are responsible for the body's defense against intracellular microbes such as viruses [10].

Antigens

Antigens, or immunogens, are substances or molecules that are foreign to the body that trigger the production of antibodies by B lymphocytes, leading to the ultimate destruction of the invader. They are usually large macromolecules (>10,000 Da) such as proteins, polysaccharides, lipids, and free nucleic acids. Antigens are recognized by specific receptors present on the surface of lymphocytes and by the antibodies or immunoglobulins secreted in response to the antigen. Antigens can take the form of any foreign substance, including bacteria, fungi, viruses, protozoa, parasites, and non-microbial agents such as plant pollens, insect venom, and foreign materials (including transplanted organs) [12].

Antigens possess immunologically active sites called antigenic determinants or epitopes. These are smaller, discrete components of the antigen that have a unique molecular shape that can be recognized by and bound to a specific immunoglobulin receptor found on the surface of the lymphocyte or by an antigen-binding site of a secreted antibody. It is not unusual for a single antigen to possess several epitopes and, therefore, be capable of stimulating several different T and B lymphocytes. For example, different proteins that comprise the influenza virus may function as unique antigens (A, B, C, H, and N antigens), each of which contain several epitopes. Hundreds of epitopes are found on structures such as a bacterial cell wall [12].

Low-molecular-weight molecules (<10,000 Da) may contain epitopes but alone are usually unable to stimulate an immune response. These molecules are known as haptens. When they are complexed with an immunogenic carrier (usually a protein), they function as antigens. Many haptens exist in nature and frequently create problems for humans. One example of a hapten is urushiol, a toxin found in the oils of poison ivy that is responsible for initiating an allergic contact dermatitis. An allergic response to the antibiotic penicillin is an example of a medically important reaction due to hapten-carrier complexes. The penicillin molecule is very small (350 Da) and usually non-antigenic. However, in susceptible people it can complex with carrier proteins in the body, which are then recognized as "foreign," initiating an antigen-antibody reaction [12].

Cells of Adaptive Immunity

The principal cells of the adaptive immune system are the B and T lymphocytes, antigen-presenting cells, and effector cells that are responsible for the elimination of antigens [5]. The functions of these cells will be discussed at length in the following sections.

Lymphocytes

Lymphocytes make up approximately 36% of the total white cell count and are the primary cells of the adaptive immune response. They arise from stem cells in bone marrow. B lymphocytes are responsible for forming the antibodies that provide humoral immunity, whereas T lymphocytes provide cell-mediated immunity. T and B lymphocytes are unique in that they are the only cells in the body capable of using cellular "memory" to assess the surfaces of microbial agents and other pathogens to recognize specific pathogens. These processes make the adaptive immune processes organism-specific [5]. Many autoimmune diseases, such as Hashimoto thyroiditis and type 1 diabetes, are caused by impairment in both B and T lymphocyte (specifically cytotoxic lymphocyte) functions, resulting in direct cellular damage because the body's immune system is no longer capable of distinguishing "self" from "non-self" [4].

The recognition of specific surface antigens by lymphocytes is made possible because of the presence of specific receptors or antibodies on the surface of B and T lymphocytes. Scientists have been able to identify these specific proteins and correlate them with a particular cellular function. This has lead to the development of a classification system for surface molecules known as the cluster of differentiation (CD). The nomenclature for the surface proteins utilizes the letters CD followed by a number that specifies the surface proteins that define a particular cell type or stage of cell differentiation and are recognized by a cluster or group of antibodies. Use of this nomenclature has spread to other immune cells and cytokines, all of which contribute to the acquired immune response [5].

Lymphocytes involved in the innate immune response, such as macrophages and dendritic cells, also play a key role in adaptive immunity because they function as antigen-presenting cells. These cells are capable of processing complex antigens into epitopes, which are then displayed on their cell membranes in order to activate the appropriate lymphocytes. Functionally, there are two types of immune cells: regulatory cells and effector cells. The regulatory cells assist in orchestrating and controlling the immune response, while effector cells carry out the elimination of the antigen. In the body, helper T lymphocytes activate the other lymphocytes and phagocytes, while regulatory T cells keep these cells in check so that an excessive immune response does not occur. Cytotoxic T lymphocytes, macrophages, and others function as effector cells in different immune responses [5].

While T and B lymphocytes are generated from lymphoid stem cells in the bone marrow, they do not stay there to mature. Undifferentiated, immature lymphocytes migrate to lymphoid tissues, where they develop into distinct types of mature lymphocytes. The T lymphocytes first migrate to the thymus gland, where they divide rapidly and develop extensive diversity in their ability to react against different antigens. Each T lymphocyte develops specificity against a specific antigen. After this differentiation occurs, the lymphocytes leave the thymus gland and migrate via the bloodstream to peripheral lymphoid tissue. At this time, they have been preprogrammed not to attack the body's own tissues, but it is believed that this process may go astray in the pathogenesis of autoimmune diseases. High concentrations of mature lymphocytes are found in the lymph tissue throughout the body including the lymph nodes, spleen, skin, and mucosal tissues [12].

T and B lymphocytes engage in all of the processes necessary for the adaptive immune response—specificity, diversity, memory, and self/non-self recognition. When antigens come in contact with lymphocytes in the lymphoid tissues of the body, specific T cells become activated and specific B cells are stimulated to produce antibodies. After the first encounter occurs, these cells can exactly recognize a particular micro-organism or foreign molecule. Cell-mediated and humoral immunity are capable of responding to millions of antigens each day because there is an enormous variety of lymphocytes that have been programmed and selected during cellular development. Lymphocytes capable of "remembering" the presenting antigen are called "memory" T and B lymphocytes. They remain in the body for a longer period of time than their predecessors and as a result can respond more rapidly on repeat exposures. The system usually can respond to commonly encountered micro-organisms so efficiently that it is undetectable [12,13].

The antigen receptor present on the B lymphocyte consists of membrane-bound immunoglobulin molecules that can bind a specific epitope. However, in order for B lymphocytes to produce antibodies, they require the assistance of helper T cells. While B lymphocytes bind to one determinant (or hapten) on an antigen molecule, the antigen-specific helper T cell recognizes and bonds to another determinant known as the "carrier." The carrier is an antigen-presenting cell that has previously picked up the specified antigen. This interaction (B cell-T cell-antigen-presenting cell) is restricted by the presence of cellular products genetically encoded by a self-recognition protein, called an MHC molecule. This allows the lymphocyte to differentiate between self and foreign peptides [12,13].

After the B and T lymphocytes are activated and amplified by cytokines released as part of the innate response, the lymphocytes divide several times to form populations or clones of cells that continue to differentiate into several types of effector and memory cells. In the adaptive immune response, the effector cells destroy the antigens and the memory cells retain the ability to target antigen during future encounters [13].

Major Histocompatibility Complex (MHC) Molecules

The lymphocytes are designed to respond to a limitless number of antigens, but at the same time, they need to be able to ignore self-antigens expressed on tissue; MHC molecules enable the lymphocytes to do just this. The MHC is a larger cluster of genes located on the short arm of chromosome 6. The complex occupies approximately 4 million base pairs and contains 128 different genes, only some of which play a role in the immune response. The MHC genes are divided in three classes (I, II, and III) based on their underlying function [13].

The class I and II MHC genes are responsible for encoding human leukocyte antigens (HLAs), which are proteins bound on cell surfaces that define the individual's tissue type. These molecules are present on cell-surface glycoproteins that form the basis for human tissue typing. Each individual has a unique collection of MHC proteins representing a unique set of polymorphisms. MHC polymorphism affects immune responses as well as susceptibility to a number of diseases. Because of the number of MHC genes and the possibility of several alleles for each gene, it is almost impossible for any two individuals to have an identical MHC profile [13].

The class I and II MHC genes also encode proteins that play an important role in antigen presentation. Protein fragments form inside the cell and are displayed on the cell surface, allowing the immune system to differentiate between the body's own tissues and foreign substances. Cells, which present unfamiliar peptide fragments on the cell surface, are attacked and destroyed by the B and T lymphocytes. Class III MHC genes encode for many of the components of the complement system and play an important role in the innate immune process [13].

MHC-I complexes contain a groove that accommodates a peptide fragment. T-cytotoxic cells can only become activated if they are presented with a foreign antigen peptide. MHC-I complexes may present degraded viral protein fragments from infected cells. MHC-II molecules are found only on phagocytic antigen-presenting cells, including the macrophages, dendritic cells, and B lymphocytes, which communicate with the antigen receptor and CD4s molecule on T-helper lymphocytes [13].

Like MHC-I proteins, MHC-II proteins have a grove or cleft that binds a fragment of antigen. However, these bound fragments form pathogens that have been engulfed and digested during the process of phagocytosis. The engulfed pathogen is degraded into free peptide fragments within cytoplasmic vesicles and then complexed with the MHC-II molecules on the surface of the cells. T-helper cells recognize the complexes on the surface of antigen-presenting cells and become activated [13].

B Lymphocytes and Humoral Immunity

The humoral immune response is mediated by antibodies produced by the B lymphocytes. The primary functions of the B lymphocytes are the elimination of extracellular microbes and toxins and subsequent "memory" for a heightened response during future encounters. Humoral immunity is more important than cellular immunity in defending against microbes with capsules rich in polysaccharides and lipid toxins, because only the B lymphocytes are capable of responding to and producing antibodies specific for many types of these molecules. The T cells, which are the mediators of cellular immunity, respond primarily to surface protein antigens [14].

As discussed, B lymphocytes are produced in the bone morrow and are classified according to the MHC-II proteins, immunoglobulins, and complement receptors expressed on the cell membrane. During development, immunoglobulin gene rearrangement takes place to ensure that only B lymphocytes are capable of producing antibodies. At each stage of development, a cell-specific pattern of immunoglobulin gene is expressed, which then serves as a phenotypic marker of these maturational stages. The B lymphocyte progenitors are known as pro-B and pre-B cells, and both develop into mature B cells. They can be functionally removed from the body as a result of interaction with a self-antigen, by undergoing programmed cell death (apoptosis), or by the process of energy metabolism, whereby they become nonresponsive in the presence of the antigen. When B lymphocytes become fully mature, they become capable of expressing IgD, in addition to the IgM on the cell membrane surface. Mature B lymphocytes are fully responsive to antigens and are capable of interacting with T cells' membrane surface [14].

T Lymphocytes and Cellular Immunity

T lymphocytes serve many functions in the immune system, including the activation of other T cells and B cells, control of intracellular viral infections, rejection of foreign tissue grafts, activation of autoimmune processes, and activation of delayed hypersensitivity reactions. These processes make up the body's cell-mediated or cellular immunity. The effector phase of cell-mediated immunity is carried out by T lymphocytes and macrophages [14].

As discussed, T lymphocytes arise from lymphoid stem cells and migrate to the thymus gland to undergo the process of maturation. The thymus gland is richly innervated and produces several peptide hormones (e.g., thymosin, thymopoietin) believed to be involved in T-cell maturation. T-cell precursors are abstracted to the thymus by thymotaxin, a chemotactic factor secreted by the epithelial cells. After the prothymocyte enters the cortex of the thymus, terminal deoxynucleotidyl transferase is expressed, causing gene rearrangement and increased TCR diversity. The pre-T lymphocytes are designated CD3, CD4, CD8, and double-negative cells. The majority of these cells go on to rearrange their alpha and beta chain gene segments. The beta segment is expressed first, resulting in the formation of a pre-TCR. This halts further gene rearrangement, enhances alpha chain gene arrangement, and causes full maturation and expression of CD4 (helper) and CD8 (cytotoxic) lymphocytes. Mature T lymphocytes leave the thymus and migrate to peripheral lymphoid tissues, where they multiply and differentiate into memory T cells and various other mature lymphocytes upon encountering an antigen [14].

The majority of TCRs recognize antigenic peptides that are bound to MHC-derived molecules. CD4 and CD8 help stabilize the TCR-antigen-MHC complex during T-cell activation. The TCR is also characterized by their surface molecules (the CD3 complex), which aid in cell signaling [14].

Lymphoid Organs

The central and peripheral lymphoid organs are responsible for the production, maturation, and storage of large numbers of immune system cells, including the B and T lymphocytes. These organs and tissues are widely distributed throughout the body and provide different, but often overlapping, functions. The central lymphoid organs are comprised of the bone marrow and the thymus and are responsible for immune cell production and maturation. The tissues and cells of the peripheral lymph node system store the cells of the immune system, where they function to concentrate and process antigens as well as support cellular processes necessary for the development of fully functioning adaptive immune responses. These peripheral lymphoid tissues are comprised of the lymph nodes, spleen, tonsils, appendix, Peyer patches in the intestine, and mucosa-associated lymphoid tissues in the respiratory, gastrointestinal, and reproductive systems. Networks of lymph channels, blood vessels, and capillaries connect the lymphoid organs and transport immune cells, antigens, and cellular debris throughout the body [7].

Thymus

The thymus is an elongated, bilobed structure located in the mediastinum above the heart and serves as a specialized immune system organ. Each lobe is surrounded by a connective issue capsule layer and is further divided into lobules. The lobules can be divided into an outer cortex and a central medulla, each of which plays a different role in the process of T-lymphocyte maturation. The outer cortex contains densely packed immature T lymphocytes (thymocytes). The inner medulla is a less dense area of tissue that contains fewer but more histologically mature lymphocytes. The medulla is comprised of Hassall corpuscles but also stores dendritic cells and macrophages [7].

The thymus is essential to the development of the immune system because it is responsible for the production of mature, immunocompetent T lymphocytes. The thymus is a fully developed organ at birth, weighing up to 15 g. It is most active in the neonatal and preadolescent periods. At puberty, when the immune cells are well established in peripheral lymphoid tissues, the thymus begins to atrophy and is replaced by adipose tissue. Nevertheless, residual T-lymphocyte production continues throughout adult life. Pre-T cells enter the thymus as functionally and phenotypically immature T cells. They then mature during different cycles and then move from the cortex to the medulla. After full maturation, they are released into the peripheral lymphoid tissues. Rapid cell division, maturation, and selection occur in the cortex under the influence of thymic hormones and cytokines. As T cells mature, they develop the TCRs that differentiate them. The majority of thymocytes die in the cortex during the process of gene arrangement and maturation because they fail to develop the appropriate receptor types on their cell membranes. Only those T cells capable of recognizing foreign antigen displayed by self MHC are allowed to mature. This process is called thymic selection. Mature, immunocompetent T-helper and T-cytotoxic cells leave the thymus in two to three days and enter the peripheral lymphoid tissues through the bloodstream [7].

Lymph Nodes

Lymph nodes are small aggregates of lymphoid tissue located along lymphatic vessels throughout the body. The lymphatic vessels carry lymph, which is a clear or yellow-tinged fluid that contains a variety of white blood cells (predominantly lymphocytes) and transports cellular debris and organisms to the nodes to be removed from the body. Each lymph node processes lymph from a discrete, adjacent anatomic site. Lymph nodes are congregated in the axilla and groin and along the great vessels of the neck, thorax, and abdomen. These nodes receive lymph from the collecting ducts, which ultimately drain into the thoracic duct in the left side of the chest at the level of the subclavian vein. Lymph nodes have two functions: removal of foreign material before it enters the bloodstream and proliferation and organization of immune cells [7].

Lymph nodes are bean-shaped, encapsulated tissues, approximately 0.5–1 cm in diameter. Lymph enters the node through afferent lymph channels and leaves through the efferent lymph vessels located in the deep indentation of the hilus. Lymphocytes and macrophages move slowly through the lymph nodes so they have adequate time to engulf micro-organisms and interact with circulating antigens. The lymphatic system provides a large surface upon which macrophages and dendritic cells can more easily present antigens to T lymphocytes [7].

Lymph nodes are divided into three distinct and specialized areas: an outer cortex, a paracortex, and an inner medulla. T lymphocytes predominate in the paracortex. Within the follicles, the lymphocytes continue to mature, replicate, and interact with the antigen-presenting cells in the nodes (e.g., macrophages, follicular dendritic cells). Activated B cells then migrate to the medulla of the lymph node, where they complete their maturation to plasma cells. Large quantities of antibodies are then released into systemic circulation [7].

Spleen

The spleen is a large, ovoid, secondary lymphoid organ located high in the left upper quadrant of the abdominal cavity, between the diaphragm and the stomach. The spleen filters antigens from the blood and is important in the response to systemic infections. It is divided into two distinct areas: the white pulp and the red pulp. The red pulp is well-supplied with arteries and venous sinusoids and is the area where senescent and injured red blood cells are removed. The white pulp contains lymphatic nodules and diffuse lymphoid tissues. This is where concentrated areas of B and T lymphocytes permeated by macrophages and dendritic cells exist. The lymphocytes (primarily T cells) that surround the central arterioles form the periarterial lymphoid sheath. There is also a diffuse marginal zone that contains the follicles and germinal centers and is rich in B cells. This separates the white pulp from the red pulp and allows lymphocytes to move easily between the blood and the lymphatic tissue. A sequence of activation events similar to that seen in the lymph nodes occurs in the spleen [7].

Other Secondary Lymphoid Tissues

Other secondary lymphoid tissues include the mucosa-associated lymphoid tissues, which are nonencapsulated clusters of lymphoid tissue located around membranes lining the respiratory, digestive, and urogenital tracts. These organ systems constantly come in contact with pathogens and toxins and therefore require the presence of immune cells in order to respond to the potential invasion. In some tissues, the lymphocytes are organized in loose, nondescript clusters, but in other tissues (e.g., the tonsils, Peyer patches in the intestine, the appendix) their structure is better organized. These tissues contain all the cellular components (i.e., T cells, B cells, microplates, and dendritic cells) required to mount an immune response. Immunity at the mucosal layers helps to exclude many pathogens from the body and, as a result, protects the more vital internal structures [7].

3. IMMUNITY IN SPECIAL POPULATIONS

TRANSFER OF IMMUNITY FROM MOTHER TO INFANT

Development of the immune system begins early in fetal life, at approximately 5 to 6 weeks' gestation, when the fetal liver actively begins hematopoiesis. At about the same time (6 weeks' gestation), the thymus arises from the third branchial arch, with the cortex arising from its ectodermal layer and the medulla from the endoderm. Over the next two to three weeks, lipoid cells initially migrate from the yolk sac and fetal liver and then from the bone marrow to colonize the fetal thymus. Development of the secondary lymphoid organs (spleen, lymph nodes, and mucosa-associated lymphoid tissues) begins soon after. The secondary lymphoid organs are rather small but well-developed at birth and mature rapidly after exposure to microbes during the postnatal period. The thymus is the largest lymphoid tissue in the neonate relative to body size and normally reaches its mature weight by 1 year of age [5].

Neonates are protected against antigens in early life as result of passive transfer of maternal IgG antibodies through the placenta and IgA antibodies in colostrum. Maternal IgG antibodies readily cross the placenta during fetal development and remain functional in the newborn for the first few months of life, providing passive immunity until immunoglobulin production is well established in the newborn. IgG is the only class of immunoglobulins able to cross the placenta. Maternally transmitted IgG is effective against most micro-organisms and viruses that a neonate encounters. The largest amount of IgG crosses the placenta during the last weeks of pregnancy and is stored in fetal tissues. Infants born prematurely may be deficient in maternal antibodies and, therefore, more susceptible to infections. Because of transfer of IgG antibodies to the fetus, an infant born to a mother infected with human immunodeficiency virus (HIV) has a positive HIV antibody test result, although the child may not be infected with the virus [3].

Cord blood does not normally contain IgM or IgA. If present, these antibodies are of fetal origin and represent exposure to intrauterine infection. Normally, the neonate begins producing IgM antibodies shortly after birth, as a result of exposure to the antigens normally found in the surrounding environment. However, this IgM is of lower binding affinity and is effective only against a limited range of antigens. It has been demonstrated that premature infants can produce IgM as well as term infants. At approximately 6 days of age, the IgM level rises sharply, and this rise continues until approximately 1 year of age, when the adult level is achieved against a limited range of antigens [3].

Serum IgA is typically not present at birth but is detected in the neonate approximately 13 days after birth. The levels of IgA increase during early childhood and reach a normal range between 6 and 7 years of age. While maternal IgA is not transferred in utero, it is transferred to the breast-fed infant in colostrum and breast milk. Because IgA antibodies are associated with mucosal membranes, these antibodies provide local immunity for the intestinal system during early life [3].

IMMUNE RESPONSE IN THE OLDER ADULT

As people age, the ability of the immune system to protect the body from pathogenic organisms and environmental toxins declines in relation to an overall decline in both cell-mediated and humoral immune responses. Therefore, older adults are more susceptible to infections, have more evidence of autoimmune and immune complex disorders, and have a higher incidence of cancer than younger people. In addition, the immune system of older adults is less likely to respond appropriately to immunization, resulting in a weakened response to vaccination. Older adults also frequently have comorbid conditions that impair normal immune function and compromise the immune response [10].

Many changes occur with aging, but the exact immunologic mechanisms are not completely understood and are believed to be multifactorial. There is a continued decrease in the size of the thymus gland, which begins during puberty and affects overall T-cell production and function. Later in life, the size of the thymus diminishes to 15% or less of its maximum size. There may also be a decrease in the number of the lymphocytes in the peripheral lymphoid tissue. The most common finding is a slight decrease in the proportion of T cells to other lymphocytes and a decrease in CD4 and CD8 cells [10].

Aging also produces qualitative changes in lymphocyte function. Lymphocytes seem to exhibit altered responses to antigen stimulation, with an increased proportion becoming unresponsive to activation. It appears that CD4 T lymphocytes are most severely affected, because there is a decreased rate of synthesis of the cytokines that stimulate the proliferation of lymphocytes and expression of the specific receptors that interact with the circulating cytokines. Specifically, IL-2, IL-4, and IL-12 levels decrease in older adults. While actual B-cell function is compromised with age, the range of antigens that can be recognized by B cells does not change [10].

4. IMMUNE HYPERSENSITIVITY DISORDERS

ALLERGIES

An immune system that is malfunctioning predisposes an individual to the development of a wide variety of diseases ranging from severe infection to autoimmune disease and the resultant tissue injury [12]. Nurses care for patients with allergic conditions far more often than might be suspected. Allergic rhinitis, asthma, and dermatitis are a few examples of these immunologic diseases [11].

The genetic predisposition to develop allergies that involve IgE antibody formation is known as atopy. The terms atopic, allergic, and hypersensitive are frequently used interchangeably. Allergy (or, more appropriately, hypersensitivity) describes the increased immune response to the presence of an antigen. Between 20% and 30% of the population have allergies. Although it is not possible to predict who will have allergies, there is a higher incidence of allergies among children of parents with allergies [11,15].

The development of allergy is a two-step process. Step one is sensitization. Sensitization occurs when one develops IgE antibodies against a substance that is inhaled, ingested, or injected. Newly formed IgE antibodies stick to basophils and mast cells, which are found in the skin's mucosal surfaces and in the respiratory and gastrointestinal tracts. Hypersensitivity develops only after IgE antibodies against a certain foreign substance and have formed and are bound to the surface of tissue mast cells and circulating basophils [11,15].

Sensitization does not produce any of the manifestations typically associated with allergic disease. It is not until step two—re-exposure to the allergen—that allergic manifestations and anaphylaxis occur. Although the cellular events for all immediate allergic reactions tend to be similar, differences are found in the clinical sequelae, based on the state of the individual's host defenses, the nature of the allergen, the concentration and amount of the allergen, the route of exposure, and which organ is affected [11,15].

Etiology and Risk Factors

Host Defenses

Some people are more susceptible to hypersensitivity than others for reasons that are unclear. The increasing prevalence of allergic disease suggests that environmental factors acting either before or after birth contribute to the regulation of the development of the T helper type 2 cells or their functions. T helper type 2 cells play a triggering role in the activation and recruitment of IgE antibody-producing B cells, mast cells, and eosinophils, the cellular triad involved in allergy. The decrease in the number of reported childhood infectious diseases that has resulted from vaccination programs, antimicrobial therapy, and changing lifestyles is an important factor in an individual's response to an allergen. Specific IgE formation can be influenced by viral infections, especially those caused by cytomegalovirus (CMV) and mononucleosis. Other factors, including sex, age, and exposure to secondhand smoke and other air pollution, can influence the manifestation of allergies [15].

Researchers believe that IgE once helped individuals ward off common ancient parasites; although IgE is not needed today, the body continues to manufacture it [16]. Most individuals are unaffected by the presence of IgE, as it only accounts for about 1% of all antibodies [16]. However, millions of individuals have inherited the genetic predisposition to overproduce IgE; in some cases, B cells release up to 20 times the normal amount of IgE. If an excess of the antibody is produced, the immune system may over-react to routine substances. Each substance to which an individual is sensitive triggers a different IgE antibody; any one of these substances could result in allergies.

Nature of the Allergen

Allergens are proteins that are capable of inducing IgE antibodies, thus triggering an allergic response. Haptens, along with other environmental allergens, are carried on vectors that may become airborne (e.g., pollen, molds, dust particles, animal dander). Contact with these allergens causes sensitization and evokes the acute manifestations of allergy. Some haptens (e.g., penicillin) are highly antigenic [15].

Concentrations of the Allergen

Higher concentrations of an allergen in an initial exposure usually result in hypersensitivity responses of greater intensity. Lower concentrations of the allergen may then cause severe manifestations when a re-exposure occurs [15].

Routes of Exposure

Routes by which allergens may enter the body include inhalation, injection, ingestion, and direct contact. Most allergens are inhaled [17].

Exposures to the Allergen

Factors that influence the likelihood of allergy development include a person's age at the time of exposure (i.e., exposure early in life), the type of allergen (e.g., house dust mite, cockroach, various medications, pollen), the allergen load, and the month of a person's birth (as a greater affinity for allergies is seen in those born in the spring and fall) [17,18].

Types of Hypersensitivity Reactions

Hypersensitivity relations are divided into four main types [19]:

- Type 1: Immediate or anaphylactic

- Type 2: Cytolysis or cytotoxic

- Type 3: Immune complex

- Type 4: Cell-mediated or delayed

Type 1 (Immediate or Anaphylactic) Hypersensitivity

Examples of type 1 hypersensitivity reactions include anaphylaxis, allergic rhinitis, asthma, and acute allergic drug reactions [19]. The immediate (antigen-antibody) reaction occurs within minutes after exposure to the allergen. The resultant IgE production induces the immediate response by activating mast cells and basophils, causing them to degranulate and release mediators such as histamine, leukotrienes from basophils and prostaglandins, and platelet-activating factors from eosinophils. The mediators, whether preformed or formed after activation, are able to increase vascular permeability, dilate vessels, contract smooth muscle, and ignite other inflammatory cells [18].

Manifestations of mediator release vary, depending on the organ where the mediator's receptors are found. For example, histamine is a preformed mast cell mediator that has receptors in the skin, oral and nasal mucosa, lungs, and smooth muscle in the gastrointestinal tract. After histamine binds to its receptor, it can cause many reactions. Vasodilation causes edema; smooth muscle contraction results in dangerous airway narrowing; and glandular stimulation leads to increased secretion of mucus in the nose, lungs, and gastrointestinal tract [18].

Newly formed mediators, including lipid mediators and cytokines, are made after the mast cell had been activated and have similar actions to those of histamine. However, their effects tend to last much longer. Once released into the blood and after binding to their receptors, these mediators cause more bronchial smooth muscle contraction, vasodilation, nasal congestion, and edema [18].

Type 2 (Cytolysis or Cytotoxic) Hypersensitivity

Cytolysis or cytotoxic reactions are complement-dependent and thus involve IgG or IgM antibodies. The antigen-antibody binding results in activation of the complement system and destroys the cell on which the antigen is bound (usually a circulating blood cell), causing tissue injury. Examples of tissue injury caused by type 2 hypersensitivity include hemolytic anemia, Rh hemolytic disease in newborns, autoimmune hyperthyroidism, myasthenia gravis, and blood transfusion reactions [19].

During a blood transfusion, blood group incompatibility causes cell lysis, which results in a transfusion reaction. The antigen responsible for initiating the reaction is a part of the donor red blood cell membrane. Manifestations of a transfusion reaction result from intravascular hemolysis of red blood cells and include headache, flank pain, chest pain similar to angina, nausea and vomiting, tachycardia, hypotension, hematuria, and urticaria [19].

Transfusions of more than 100 mL of incompatible blood can result in severe, permanent renal damage, circulatory shock, and death. Therefore, if manifestations develop, the transfusion should be stopped at once [19]. However, routine blood typing prior to transfusion makes this complication very unlikely. More commonly, hemolytic disease develops in newborns whose blood type is incompatible with the mother's. In these cases, the newborn may display edema, jaundice, anemia, enlarged liver or spleen, and hydrops. Treatment usually consists of antibody (intravenous immunoglobulin) and fluid administration. In severe cases, exchange transfusion may be necessary.

Type 3 (Immune Complex) Hypersensitivity

Immune complex reactions result when antigens bind to antibodies, leading to tissue injury. The molecular size of the antigen-antibody complex is an important factor, as larger complexes are rapidly cleared by phagocytic cells. The smaller complexes formed in antigen excess persist longer in the circulation because they are not so easily captured by phagocytic cells in the spleen and liver. Inflammation results and leads to acute or chronic disease of the organ system in which the immune complexes were deposited [19,20].

Immune complex-mediated inflammation is produced by IgG or IgM antibodies, antigens, and complements. The mediators of inflammatory injury include the complement peptides, which can activate mast cells, neutrophils, monocytes, and other cells. The release of lysosomal granules from white blood cells and macrophages causes further tissue injury [19,20].

The antigen may be tissue-fixed or released locally, as in Goodpasture syndrome. In this syndrome, circulating antibodies react with autologous antigens in the glomerular basement membranes of the kidneys, causing inflammation of the glomerulus [19,20].

Antigen-antibody complexes are formed in the bloodstream and get trapped in capillaries or deposited in vessel walls, causing urticaria, arteritis, or glomerulonephritis. Alternatively, antigen-antibody complexes may form in the joint space, with resultant synovitis, as in rheumatoid arthritis and systemic lupus erythematosus. An Arthur reaction is a localized area of tissue necrosis that results from immune complex hypersensitivity [19,21].

The antigen may also be circulating, as in serum sickness. Serum sickness develops 6 to 14 days after injection with a foreign serum. Deposition of complexes on vessel walls causes complement activation, with resultant edema, fever, inflammation of blood vessels and joints, and urticaria. Classic serum sickness is rare because large doses of heterologous serum (horse antiserum to human lymphocytes) are seldom used today [19,21]. A serum sickness-like reaction may occur, however, after administration of such medications as penicillin, sulfonamides, streptomycin, thiouracils, and hydration compounds. Rather than being dominated by cutaneous vasculitis, these reactions more often manifest with fever, arthralgia, lymphadenopathy, and urticaria. The illness is usually benign and self-limiting, and it reverses after discontinuation of the offending medication(s) [19,21].

Type 4 (Cell-Mediated, Late-Phase, or Delayed) Hypersensitivity

In cell-mediated hypersensitivity, sensitized T cells respond to antigens by releasing lymphocytes, some of which direct phagocytic cell activity. This reaction occurs 24 to 72 hours after exposure to an allergen. Delayed hypersensitivity is induced by chronic infections or by contact sensitivities (e.g., contact dermatitis) [21,22].

A type 4 reaction is used to test for tuberculosis infection. An injection of tuberculosis antigen or purified protein derivative is given, and if the patient has been sensitized to tuberculosis, T cells react with the antigen at the injection site. The reaction leads to local edema and fibrin deposits, which result in the induration characteristic of a positive tuberculosis reaction [21,22].

Graft-versus-host disease and transplant rejection are also type 4 reactions. In graft-versus-host disease, donor immune cells (the graft) react against various antigens in the recipient (host). It is particularly common after allogeneic bone marrow transplant. Various clinical manifestations result, including dermatitis, hepatitis, and enteritis [21,22].

Contact dermatitis is a type 4 reaction that occurs after sensitization to an allergen, commonly a cosmetic, adhesive, topical medication, drug additive (e.g., lanolin added to lotions), or plant toxin (such as poison ivy). With the first exposure, no reaction occurs, but antigens are formed. On subsequent exposures, hypersensitivity reactions are triggered, which lead to pruritus, erythema, and vesicular lesions [21,22].

Diagnosis

The diagnosis of an allergic disease is based on the patient's history, manifestations experienced during or after allergen exposure, and the results from allergy testing. Common allergy tests include [22]:

- Skin testing

- Blood testing with radioallergosorbent test (RAST), enzyme-linked immunosorbent-assay (ELISA), or fluoroenzyme immunoassay (FEIA) to measure IgE levels to certain allergens in vitro

- Pulmonary function tests to diagnose asthma

- Blood assays for IgE levels

Patient History and Nursing Assessment

Nurses play a crucial role in obtaining a detailed medical history of the patient and ensuring that appropriate diagnostic tests are performed. The most important part of evaluating a patient with suspected allergy is the history. The history should elicit all the patient's current manifestations and triggers. It is important for clinicians to know whether the manifestations are always present or if they worsen at specific times of the day or year [23].

Indoor allergens can cause significant distress. House dust mites, cockroaches, and animal allergens are problematic and are present year-round in many homes. Nurses should assess whether animals are present in the home and, if so, how many. Is the house filled with plants that could harbor mold spores? Is the patient exposed to moist rooms, such as a basement that is constantly damp [23]?

Environmental factors (e.g., smoke) can exacerbate allergic manifestations. Determining where and when these manifestations present is very important. Many occupations involve exposure to certain allergens (e.g., smoke, latex, chemicals, animals), and manifestations may be reported as worse during the workweek compared with the weekend. A careful search for environmental factors should be undertaken, with the patient questioned in detail regarding the home environment, including location and type of heating, insulation, humidity, bedding, carpeting, and method of house cleaning [24]. Inquiries such as these help to narrow possible causes of allergy symptoms [23].

Skin Testing

With intradermal or injection skin testing, the healthcare practitioner introduces a small quantity of allergen into the skin by quickly pricking, scratching, or puncturing it or by using intradermal injections. A wheal and flare reaction usually occurs soon after the allergen is introduced if the patient is allergic. This type of skin testing is the most accurate, but it is linked to a higher incidence of severe allergic reactions. Therefore, it should be used with caution and under close supervision. A patch test can be used to evaluate contact allergies; the allergen is applied directly to the skin and then covered with a gauze dressing [25]. Skin testing is generally considered safe, but it always carries a risk of causing a systemic reaction such as anaphylaxis [25].

Nurses often administer skin tests and interpret test results. An immediate reaction (appearing within 10 to 20 minutes after exposure), marked by erythema and wheal formation greater than 3 mm of the positive control (usually histamine), denotes a positive reaction. Positive reactions indicate antibody response to previous exposure to this antigen and suggest that the patient is allergic to the particular substance. Negative reactions may be inconclusive, requiring further assessment. Negative results may indicate antibodies have not formed to this antigen, the antigen was deposited too deeply into the skin (subcutaneously), the patient is immune suppressed from disease or therapies (e.g., steroids, chemotherapy, radiation therapy), or the patient has taken antihistamines within the past 72 hours [25].

Problems that arise from skin testing range from minor itching to anaphylaxis. Itching and discomfort at the site are common and can be relieved by the application of cool compresses, topical steroid or antihistamine creams, and/or oral antihistamines such as diphenhydramine (Benadryl). Ulceration of the injection site is best treated by keeping the area clean and dry. Anaphylactic shock is a rare but potentially lethal complication of skin testing. A patient with a history of an anaphylactic reaction to a substance should never undergo skin testing for an allergy to that substance, particularly if the allergen is known to cause severe reactions (e.g., penicillin) [25].

Radioallergosorbent Test

The RAST uses the principle of immune absorption and reveals elevated levels of allergen-specific IgE associated with atopy. The allergen of interest is first bound to an insoluble material, which is then incubated with the patient's blood. If the patient has antibodies specific to the allergen being tested, they bind to that allergen. The unbound antibodies are washed away, and the level of antigen-specific IgE can be measured. This test is somewhat less sensitive than skin testing and is more time-consuming and costly [24]. It has generally been replaced by FEIA or ELISA tests.

ELISA and ImmunoCAP FEIA

Immunometric blood assays, also known as sandwich ELISAs, measure the total amount of IgE normally present in the circulation. Most studies have shown that blood concentrations of IgE are increased in the presence of allergic disease; however, a normal or even decreased level may occur in IgE-mediated sensitivities. Elevated serum eosinophil levels also may suggest hypersensitivities [24].

ImmunoCAP FEIA uses a flexible, hydrophobic cellulosic disk to which an allergen has been linked. The advantage of this system is that it has a very high antigen-binding capacity and minimal nonspecific binding, with high total IgE output. This test is more widely used today than RAST based on its increased sensitivity and equal specificity [24].

Pulmonary Function Tests

Pulmonary function tests calculate the amount and rate of air expelled during a single breath, helping to discern whether constricted airways are responsible for blocked airflow [16]. Guidelines for normal breathing are based on analysis of data obtained from large segments of the population. A patient's information is plotted on a continuum, allowing comparison to average breathing patterns for healthy individuals of the same sex, age, and size. Two common methods of measuring airflow assess forced expiratory volume (FEV_1) and peak expiratory flow (PEF) [16,26].

A spirometer is a simple machine used to determine both the total amount of air that can be forcefully exhaled after maximum inspiration, referred to as forced vital capacity (FVC), and how fully air can be expelled from the lungs, measured by the amount of air forced from the lungs in one second, which is expressed as FEV_1 [16,26]. The spirometer is generally used in diagnosis to establish airflow obstruction and reversibility [27]. Obstruction may be ascertained if the FEV_1 is less than 80% of the predicted value or if FEV_1 divided by FVC is less than 65%. Normally, the FEV_1 should account for more than 75% of the FVC; anything less than 75% indicates a possible obstruction and 65% or less may indicate a diagnosis of asthma [27].

A peak flow meter measures the speed of exhalation. The highest speed or best flow is PEF or peak flow. The peak flow meter is less sophisticated than a spirometer, which provides a more thorough assessment of lung function. However, the meter has the advantages of being less expensive, portable, and easy to use [26]. The severity of a patient's asthma can be determined by careful and consistent monitoring of peak flow and comparison of a patient's best peak flow to standard measurements. Studies confirm that short-term peak flow measurements assist healthcare providers in assessing asthma severity [16].

Studies have shown that measuring exhaled nitric oxide is also helpful in evaluating and diagnosing asthma [27]. Nitric oxide is a mediator for the inflammation that occurs during an asthma episode; the amount of nitric oxide measured during exhalation will directly correlate with the inflammation in the bronchial tubes [28].

Prognosis and Medical Management

Allergies are among the most common disorders in medicine. Patients often require a combination of treatments, ranging from avoidance of known allergens and environmental control to pharmacotherapy, immunotherapy, and follow-up [24].

It is expected that patients will obtain relief from allergic manifestations when the treatment regimen is followed. This assumes that the patient will be able to avoid or control risk factors for allergic manifestations, avoid anaphylactic events, and obtain treatment before serious problems develop [29]. However, this is not always possible.

Some patients will experience anaphylaxis as a result of an uncontrolled allergic reaction. While foods and food additives are the most common causes of anaphylaxis, it may also develop in response to other triggers, including latex and exercise. The management of anaphylaxis is detailed later in this course.

Allergen Avoidance

Avoidance of the allergen is often the easiest, most cost-effective, and safest way of managing allergies. However, identification of the specific allergen may be difficult, especially if the patient refuses, cannot afford, or cannot locate allergen-testing services. Even if an allergen is identified, complete avoidance may not be possible, as with pollens and occupational exposures [24].

Environmental Control

Environmental control can help to eliminate airborne allergens. Changing offending objects in the home, deep cleaning, pest control, and air filters that remove small particles from the air can eliminate many allergens [30].

Pharmacotherapy

Patients with atopy benefit greatly from select prescription and over-the-counter medications. Usually, patients self-administer these agents, although in some settings the nurse or a family member administers them [30]. Common medications include antihistamines, decongestants, leukotriene antagonists, and bronchodilators.

Immunotherapy

Immunotherapy (desensitization therapy) is designed for the treatment of type 1 (IgE-mediated) hypersensitivity. With this approach, precise doses of allergens are injected at intervals over a prolonged period with the goal of altering (decreasing) the immune system's response to the allergen. The doses are increased gradually over time or injections may be given several times per day in increasing doses in "rush" protocols. Immunotherapy increases IgG antibody levels and may increase suppressor T-cell functions. Specific IgG interferes with IgE binding to allergens and thus mitigates the hypersensitivity response. Immunotherapy is widely used in the treatment of allergic rhinitis (hay fever), for which its greatest success has been achieved because immunotherapy blunts the seasonal rise in specific IgE antibody levels. It has also been used for Hymenoptera (bee, yellow jacket, wasp, hornet) venom sensitivity with reportable success. There is some controversy regarding the efficacy of this treatment in the management of asthma [30].

Nurses often administer these injections and assess and treat side effects. Patients are asked to wait at least 30 to 40 minutes after receiving the injections so immediate reactions can be identified and treated. Side effects are similar to those seen in skin testing [30].

Patient Teaching

Although patients usually self-administer allergy medications, nurses are responsible for instructing patients and their families about their use. The patient should receive education on the medications available, their actions, how and when to take them, and possible side effects. Patients should also receive instruction on management of an anaphylactic reaction [29].

Some patients will need information on performing desensitization injections themselves, including proper injection technique and potential untoward reactions, such as shortness of breath, hoarseness, urticaria, and generalized flushing. Patients at risk for anaphylaxis should carry epinephrine with them at all times and should wear a medical-alert bracelet [29].

Allergic Rhinitis

Manifestations of allergic rhinitis are persistent and show seasonal variation. Nasal manifestations are often accompanied by eye irritation, which causes pruritus, erythema, and excessive tearing. Numerous allergens may cause these manifestations, including tree pollens (spring), grasses (summer), ragweed (fall), or dust mites and animal dander (year-round) [17].

When the nasal mucosa is exposed to an allergen, a series of events is set in motion. Allergen exposure increases the production of IgE, which binds to the receptors on mast cells and basophils and eventually causes a release of mediators. Mediator release leads to increased swelling (nasal blockage), watery discharge, sneezing, and nasal itching [17].

Medical Management

Nasal glucocorticoid sprays are used with good results for the treatment of allergic rhinitis. Nonsedating antihistamines are beneficial in maintaining control over allergic rhinitis and are a crucial component of therapy [31].

Nursing Management

Evidence Based Practice Recommendation

The British Occupational Health Research Foundation recommends that healthcare providers provide more frequent health surveillance to workers who develop rhinitis when working with agents known to cause occupational asthma and ensure that the workplace and working practices are investigated to identify potential causes and implement corrective actions.

https://www.bohrf.org.uk/downloads/OccupationalAsthmaEvidenceReview-Mar2010.pdf

Last Accessed: October 25, 2019

Level of Evidence: ** (One study with high quality and at least two studies with medium quality)

Educating patients is the most important component of therapy for allergic rhinitis. Patients should avoid allergens and use air filters and air conditioning, when feasible. Compliance with medication is essential. Education topics include daily medication use and strategies to adjust medication to control minor flare-ups and prevent progression of the disease [32].

Atopic Dermatitis

Atopic dermatitis occurs in about 10% of the population [11]. Patients typically have a history of and/or complaints about itchy skin in addition to a history of rashes in the area of skin creases. Other common complaints are of generally dry skin (often initially experienced in children younger than 2 years of age) accompanied by manifestations of asthma, hay fever, or dermatitis. Lesions of atopic dermatitis are red and pruritic, contain exudates, and are maculopapular in younger patients, becoming drier and thicker as patients age. Lesions are typically found on the cheeks, scalp, and forehead; in later years, they may occur on the trunk and extremities [11,15].

Medical Management

Treatment is aimed at controlling and reducing the manifestations of atopic dermatitis because there is no true cure. Antihistamines are used with good results to help alleviate the itch-scratch cycle common to the condition. The mainstay of therapy is topical corticosteroids, which control inflammation of the skin lesions. Gels penetrate more effectively but are drying. Ointments should be used in more severe cases because they promote hydration; however, they can be oily and become messy in the heat. Creams and lotions are the least penetrating but are preferred by most patients. They are absorbed quickly and promote control. Antibiotics may be needed to treat superficial skin infections caused by intense pruritus and scratching [15].

Nursing Management

Nurses should teach patients with atopic dermatitis the importance of environmental control. A key strategy is to minimize allergen exposure and avoid conditions or situations that exacerbate pruritus. Patients can reduce itching by wearing loose cotton clothing, using gentle detergents, rinsing clothing completely, and avoiding extreme changes in temperature. Patients should be advised to avoid chemical irritants, emotional stress, aeroallergens (e.g., dust, animal dander), and dietary allergens. Patients should be instructed on general skin care measures, such as [31]:

- Maintaining good skin hydration by bathing in lukewarm water

- Using gentle soaps

- Applying moisturizer immediately after bathing

- Avoiding scratching

- Keeping fingernails trimmed to avoid infection

Urticaria

Urticaria (or hives) is a cutaneous reaction associated with several different causes. It occurs in as many as 25% of all people at some time [33]. Urticaria that is present daily or intermittently over a period of less than six weeks is considered acute, while hives present for more than six weeks are chronic [33].

Urticaria is characterized by transient erythematous, raised, well-demarcated plaques that are often intensely pruritic. The plaques frequently have central pallor and blanch when pressure is applied. The lesions are round or oval and range in size from a few millimeters to several centimeters; they typically fade within 24 hours [33]. They are usually the result of an inflammatory reaction [34,35]. Approximately 20% of cases of acute urticaria are caused by IgE-mediated reactions [34].

Mast cells and their mediators may play a key role in urticaria, causing pruritus and vascular changes. A biopsy of the lesion may be done to identify the types of inflammatory cells present, which can inform treatment planning. The most common causes of urticaria are medications, foods and food additives, and infections; insect bites and stings, contact irritants, inhalants, heat, cold, light, and pressure may also be triggers [33].

Medical Management

Although management of urticaria focuses on identifying and eliminating any known causative factors, in about 80% of chronic cases no cause is found [36]. All patients with urticaria should be cautioned about aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), which may exacerbate existing hives. Opioids should be used cautiously as well because they are typically mast cell degranulators [33].

Antihistamines are the mainstay of therapy for urticaria. Nonsedating antihistamines are recommended during the day; sedating antihistamines may be preferred at night. Doxepin (Sinequan), a tricyclic antidepressant, is sometimes used in refractory cases because of its actions on both H1 and H2 receptors. Corticosteroids should not be used except for short-term amelioration of symptoms [33].

Adults and adolescents 12 years of age and older with chronic idiopathic urticaria who remain symptomatic despite H1 antihistamine treatment may be prescribed omalizumab. The usual dosage is 150 mg or 300 mg every four weeks [37].

Nursing Management

Urticaria tends to evoke anxiety and frustration in both patients and clinicians. The most effective treatment is to eliminate triggers, and patients should be helped to identify factors that may be triggers. Elimination diets and challenges are indicated if foods or food additives are thought to provoke manifestations. Patients should also avoid factors that cause pruritus, such as pressure from tight clothing, heat, vibration, sunlight, and rubbing of the skin. Maintaining good skin hydration is necessary. Patients should be advised to avoid harsh soaps and irritants and to apply moisturizing lotions after bathing while the skin is still damp [32].

Anaphylaxis

Until 2006, there was no universal agreement on the definition of anaphylaxis or the criteria for its diagnosis. The National Institute of Allergy and Infectious Diseases (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN) held two symposia to collaborate with representatives from 16 organizations and government bodies to develop a universally accepted definition of anaphylaxis as well as criteria for its diagnosis. They defined anaphylaxis as, "a serious allergic reaction that is rapid in onset and may cause death" [38]. The collaborative effort also led to the establishment of clinical criteria for diagnosis (Table 1) [38,39,40].

Table 1: CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS

Anaphylaxis is highly likely if any one of the following three criteria is fulfilled:

1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips/tongue/uvula)
And at least one of the following:

1. Respiratory compromise (e.g., dyspnea, wheeze/bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)

2. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence)

2. Two or more of the following that occur rapidly (minutes to several hours) after exposure to a likely allergen for that patient:

1. Involvement of the skin/mucosal tissue (e.g., generalized hives, itch, flush, swollen lips/tongue/uvula)

2. Respiratory compromise (e.g., dyspnea, wheeze/bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)

3. Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, incontinence)

4. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)

3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several hours):

1. Infants and children: low systolic blood pressure (age specific) or greater than 30% decrease in systolic blood pressurea

2. Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from that person's baseline

aLow systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than 70 mm Hg +(2 x age) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.

Source: Reprinted from Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. Ann Emerg Med. 2006;47:373-380, with permission from The American College of Emergency Physicians.

Clinical Manifestations

Early recognition of the clinical signs and symptoms of anaphylaxis is necessary to ensure immediate, appropriate treatment. In most cases, these signs and symptoms will occur within one hour after the accidental exposure (ranging from less than one minute to a few hours) and will vary in terms of presence, sequence, and severity [41]. In 1% to 20% of anaphylaxis cases, there will be a biphasic response, with recurrence of symptoms 8 to 12 hours later, after the individual had seemed to recover [41]. The interval between the initial reaction and the recurrence has ranged from 1 to 72 hours [38,42]. A biphasic reaction occurs in approximately 6% to 11% of children; such reactions typically occur within 8 hours after the first reaction but may occur as long as 72 hours later [43].

As with less severe allergic reactions, cutaneous manifestations are the most common, followed by respiratory and gastrointestinal symptoms [42,44,45,46]. In one study of more than 600 children, cutaneous manifestations were documented in 87% to 98% of children; respiratory manifestations, in 59% to 81%; and gastrointestinal manifestations, in 50% to 59% [46]. The cardiovascular system is less frequently involved and is more often involved in adolescents [43,46]. Still, cutaneous manifestations may be absent in about 10% to 20% of cases of anaphylaxis, which may contribute to under-recognition [44].

Medical Management

Appropriate treatment of anaphylaxis must be immediate, as death can occur within 30 to 60 minutes [44]. Guidelines for the treatment of anaphylaxis have been developed jointly by the American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology as well as by the NIAID and by the World Allergy Organization [38,39,42,44,47]. The drug of choice for the treatment of anaphylaxis is epinephrine, and several studies have shown that the lack of early epinephrine is associated with an increase in biphasic reactions as well as greater morbidity and mortality [43,44,48]. Yet, healthcare professionals often fail to use epinephrine, with geographic variations in practice patterns [47,49,50,51,52,53]. Antihistamines (H1 and H2 blockers) and corticosteroids have been used to treat anaphylaxis, and the use of antihistamines is the most common reason given for not administering epinephrine [44,48]. However, three systematic reviews have demonstrated that there are few or no data to support the effectiveness of antihistamines or corticosteroids and that epinephrine is the only first-line treatment for anaphylaxis [54,55,56]. The recommended dose of epinephrine is 0.01 mg/kg (maximum dose: 0.3 mg for children and 0.5 mg for adults), given intramuscularly every 5 to 15 minutes as necessary to control symptoms and maintain blood pressure [38,42,43,44,57]. Peak plasma concentrations are highest and achieved fastest when epinephrine is administered intramuscularly in the thigh (versus the arm) [57].

Treatment of anaphylaxis must begin before the individual is transported to an emergency care facility. The NIAID expert panel recommends that the following steps be carried out concurrently as soon as an anaphylactic reaction has started [44]:

- Eliminate additional exposure to the allergen

- Call for help (emergency response team or 911)

- Inject epinephrine intramuscularly

When the patient arrives at the emergency care facility, the first action is to assess the airway, breathing, and circulation. In the emergency care setting, additional injections of epinephrine may be necessary. There are multiple other components to treatment that vary according to many factors, most notably the individual's symptoms, the type of reactions that have occurred in the past, and the response to epinephrine [38,41,57].

Food Allergy

True food allergy affects approximately 5% to 9.3% of children and approximately 1% to 5% of adults in the United States, and the prevalence has been rising (>50% increase from 1997 to 2011) [44,58,59,60,61,62]. Despite the overall low prevalence of food allergy, particularly in comparison to skin or respiratory allergy, there is cause for concern, as allergic food reactions can be severe. It is estimated that 200,000 individuals require emergency medical care for food-induced allergic reactions, and the number of medical procedures to treat anaphylaxis from food allergy increased by 380% between 2007 and 2016 [63]. In addition, 150 to 250 deaths caused by food-related anaphylaxis occur annually [43,44,64]. Food-induced anaphylaxis is also the most frequent cause of anaphylactic reaction outside of the hospital setting and has been estimated to cost $500 million per year [43,65].

Food allergy is defined in the NIAID-sponsored guidelines as an "adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food" [44]. Adverse reactions to food are usually classified in two broad categories: IgE-mediated allergy or hypersensitivity (true food allergy) and non-IgE-mediated reactions; the latter group includes cell-mediated reactions and disorders that are a combination of IgE-mediated and cell-mediated reactions [44]. Non-IgE-mediated reactions include primarily gastrointestinal food allergies such as celiac disease, food protein-induced enteropathy and enterocolitis/proctitis, and eosinophilic disorders [44]. Allergic sensitization (presence of allergen-specific IgE) to a food can occur without clinical signs and symptoms on exposure to that food, but both sensitization and clinical symptoms are needed for a definition of food allergy [44].

With an IgE-mediated response, food-specific IgE antibodies are produced after exposure to certain proteins that bind to tissue mast cells and basophils, leading to the release of mediators such as histamines and leukotrienes [66]. The resultant reaction typically manifests in symptoms or disorders related to the skin, gastrointestinal tract, and respiratory system [66]. Symptoms occur within minutes to one to two hours after the causal food has been ingested and vary from mild (oral or cutaneous symptoms only) to a life-threatening systemic reaction [44,66]. Sensitization without clinical symptoms is common; for example, approximately 1% of the population has a true allergy to peanut (sensitization plus symptoms), whereas approximately 8% will have sensitization to peanut (a positive test result) but no symptoms [67,68].

In general, eight allergens account for approximately 85% to 90% of IgE-mediated food allergies: cow's milk, hen's egg, peanut, tree nuts (walnuts, cashews, etc.), fish (fin fish), shellfish, soy, and wheat [44,63]. With shellfish, allergy to crustaceans (shrimp, crab, and lobster) is more common than allergy to mollusks (clams, oysters).

The understanding of non-IgE-mediated reactions is not as clear as that of IgE-mediated reactions [69]. Most adverse food reactions have no immunologic basis. However, for many adverse reactions that affect primarily the gastrointestinal tract, a cell-mediated response is involved [69]. Several mechanisms have been suggested to play a role in these reactions, including an abnormal mucosal immune response and responses involving mast cells, eosinophils, macrophages, and T-cells [69,70]. In contrast to IgE-mediated reactions, the symptoms associated with non-IgE-mediated reactions are delayed, often not occurring for hours or days after the suspected food was ingested [69].

Clinical Manifestations

Food-induced adverse reactions vary from mild to severe and life-threatening. Most reactions are mild to moderate, with the exception of reactions to peanut, which are often severe [44,71]. The rate of severe reactions to food allergens overall has ranged from 11% to 51% [58,71,72].

Food allergy manifests itself primarily through the skin, gastrointestinal tract, and respiratory system, and symptoms are categorized as acute or delayed (Table 2) [44]. Cutaneous symptoms are typically the most common.

Table 2: SYMPTOMS OF FOOD-INDUCED ALLERGIC REACTIONS

Target Organ

Immediate Symptoms

Delayed Symptoms

Cutaneous

Erythema

Pruritus

Urticaria

Morbilliform eruption

Angioedema

Erythema

Flushing

Pruritus

Morbilliform eruption

Angioedema

Eczematous rash

Ocular

Pruritus

Conjunctival erythema

Tearing

Periorbital edema

Pruritus

Conjunctival erythema

Tearing

Periorbital edema

Upper respiratory

Nasal congestion

Pruritus

Rhinorrhea

Sneezing

Laryngeal edema

Hoarseness

Dry, staccato cough

—

Lower respiratory

Cough

Chest tightness

Dyspnea

Wheezing

Intercostal retractions

Accessory muscle use

Cough

Dyspnea

Wheezing

Gastrointestinal (oral)

Angioedema of the lips, tongue, or palate

Oral pruritus

Tongue swelling

—

Gastrointestinal (lower)

Nausea

Colicky abdominal pain

Reflux

Vomiting

Diarrhea

Nausea

Abdominal pain

Reflux

Vomiting

Diarrhea

Hematochezia

Irritability and food refusal with weight loss (young children)

Cardiovascular

Tachycardia (occasionally bradycardia in anaphylaxis)

Hypotension

Dizziness

Fainting

Loss of consciousness

—

Miscellaneous

Uterine contractions

Sense of ''impending doom''

—

Source: Reprinted with permission from Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergies: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126:S1-S58. With permission from Elsevier.

Diagnosis

Many individuals seek medical attention for evaluation of reactions to food, interpreting the reactions as food allergy. However, studies have indicated that 50% to 90% of food-related adverse reactions are not true food allergies [44]. Even when medical attention is sought, diagnostic testing is not always done. In one survey, among children with physician-diagnosed allergies, one-third did not have diagnostic testing [73]. The NIAID guidelines recommend a detailed history or physical examination as an essential first step in the diagnosis of food allergy but note that they alone cannot provide a definitive diagnosis of food allergy, and an objective evaluation should be carried out to confirm or disprove a suspected food allergy [44]. The history will suggest whether the reaction was IgE-mediated or non-IgE-mediated and can guide the selection of the most appropriate diagnostic testing.

Medical Management

There is currently no cure for food allergy, and the mainstay of management is avoidance of the offending food. The NIAID-sponsored guidelines recommend the following [44]:

- Individuals with IgE-mediated and non- IgE-mediated food allergies should avoid ingesting their specific allergen or allergens.

- Individuals with food allergy and their caregivers should be given information on avoiding their food allergen and emergency management that is age- and culture-appropriate.

- Individuals with food allergy and their caregivers should receive education and training on how to interpret ingredient lists on food labels and how to recognize labeling of the food allergens used as ingredients in foods.

- All children with food allergy should have nutritional counseling and regular growth monitoring.

- Follow-up diagnostic testing should be done to monitor a child's allergy status, especially for those food allergies that are most likely to be lost during later childhood (milk, egg, soy, and wheat).

Nursing Management

Parents of children with food allergy have expressed a desire for comprehensive information on the management of food allergy and have noted the following specific topics: early signs and symptoms, cross-contamination, reading of food labels, self-injectable epinephrine, and becoming a teacher and advocate [74]. Studies and surveys of children with food allergy and their families have also shown that improved education is needed in these areas [71]. Every healthcare professional involved in an individual's care should collaborate to ensure that patients with food allergy and their families understand these topics. The NIAID expert panel coined the SAFE mnemonic for patient education [44]:

- Seek support

- Allergen identification and avoidance

- Follow-up with specialty care

- Epinephrine for emergencies

The results of studies have shown that both children and adults may underestimate the severity of a food allergy, which means that education on the consequences of risk-taking behaviors is essential. Many individuals with food allergy or their parents fear that a severe reaction will occur in a setting where immediate help will not be available. However, according to a survey, most severe reactions occur in a setting that is considered to be "safe," such as home, work, or school [43,75]. Although this fact should be reassuring, it does suggest that better education is needed to help individuals with food allergy and/or their parents be better able to avoid causal foods.

Patients and their families need help in identifying so-called hidden sources of food allergens to avoid inadvertent ingestion of a food allergen by cross-contamination. For example, some deli meats may have trace amounts of dairy product if the meat was cut on a slicer also used to cut cheese. Particular emphasis should be placed on nonfood items as potential sources of allergens; for example, many cosmetics may contain milk, tree nut oils, wheat, or soy; modeling dough may contain wheat; and beanbag stuffing often includes nut shells [76,77].

ASTHMA

In 2015, 1.7 million individuals in the United States visited an emergency department and received a primary diagnosis of asthma [78]. In addition, 6.2% of patients seen by their primary care physician in 2015 had a diagnosis of asthma in their medical records [78]. The costs associated with healthcare usage related to asthma put a tremendous burden on healthcare systems and professionals as well as on patients and public organizations.

The pathogenesis of an asthma attack can be described as an inflammatory cascade composed of triggered, acute inflammation and chronic inflammatory changes. In the body of a person without asthma, the immune responses in the bronchi (e.g., swelling, excretion of mucus, recruitment of inflammatory cells) are present in a lesser degree to protect the body against any infectious agents or foreign objects (as discussed). However, a person with asthma produces an extreme reaction to otherwise relatively harmless irritants, referred to as asthmagens or triggers. Exposure to a trigger causes inflammatory mast cells to release specific inflammatory mediators, including histamine and interleukins, resulting in an acute response. Histamine causes local tissue edema; interleukins generally act as chemotactic factors and activate other inflammatory cells. Studies reveal that leukotrienes, another chemical released by mast cells, prolong bronchial muscle and airway constriction [16].

After the inflammatory cells are activated, bronchospasm occurs. Bronchospasm and local tissue edema cause narrowing of the airways. Release of interleukins and other chemotactic substances causes migration of other inflammatory cells, including eosinophils, airway macrophages, and neutrophils. The physical presence of these cells can also cause airway narrowing. The migration of the inflammatory cells starts within 30 minutes of exposure and may take hours to reach peak levels. Several different types of antibodies contribute to the inflammation process, but IgE is particularly harmful in patients with asthma.

The actual cause of the hyper-reaction by the immune system in persons with asthma is unclear. While many cases may be attributed to a reaction in response to exposure to an allergen/asthmagen, the possibility of nervous system involvement is also an accepted theory. Generally, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) work in harmony to balance the body's functions; the PNS stimulates the bronchial tubes to constrict while, at the same time, the SNS stimulates the bronchial tubes to dilate [16]. Ideally, these two systems coordinate to maintain open airways, allowing an effortless flow of air during inhalation and exhalation. In the lung of a person with asthma, it is thought that the balance may be tipped toward the PNS and that this imbalance may result in narrowed bronchial tubes and asthma symptoms [16]. There was once a belief that the PNS was solely responsible for airway sensitivity; however, studies now seem to indicate that, although the PNS is involved, it is not the major reason for inflammation in asthma [16]. Researchers continue to study the importance of these neurotransmitters relative to bronchial muscle tone.

Additionally, there is a proposed theory that some people with asthma have abnormal beta receptors and the proper neurotransmitters are blocked from reaching the appropriate receptors [16]. When the nervous system becomes unbalanced due to this blockage, the parasympathetic nerves over-react and constrict the bronchial tubes. For some researchers, the "beta blockage theory" offers a better explanation of the cause(s) of asthma symptoms present in some patients after exposure to what are known as nonspecific triggers, such as viruses and extreme weather changes [16]. However, it is still not understood how and when beta receptors would become defective.

Clinical Manifestations

Asthma is marked by recurrent episodes of wheezing, breathlessness, chest tightness, and/or coughing. Usually, these periods are associated with widespread but variable airflow obstruction followed by a period of relief, either spontaneously or in response to treatment [79].

Clinical signs of airway narrowing generally consist of wheezing, increased respiratory rate, retractions, nasal flaring, and grunting. Later signs can include tripoding (using accessory muscles to breathe) and altered mental status. In general, asthma symptoms are revealed in different combinations and varying intensities.

Asthma has many puzzling aspects, and its symptoms may wax and wane, especially seasonally [16]. Unlike other respiratory diseases, such as COPD and emphysema, in which air trapping and hyperinflation of the lungs also occur, asthma is reversible with the use of proper medications and therapies.

Diagnosis

In some instances, a physical examination and a thorough exploration of a patient's medical history offer enough information for an accurate asthma diagnosis. There are several main criteria that should be present for a diagnosis of asthma to be ascertained. It is vital that a history of episodic asthma symptoms, characterized by airflow obstruction, be established. Symptoms that increase the probability of an asthma diagnosis include episodic wheeze, chest tightness, allergic rhinitis, atopic dermatitis, shortness of breath, and cough. It should also be noted if symptoms worsen at night or in the presence of aeroallergens, irritants, or exercise. A family history of asthma, allergies, sinusitis, or rhinitis is also an indication of potential asthma. According to the National Institutes of Health, most recurrent episodes of coughing and/or wheezing may be attributed to asthma [80].

Most physicians order tests to confirm an asthma diagnosis or to rule out any complications and evaluate the severity of the condition. The objectivity of pulmonary tests allows for a reliable analysis of lung function that patient history and physical examination may not provide; this information may be valuable to the diagnosis process. The most critical tests for evaluating asthma assess pulmonary function. As discussed, common methods of measuring airflow in patients with asthma assess FEV_1 and PEF [16,26].

Medical Management

The National Asthma Education and Prevention Program (NAEPP) advocates the use of a stepwise approach to asthma management [80]. In this program, the asthma classifications are treated as separate steps, beginning with mild intermittent at step 1 and advancing to severe persistent at step 6.

Asthma is classified based on symptom severity and frequency [80,81]. Patients for whom symptoms occur more frequently (i.e., more than two times per week) and who experience interference with normal activity as a result of asthma symptoms are classified as having persistent asthma. Patients who experience asthma fewer than two times per week, have fewer than two night-time awakenings due to asthma per month, use rescue inhalers fewer than two times per week, have no interference with normal activity, and have "normal" peak FEV_1 are categorized as having intermittent asthma. The asthma is then further classified as mild, moderate, or severe based on the extent of interference in daily life, lung function tests, and use of rescue medications. After asthma severity has been classified, the treatment step is determined and begun (Table 3).

Table 3: STEPWISE APPROACH FOR MANAGING ASTHMA IN PATIENTS 12 YEARS OF AGE AND OLDER

Step

Preferred Treatment

Alternative Treatment

Indication

1

Short-acting beta_2 agonist as needed

—

Intermittent asthma

2

Low-dose inhaled corticosteroid

Cromolyn, leukotriene antagonist, nedocromil, or theophylline

Persistent asthma (Consider subcutaneous allergen immunotherapy for patients who have allergic asthma)

3

Either low-dose inhaled corticosteroid and long-acting inhaled beta_2 agonist OR medium-dose inhaled corticosteroid

Low-dose inhaled corticosteroid AND either leukotriene antagonist, theophylline, OR zileuton

4

Medium-dose inhaled corticosteroid AND long-acting inhaled beta_2 agonist

Medium-dose inhaled corticosteroid AND either leukotriene antagonist, theophylline, OR zileuton

5

High-dose inhaled corticosteroid AND long-acting inhaled beta_2 agonist

Consider omalizumab for patients with allergies

—

6

High-dose inhaled corticosteroid, long-acting inhaled beta_2 agonist, AND oral corticosteroids

Consider omalizumab for patients with allergies

—

Quick relief of asthma exacerbations in all patients with short-acting beta_2 agonist, up to three treatments at 20-minute intervals as needed. Short course of oral systemic corticosteroids may be needed. Use of short-acting beta_2 agonists more than two days per week for symptom relief generally indicates inadequate control and the need to step up treatment.

Source: [80]

When considering pharmacologic treatment of asthma, the dosage, timing, and type of medication should be tailored to individual needs. Optimal treatment should include methods to reverse airflow barriers, stop symptoms from occurring, prevent serious attacks and need for emergency care and hospitalization, keep asthma from interfering with activities of daily living, minimize side effects, and control symptoms with the least amount of medication [16]. As with the approach to management, medication therapy generally adheres to two possible uses: to relieve symptoms quickly with the use of bronchodilators, or to reduce chronic airway inflammation with anti-inflammatory medications, preventing asthma from recurring in the future.

Bronchodilators are used to address the acute symptoms of an asthma attack. They act by relaxing the muscles surrounding airways, thereby dilating bronchial tubes. The primary categories of bronchodilators are beta2 agonists, theophylline derivatives, and anticholinergics [16]. Most often, bronchodilators are prescribed in inhaler or aerosol form. They are also available in liquid, tablet, and capsule forms, but these are generally not used due to gastrointestinal side effects. The bronchodilator inhaler is usually the first line of defense in an asthma attack [16].

In 2007, a panel of experts, under the guidance of the NAEPP, noted that the critical role of airway inflammation in asthma has been further substantiated since the 1990s, when this inflammatory role was first acknowledged and treatment was shifted away from calming acute flare-ups to engaging in preventative measures [16,80,82]. The NAEPP also noted that bronchodilators work best for acute asthma situations and for preventative treatment before exertion or exercise, but it emphasized anti-inflammatory medications as the foundation for long-term treatment of asthma; this was reaffirmed in the 2018 Global Initiative for Asthma guidelines [80,82]. This approach relies on daily medication to maintain healthy lungs. Patients who require regularly administered bronchodilators should switch to longer-acting drugs designed to reduce airway inflammation [16,80,82].

Anti-inflammatory medications block production of substances from cells involved in inflammation, such as mast cells; this action reduces or reverses the swelling that causes asthma symptoms [16]. Equally important, these medications lessen airway sensitivity, which prevents edema [16]. If asthma symptoms appear more than once or twice per week and less powerful options cannot control them, anti-inflammatory medication is indicated [16]. Before newer drugs were developed, the only anti-inflammatory asthma medication available was an oral corticosteroid, such as prednisone. Long-term treatment with oral corticosteroids is associated with serious side effects, including stunted growth in children, hyperlipidemia, thinning skin, and immune system impairment, making patient compliance difficult. As a result, several inhaled anti-inflammatory drugs were developed, which greatly reduced negative reactions [16]. The four primary types of anti-inflammatory drugs are corticosteroids, mast cell stabilizers, antiallergic medications, and antileukotriene medications [16].

The most effective nonpharmacologic intervention for the treatment and/or prevention of asthma at this time is trigger avoidance. Knowing and eliminating any possible asthma triggers is one of the most important elements of any management plan. Additionally, peak flow meter use and increased patient education contribute to an enhanced understanding and control of asthma symptoms. Immunotherapy and complementary medicine modalities have also been used by patients with asthma. Strong patient education and communication is vital to the successful management of the disease.

Nursing Management

It is important that nurses are able to discuss the different aspects of asthma symptoms as well as treatment and management to ensure that patients are able to understand and follow the established plan. In addition to the treatment plan and common symptoms associated with asthma episodes, patient education should outline the importance of compliance, trigger avoidance, and the continuous monitoring of their condition.

The main problem seen in both adult and pediatric asthma populations is compliance with a prescribed treatment plan and control of asthma symptoms. It is important that, as a part of patient education, adherence to the treatment plan is stressed. Much of the treatment and management responsibilities associated with controlling asthma and asthma symptoms falls on the patient. The more patients understand their treatment and the value of each aspect, the more likely they will be to adhere to the established treatment plan. Nurses should take into account the possible barriers to care, such as income level, education, language, and cultural beliefs.

There are many different types of triggers; some act in isolation, and others work together. The severity of an asthma attack depends upon the number of irritants, allergens, or other stimuli in the environment and the degree of lung sensitivity to these triggers [16,83]. If a patient has known asthma triggers, avoidance of these items, substances, or situations may greatly improve, or even eliminate, asthma symptoms. Information regarding these asthmagens, where they may occur, and ways to avoid triggering an attack should be incorporated into initial patient education.

5. RHEUMATIC DISORDERS

Rheumatic disorders are inflammatory disorders and have been called the primary crippling diseases of the developed world. They are the most prevalent chronic conditions and a leading cause of disability in the United States [18].

The triad of pain, fatigue, and stiffness is common in rheumatic disorders and must be controlled so function is enhanced or maintained. If this triad, which represents a runaway inflammatory response, is not controlled, essential self-care deficits develop. Difficulty with self-care is usually accompanied by sleep disturbances, altered nutrition, and impaired mobility. All of these problems can adversely affect an individual's self-concept and self-esteem and lead to social isolation.

Although rheumatic conditions have different clinical patterns, pain and impaired mobility are commonalities. Chronic pain and progressive physical impairment of the joints and soft tissues are typical characteristics. When caring for patients with rheumatic disorders, the ultimate goals are to reduce pain and other physical manifestations, assuage psychologic distress, improve physical function, and generally aid in the well-being of the patient [18].

Systemic manifestations can be as devastating as musculoskeletal manifestations, and patients may experience acute exacerbations. The unpredictable nature of these disorders results in considerable uncertainty, which in turn leads to a cycle of ineffective coping, disturbed self-esteem, helplessness, and powerlessness. In many respects, the psychologic and social problems associated with these chronic illnesses are more disabling than the physical complaints.

Because of the chronicity of these disorders, patients require skilled, knowledgeable nursing care that draws on the disciplines of rehabilitation, counseling, and self-care. The unique role of the nurse is one that assumes accountability and responsibility for guiding and directing the patient through the healthcare system. Patients with chronic and often systemic illnesses require multiple therapies and follow-up appointments for pharmacologic adjustments, nutritional counseling, lifestyle assessment, physical and occupational therapy, and psychologic support. The personal and financial costs of rheumatic disorders can exhaust a patient's enthusiasm, job security, support systems, and sense of purpose in life. The nurse can provide a sense of consistency, hope, and reassurance, and the patient can learn to cope with, and positively adapt to, the demands of a chronic illness.

Rheumatic disease is often, but not always, the result of autoimmune dysfunction. Autoimmune diseases are defined as conditions in which immunologic self-tolerance has been disrupted, with resultant damage to body tissues. Rheumatic autoimmune disorders include rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, and mixed connective tissue disease [19]. Another important aspect of autoimmune disease is familial aggregation (or clustering), which suggests that there is a genetic predisposition to the development of specific disorders [19].

RHEUMATOID ARTHRITIS

An estimated 1.5 million American adults are affected by rheumatoid arthritis [84]. The yearly incidence of rheumatoid arthritis is approximately 53 per 100,000 for women and about half that (27.7 per 100,000) for men [84]. These figures vary significantly based on the age of the cohort. The data show that the incidence of rheumatoid arthritis increases steadily with age in both sexes, until approximately 65 to 74 years of age, when incidence peaks [84]. However, women in all age groups have a much higher incidence compared with men.

Rheumatoid arthritis is defined as a chronic inflammatory disease characterized by uncontrolled proliferation of synovial tissue and a wide array of multisystem comorbidities [85]. In its most common presentation, rheumatoid arthritis affects the joints, causing inflammation of the synovium and cartilage and bone loss. The precise etiology of rheumatoid arthritis is presently unknown. Most likely it has an autoimmune origin (whereby an individual's immune system confuses healthy synovial tissue for foreign substances, thereby attacking the synovial joint surfaces) given that autoantibodies (e.g., rheumatoid factor, anti-citrullinated protein antibody) are present and often precede the clinical manifestation of rheumatoid arthritis by many years [86,87,88].

Clinical Manifestations

Findings on general physical examination of the patient with rheumatoid arthritis are normal except for an occasional low-grade fever (38°C) and a slightly elevated pulse rate. The characteristic patient initially presents with complaints of pain and stiffness in multiple joints. There is prominent and prolonged morning stiffness (lasting more than one hour) that usually begins gradually with fatigue, loss of appetite, widespread muscle aches, and weakness [86,89,90].

After this initial presentation, joint pain appears. When the joint is not used for some time, it can become warm, tender, and stiff. After inflammation of the joint, increased synovial fluid is produced and the joint becomes swollen. There is accompanying soft tissue swelling, and joint pain is often felt bilaterally, affecting the fingers, wrists, elbows, shoulders, hips, knees, ankles, toes, and neck [86]. Though the joints are tender, the small joints of the hands and feet are not usually painful when the patient is at rest. Palmar erythema and prominent veins on the dorsum of the hand and wrist indicate increased blood flow. Distal interphalangeal joints are rarely involved. The temperature over the involved joints (except the hip) can be elevated, but there is usually no accompanying erythema. There are limitations in the range of motion, muscle strength, and function around inflamed joints.

Evidence Based Practice Recommendation

For patients with chronic extremity joint pain and suspected rheumatoid arthritis, the American College of Radiology recommends x-ray as the imaging study of choice for evaluation.

https://acsearch.acr.org/docs/3097211/Narrative

Last Accessed: October 25, 2019

Strength of Recommendation: 9 (Usually appropriate)

In addition, soft, poorly delineated subcutaneous nodules (rheumatoid nodules) are often found in the extensor surface of the forearm. Soft, small lymph nodes are found occasionally in epitrochlear, axillary, and cervical areas [85]. Other symptoms that may present include anemia due to deficits in bone marrow production; eye burning, itching, and discharge; or lung inflammation (pleurisy) [85,86,89,90]. Joint destruction may occur within one to two years after the appearance of the disease.

Diagnosis

The history and physical examination are the most sensitive and specific tools for rheumatoid arthritis diagnosis. In addition, the 2010 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) joint working group recommends several laboratory tests for the diagnosis of rheumatoid arthritis, including rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and anti-cyclic citrullinated peptide antibody [88].

Medical Management

Rheumatoid arthritis has no known prevention or cure. Lifelong treatment is usually required, including medication, physical therapy, exercise, and possibly surgery. The 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis is now a well-established diagnostic and prognostic tool; as such, guidelines recommend that patients start treatment with a disease-modifying antirheumatic drug (DMARD) immediately following a rheumatoid arthritis diagnosis [91]. Therapeutic goals include preservation of function and quality of life, minimization of pain and inflammation, joint protection, and control of systemic complications, with the ultimate aim being low disease activity or remission [85,89,90,91,92].

Today, the recommended standard of treatment is a tightly controlled, aggressive strategy tailored to each patient, with modifications to the individual medication regimen to achieve a particular target (remission, or alternatively, low disease activity) in a specific period of time (usually six months) [91,93]. The "treat-to-target" approach for a patient with early high disease activity and poor prognostic features typically involves initiation of methotrexate and/or another DMARD(s) immediately upon diagnosis [91,92,93]. Initial combination therapies with DMARDs, particularly those including a biologic anti-TNF agent, appear to provide earlier clinical improvement and less joint damage progression in patients with early moderate or highly active disease; they can be withdrawn successfully, and fewer treatment adjustments are needed than with initial monotherapies [91,93,94,95,96]. Patients with active disease are monitored closely (every one to three months), and it is recommended that treatment adjustments be made if there is no improvement at three months (or if the six-month target has not been reached) [91,93]. Patients with low-to-moderate disease activity or high disease activity without poor prognostic features are typically started on DMARD monotherapy. NSAIDs, glucocorticoids, or cyclooxygenase-2 (COX-2) inhibitors are often used concurrently to treat rheumatoid arthritis-associated joint pain and inflammation. However, they do not alter the disease course and should not be used as single therapy.

Occasionally, surgery is needed to correct severely affected joints. Surgeries serve to relieve joint pain, correct deformities, and modestly improve joint function [85,89,90]. The most successful locations of surgery are those performed on the knees and hips [85,89,90].

Range-of-motion exercises and individualized exercise programs prescribed by a physical therapist can also delay the loss of joint function. Joint protection techniques, heat and cold treatments, and splints or orthotic devices to support and align joints may be of assistance [85,89,90]. Some therapists will use specialized devices to apply deep heat or electrical stimulation to reduce pain and improve joint mobility [85,89,90]. Occupational therapists can construct splints for the hand and wrist and teach patients with rheumatoid arthritis how to protect and use their joints most effectively. In addition to physiotherapy, occupational therapists can also show patients with rheumatoid arthritis how to better cope with limitations that can affect their daily tasks at work and at home. For example, many clinicians have recommended frequent rest periods between activities and proper sleeping habits (e.g., 8 to 10 hours of sleep per night) [97].

Nursing Management

In order to provide the best outcomes, patients should be educated regarding the most appropriate treatment regimens for their disease manifestations, as earlier rheumatoid arthritis diagnosis can assist in aggressive early treatment (when indicated), thereby delaying joint destruction. In addition to the medical management of rheumatoid arthritis, several lifestyle changes may improve symptom severity and decrease the number of flare-ups. The National Institute of Arthritis and Musculoskeletal and Skin Disorders recommends advising patients regarding rest and exercise, use of orthotic devices, stress reduction, and healthful diet [89].

As most patients with rheumatoid arthritis will be utilizing pharmacotherapy, regular blood or urine tests may be necessary to evaluate the efficacy and incidence of adverse effects related to medication. Because rheumatoid arthritis may cause eye complications, patients should have regular eye exams. In addition, patients with rheumatoid arthritis should have yearly cardiovascular assessment examinations.

Another management trend for patients with rheumatoid arthritis has been toward self-assessment. For the individual patient, health assessment questionnaires may be a more useful means of evaluating disease progression. Examples include the EULAR response criteria for rheumatoid arthritis (which classifies trial participants as "good," "moderate," or "non-responders" using individual change from baseline in disease activity score), disease activity indices, and various daily activity score surveys [93,98]. Outcome measures, some based on patient-reported outcomes (such as the Rheumatology Assessment Patient Index Data), some based on a combination of laboratory and physician-derived measures (such as the Disease Activity Score, Simplified Disease Activity Index, and Clinical Disease Activity Index), should be used routinely to ensure that nurses are providing optimum care for patients with rheumatoid arthritis. (Various versions of the Disease Activity Score are available online at https://www.das-score.nl/das28/en.)

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus, often referred to simply as lupus, is a chronic inflammatory autoimmune disorder of the connective tissue, primarily affecting the skin, joints, blood, and kidneys [99,100,101]. In this autoimmune disorder, antibodies are formed within the body that target healthy body systems, causing inflammation and structural changes. The word lupus means "wolf" in Latin, while erythematosus means "redness." The disease is named for the characteristic red rash that appears on the face and is thought to resemble a wolf's face [100,101]. The term "lupus erythematosus" was coined in 1851 by Pierre Cazenave, a French dermatologist, but writings describing lupus date to ancient Greece [101,102].

In patients with lupus, the body produces an accelerated inflammatory response, resulting in the production of autoantibodies, causing immune complexes [101,103]. These autoantibodies and complexes assault the body's own healthy cells and tissues [100,101,102,104]. Antigen-antibody complexes can attack or suppress the body's normal immunity and cause damage to tissues. Symptoms of lupus are the result of the damage to the body's tissues secondary to the immunologic response.

A shortage or functional failure of T lymphocytes is believed to be partially responsible for this autoimmune reaction. Red blood cells, neutrophils, platelets, lymphocytes, or almost any organ or tissue in the body may be attacked. One of the hallmark indicators of lupus is the formation of autoantibodies, and the presence of autoantibodies in the blood is a key factor to the diagnosis of lupus [100,101,104].

Clinical Manifestations

Lupus has been characterized as a multidimensional, unique, complex, challenging, unpredictable, and often elusive disease [100]. It is a non-organ-specific systemic disease with a varying prognosis that can be mild, serious, life-threatening, or even fatal. The disease is characterized by recurring remissions and exacerbations, often called flares, that occur most commonly in the spring and summer [99,104]. Periods of remission vary considerably among those diagnosed with lupus [100].

The onset of lupus may be acute or insidious, vague, or even nonspecific. On average, individuals with lupus have symptoms of the disease for two to three years before a diagnosis is made [101].

Common symptoms of lupus include fever, weight loss, malaise, fatigue, skin rashes, polyarthralgia, vasculitis, Raynaud syndrome, patchy alopecia (hair loss), and painless ulcers of the mucous membranes [104]. Fatigue is probably the most universal symptom, described as a persistent complaint of a paralyzing fatigue that normal rest may not relieve [100]. Vague symptoms of lupus include aching, fatigue, low-grade or spiking fever, chills, and malaise. Episodic fever is reported by more than 80% of all patients with lupus, with a low-grade fever most often noted [100]. Infection is certainly a major concern and is a potential symptom for patients with lupus. Those with lupus are more susceptible to opportunistic infections due to alterations in their hematologic system, especially in white blood cells. Women with lupus may also experience irregular periods or amenorrhea due to the disease process [100,101].

Skin rashes are very common among patients with lupus; approximately 80% of patients report skin involvement [100]. A red, raised rash over the nose and cheeks characterizes the classic "butterfly rash" of lupus. The butterfly rash is reported by 55% to 85% of all patients with lupus at some point during their disease process [100]. Discoid lupus lesions may also be seen. Ultraviolet light often aggravates skin eruptions, and approximately one-third of all patients with lupus are found to be photosensitive [100,105]. Oral, nasal, and vaginal ulcers may occur. Conditions such as alopecia, pruritus, alteration in wound healing, and bruising are other common dermatologic symptoms.

Diagnosis

The diagnosis of lupus can be facilitated with a physical examination, extensive patient history, various laboratory tests, and radiographic evaluations [101,104]. There are several laboratory procedures that help to diagnose and monitor individuals with lupus; these various tests have different implications for the patient, but the antinuclear antibody (ANA) test is the most specific and sensitive test for lupus and is therefore the most commonly used autoantibody test. Ninety-seven percent of patients with lupus have a positive ANA blood test. The titer and patterns of the blood sample are reported. A titer greater than 1:80 is usually considered positive [106]. It is important to note that a positive ANA test is found in 97% of patients with lupus, but alone, it does not indicate a conclusive diagnosis of lupus [106]. A positive ANA test, although not always found, satisfies one of the four typical clinical characterizations required for a definitive diagnosis of lupus. ANA tests may also be positive in patients with other connective tissue diseases, chronic infectious diseases, and autoimmune diseases [106].

Evidence Based Practice Recommendation

The American College of Rheumatology Task Force Panel recommends that all patients with clinical evidence of active lupus nephritis, previously untreated, undergo renal biopsy (unless strongly contraindicated) so glomerular disease can be classified.

https://www.rheumatology.org/Portals/0/Files/ACR%20Guidelines%20for%20Screening,%20Treatment,%20and%20Management%20of%20Lupus%20Nephritis.pdf

Last Accessed: October 25, 2019

Level of Evidence: C (Consensus opinion of experts, case studies, or standard of care)

Other laboratory tests are available to assist in diagnosis or to monitor the effects of treatment. The anti-DNA blood test indicates disease activity, especially renal involvement. The anti-DNA test is most often used to monitor response to treatment. In remission, the anti-DNA test response is reduced or absent. In addition, the complement assay levels can assist with the diagnosis and monitoring of active lupus. The most common complements associated with lupus are C3, C4, and CH50. When these complement levels are decreased, they can indicate an increase in disease activity [107]. Skin and kidney biopsies can also be used.

Medical Management

There is currently no cure for lupus, and long-term disease management is required. Due to the variability of lupus symptoms, treatment protocols differ for each individual. The range of treatments, however, is increasing and becoming more effective; thus, the disease can be controlled reasonably well in most people. According to the U.S. Department of Health and Human Services, "the best way to treat lupus is to listen to the patient, whether she or he was diagnosed today or years ago" [100]. The ultimate goal of treatment is to suppress immune system abnormalities, prevent disease flares, and reduce inflammation and other complications secondary to lupus [104]. Treatment is based on such factors as symptoms and severity, overall general health, activity level, school and/or family schedule, age, family and social situations, other medical conditions, and financial and insurance considerations [102].

There are several types of drugs available to aid in the treatment and management of secondary symptoms. Among these drug classes are NSAIDs, corticosteroids, antimalarials, biologics, and immunosuppressives. In cases of severe lupus kidney disease not helped by pharmacologic intervention, dialysis or kidney transplant may be necessary.

In 2011, the U.S. Food and Drug Administration approved a new drug for the treatment of lupus—the first in more than 50 years [108]. The medication, belimumab, is a human monoclonal antibody that inhibits B-lymphocyte stimulator and acts to suppress abnormal B cells. In clinical studies, belimumab was more effective in lessening disease activity than placebo in patients with mild-to-moderate forms of the disease, although more research is necessary to determine if the drug is effective in patients with African American heritage and in patients with severe manifestations. The drug has been approved to treat patients with active, autoantibody-positive lupus who are receiving standard therapy [108]. It is administered via an intravenous infusion, and infusion reactions may occur. This can be prevented in most cases with pretreatment with an antihistamine. Other possible side effects of belimumab use include fever, diarrhea, and nausea [108,109,110].

Nursing Management

Individuals diagnosed with lupus should be encouraged to do all of the following [100,101,102,104]:

- Get plenty of physical and emotional rest.

- Maintain a healthy diet.

- Establish an exercise regimen.

- Avoid sunlight.

- Seek prompt treatment of infection.

- Limit stress.

- Set realistic goals and priorities.

- Maintain effective communication with their healthcare providers.

- Develop a support system, including family, friends, healthcare professionals, community organizations, and organized support groups.

- Avoid triggering or aggravating factors.

- Seek regular health care.

SJÖGREN SYNDROME

Sjögren syndrome is a systemic chronic inflammatory condition characterized primarily by decreased function of lacrimal and salivary glands, enlargement of the parotid gland, and often, extraglandular manifestations. The syndrome is classified as primary when it develops in a previously healthy individual and as secondary when it is associated with an underlying rheumatic disease.

The pathogenesis of Sjögren syndrome primarily involves organ-specific autoantibodies—antibodies to cellular antigens of salivary ducts, the thyroid gland, the gastric mucosa, erythrocytes, the pancreas, the prostate, and nerve cells. In addition, non-organ-specific autoantibodies are found in approximately 60% of individuals with the disease [111].

Clinical Manifestations

The typical clinical features of Sjögren syndrome are dry eyes (xerophthalmia or keratoconjunctivitis sicca) and dry mouth (xerostomia), which have been reported to occur in 93% and 98% of cases, respectively [112]. In addition to dryness, symptoms related to xerophthalmia include grittiness, itchiness, and sensation of a foreign body in the eye. Symptoms related to xerostomia include difficulty eating, swallowing, and speaking and the premature and accelerated loss of teeth. As with other autoimmune diseases, nearly half of individuals report debilitating fatigue [111].

Among the most common manifestations of extraglandular involvement are joint pain and/or swelling (37% to 75%), gastrointestinal symptoms (54%), pulmonary disease (e.g., chronic cough, recurrent bronchitis, fibrosis) (29%), and Raynaud phenomenon (16% to 28%) [112,113]. Occurring less frequently are cutaneous vasculitis, lymphadenopathy, and renal involvement (e.g., proteinuria, interstitial nephritis, glomerulonephritis) [112,113]. Peripheral neuropathies are often associated with Sjögren syndrome, and the reported prevalence of this complication has ranged widely, from 10% to more than 60% [114,115]. Cognitive dysfunction has been reported in about half of individuals [114].

Diagnosis

Diagnosing primary Sjögren syndrome is challenged by its slow, insidious onset, its variable course, its wide range of clinical features, and its symptoms, which are nonspecific and not always concurrent [111,116]. These factors have led to delays in diagnosis, often over several years [111]. Early diagnosis is essential, however, to prevent complications and to allow for surveillance to detect serious systemic manifestations.

There is no single diagnostic characteristic of Sjögren syndrome. Although xerophthalmia and xerostomia are found in nearly all individuals with the syndrome, they may be symptoms of other conditions. As a result, the diagnosis should be based on a combination of characteristic symptoms, the history and physical examination, diagnostic testing, and the distinguishing of Sjögren syndrome from other conditions with similar signs and symptoms. Differentiating Sjögren syndrome from other autoimmune diseases with similar clinical features, such as systemic lupus, rheumatoid arthritis, and scleroderma, is important to ensure appropriate treatment [111]. Healthcare professionals should remember that if another rheumatic condition is diagnosed, Sjögren syndrome may still be present, given the high rate of secondary disease [111].

Medical Management

No evidence-based guidelines are available for the treatment of Sjögren syndrome. Treatment focuses on alleviating symptoms and preventing complications, as no cure is available.

Treatment of dry eye involves artificial tears to replace moisture, and a topical anti-inflammatory agent should be used for moderate-to-severe symptoms. Preservative-free artificial tears have been better tolerated than tear solutions with preservatives because of the irritation that can be caused by frequent use of the latter type [111]. Randomized controlled trials have shown that topical ocular cyclosporine (0.05%) significantly improves objective measures of dry eye, blurred vision, and use of artificial tears in patients with moderate or severe dry eye [117]. In its guidelines for dry eye, the American Academy of Ophthalmology (AAO) includes topical cyclosporine as a level IA recommendation for moderate dry eye [118].

If symptoms are not relieved by artificial tears or anti-inflammatory agents, a muscarinic agonist can increase tear production by stimulating muscarinic receptors. These receptors are a type of cholinergic receptor and are present on exocrine glands as well as on heart muscle and smooth muscle [119]. The two muscarinic agonists shown to be effective for dry eye are pilocarpine (a nonselective agonist) and cevimeline (a selective muscarinic agonist). According to a review of the literature, placebo-controlled trials have provided evidence of improvement with these agents. In three trials, pilocarpine was associated with subjective and objective improvement of dry eye in 42% to 53% of patients (compared with 26% for the control), and in two trials, cevimeline was associated with improvement in 39% to 72% (compared with 24% to 30% for the control) [117]. Systemic cholinergic agents, such as pilocarpine and cevimeline, are a level IA recommendation for severe dry eye in the AAO guidelines [118].

Treatment of dry mouth involves stimulating production of saliva and using saliva substitutes; muscarinic agonists can be used for severe dry mouth. Saliva production can be stimulated with the use of sugar-free chewing gum and sour lozenges [119]. Saliva substitutes are available as over-the-counter and prescription products and are manufactured as lozenges, rinses, sprays, and swabs [111].

Nursing Management

Patient education should focus on the importance of careful eye and oral care. Oral care should include frequent dental examinations, use of fluoride, and daily rinsing with an antimicrobial solution [111,120]. Nurses should emphasize the importance of maintaining general health, reporting any changes in symptoms, following the prescribed use of medications, and keeping appointments for follow-up visits.

SCLERODERMA

Scleroderma literally means "hard" (sclerosis) "skin" (derma), but the disease may present with internal organ involvement (diffuse scleroderma or systemic sclerosis) in addition to cutaneous signs. Systemic sclerosis is one of the least well understood of the rheumatic disorders. It occurs as a multisystem inflammatory disease characterized by skin thickening (scleroderma) and deposition of excessive quantities of connective tissue (particularly collagen), which eventually results in severe fibrosis. The skin, blood vessels, synovium, and skeletal muscles are affected along with the microvasculature of internal organs. Widespread vascular involvement, perhaps the earliest and most significant pathologic change, is also a prominent feature [24,25].

Medical Management

Management of systemic sclerosis is typically complicated, as it can have many variations. In general, management focuses on treatment of each affected organ system, and there are a range of pharmacotherapeutic options for the various systems.

SPONDYLOARTHROPATHIES

The spondyloarthropathies are a group of inter-related disorders that include psoriatic arthritis, reactive arthritis, and ankylosing spondylitis [24].

Psoriatic Arthritis

Psoriasis is a common skin disorder characterized by stippled nails, pruritus, and silvery scales on bright-red plaques, usually on the elbows, knees, and scalp. Several types of psoriatic arthritis have been proposed. In asymmetrical oligo arthroplasty, there is asymmetrical involvement of both large and small joints, and sausage-shaped joints are common. With this type of arthritis, the asymmetrical pattern involves the interphalangeal and metatarsophalangeal joints of the feet and the distal interphalangeal joints of the fingers. The second type, symmetrical polyarthropathy, closely resembles rheumatoid arthritis. Arthritis mutilans, a severe form of destructive arthritis, is characterized by telescoping digits, also known as the "opera-glass hand." Psoriatic spondylitis is characterized by the sacroiliitis of ankylosing spondylitis [30].

The cause of psoriatic arthritis appears to be a complex combination of immunologic, genetic, and environmental factors. Immunologic changes seen in some patients include elevated titers of IgG and IgA and the presence of immune complexes [30].

Clinical Manifestations

The diagnosis of psoriatic arthritis is usually confirmed after a positive history of psoriasis and specific x-ray findings. However, it is important to realize that in some patients, particularly children, joint changes precede skin changes. Nevertheless, most rheumatologists agree that the diagnosis cannot be made without evidence of psoriatic skin or nail changes [30].

Medical Management

Evidence Based Practice Recommendation

The American College of Rheumatology/National Psoriasis Foundation recommend that patients with active psoriatic arthritis use some form or combination of exercise, physical therapy, occupational therapy, massage therapy, and acupuncture.

https://www.rheumatology.org/Portals/0/Files/PsA-Guideline-2018.pdf

Last Accessed: October 25, 2019

Level of Evidence: Low

In 2018, the American College of Rheumatology and the National Psoriasis Foundation published updated guidelines for the treatment of psoriatic arthritis. The guideline "covers the management of active psoriatic arthritis in patients who are treatment-naive and those who continue to have active psoriatic arthritis despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, IL-12/23 inhibitors, IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib)" [121]. Nonpharmacologic approaches to management include physical therapy, smoking cessation, weight loss, massage therapy, and exercise.

Ankylosing Spondylitis

Literally, ankylosing spondylitis refers to fusion (ankylosis) of inflamed vertebrae (spondylitis). The disease typically begins in the spine of young men in their late teens or early twenties. The average annual age-adjusted incidence of ankylosing spondylitis has been reported to be 6.6 per 100,000 population, with men being affected three times as frequently as women. Although the usual age of onset is set between 15 and 35 years, the age group with the highest incidence is those 25 to 34 years of age [24].

Most patients have bilateral sacroiliitis that causes pain and some degree of restricted motion in the lumbar spine. Peripheral arthritis of the large joints, usually the hips, shoulders, and more rarely the knees, occurs in 20% to 30% of persons with ankylosing spondylitis [24]. Chest expansion can also be decreased as a result of associated costovertebral arthritis. By the time the patient is 50 or 60 years of age, the fusion of the lumbar spine has proceeded to the cervical region. If ankylosing spondylitis is not treated, the disease tends to progress, with remissions and exacerbations, to a final stage of rigid lumbar and thoracic kyphosis that leaves the neck in a flexed position. Ankylosing spondylitis is associated with a shortening of the life span [24].

Clinical Manifestations

Initially, morning backache and stiffness begin during adolescence or young adulthood. The back pain and stiffness subside with movement but often return with inactivity. Back pain throughout the spinal column, difficulty sleeping, fever, and neurologic changes (e.g., bowel and bladder incontinence, paresthesia, numbness) may also occur. Several other systemic manifestations of ankylosing spondylitis can be seen, including uveitis, pulmonary fibroids, inflammatory bowel disease, and aortic insufficiency. Uveitis occurs in up to 25% of patients with ankylosing spondylitis [24].

Medical Management

According to current guidelines, in patients with active ankylosing spondylitis, the strongest recommendations include use of NSAIDs, use of TNF inhibitors when activity persists despite NSAID treatment, not to use systemic glucocorticoids, physical therapy, and hip arthroplasty for patients with advanced hip arthritis [122].

Nursing Management

The nurse plays a key role in teaching patients with ankylosing spondylitis about health promotion activities, exercise, and the management of pain. One of the most critical areas for skillful nursing intervention involves being attentive to and providing positive, unconditional regard for those persons with changing appearances. Another important area for nursing intervention, especially as the disease progresses, is the maintenance of effective breathing patterns and adequate oxygenation [29].

Reactive Arthritis

Reactive arthritis is a form of peripheral arthritis, often accompanied by one or more extra-articular manifestations, that appears shortly after certain infections [30]. Specifically, reactive arthritis occurs following exposure to a bacterial gastrointestinal or genitourinary infection [30].

Clinical Manifestations

Reactive arthritis may manifest in almost every system of the body; the most common features are polyarthritis, urethritis or cervicitis, and conjunctivitis. Urethritis can occur with clinical manifestations (e.g., discharge, slight burning on urination) or can be asymptomatic, which contributes to the difficulty in establishing a diagnosis. Reactive arthritis has also been associated with HIV infection [30].

Medical Management

Reactive arthritis runs a self-limited course of days or weeks in most patients. However, some studies suggest that many patients continue to be plagued by musculoskeletal manifestations [30]. This chronic form of the disease may require treatment with a DMARD.

IDIOPATHIC INFLAMMATORY MYOPATHY

Inflammatory diseases of muscle are a heterogeneous group of disorders characterized by proximal muscle weakness and nonsuppurative inflammation of skeletal muscle. The idiopathic myopathies are categorized more specifically as polymyositis (affecting both sides of the body), dermatomyositis(characterized by a distinctive rash), inclusion body myositis (the most common form in older adults), and necrotizing autoimmune myopathy. As a group, these are relatively rare diseases, and accurate estimates of their prevalence are difficult to obtain. Muscle weakness with an underlying malignancy develops in a subset of patients with inflammatory myopathies. Malignancy may precede or follow the onset of muscle weakness.

Clinical Manifestations

The most frequently occurring idiopathic myopathies in adults are diffuse, systemic, inflammatory connective tissue diseases. Although these disorders can have an acute onset and progress rapidly, more typically there is a slower progression. Patients gradually develop significant weight loss, fatigue, and weakness over a period of months. These diseases cause symmetrical progressive weakness of the proximal or limb-girdle muscles and occasional atrophy of the muscles of the limbs, neck, and pharynx. Decreased muscle strength occurs in the pelvic girdle first, followed by weakness of the legs, shoulders, and arms. Weakness of the flexor muscles of the neck occurs in about half of those affected with inflammatory myopathy. Falling and tripping may be early signs. With dermatomyositis, the first sign is often a violet or red rash developing on the face/eyelids, knuckles, elbows, knees, chest, and/or back.

Medical Management

Treatment of inflammatory myopathy usually begins with the daily administration of high doses of oral corticosteroids. Prednisone (1–2 mg/kg/day) is given until elevated muscle enzymes begin to decrease toward normal and patients show improvement in their ability to perform activities of daily living [123]. Unfortunately, inclusion body myositis is refractory to any known treatments and does not respond to corticosteroid therapy. For these patients, palliative care and physical therapy are indicated.

VASCULITIS

Vasculitis encompasses a group of disorders leading to inflammation and neuritis of blood vessel walls. Soluble immune complexes are deposited in blood vessel walls in areas where capillaries have increased permeability. After deposition, the immune system is activated and the complex is destroyed along with the blood vessel wall. These disorders include Behçet disease, Kawasaki disease, polymyalgia rheumatica, and giant cell (temporal) arteritis. Inflammation and damage to large and small vessels result in end-stage organ damage [123].

Behçet Disease

Behçet disease is a chronic multisystem inflammatory disorder characterized by ulcers affecting the mouth and genitals, various skin lesions, and ocular abnormalities. In some people, the disease also results in arthritis, skin problems, and inflammation of the digestive tract, brain, and spinal cord [124]. The exact cause of Behçet disease is still unknown, but it is thought that it is an autoimmune disease, whereby the abnormal immune activity is triggered by exposure to an environmental agent (such as an infection) in people with a genetic predisposition to develop the disease. There is no known cure, and treatment is symptomatic and supportive.

Kawasaki Disease

Kawasaki disease is an autoimmune vasculitis typically diagnosed in young children. It begins with a fever that lasts at least five days. In 80% to 99% of patients, the following clinical signs/symptoms are present: cheilitis, conjunctivitis, erythema, lymphadenopathy, and proteinuria [125]. In some cases, the disease affects the coronary arteries and can lead to serious heart problems. An infection along with genetic factors may be involved in the pathogenesis [125]. Treatment includes intravenous gamma globulin and high doses of aspirin in a hospital setting.

Polymyalgia Rheumatica

Polymyalgia rheumatica is a clinical syndrome occurring more commonly in women than in men. It is a disease of aging, rarely occurring before 60 years of age. It is characterized by pain and stiffness in the neck, shoulder, back, and pelvic girdle, especially in the morning. Headaches or painful areas on the head may be present. The patient also may have a low-grade fever or temporal arteritis [123]. Rarely, the aorta is affected, increasing the risk for aortic aneurism. Treatment is corticosteroid therapy to reduce inflammation and pain. Effective treatment may take more than one year, and relapse is possible.

Giant Cell Arteritis

Giant cell (temporal) arteritis is systemic large- and medium-sized vessel vasculitis. Most often, it involves the external carotid arteries [126,127]. It typically begins as an intermittent soreness or burning headache and steadily escalates over several weeks or months to become a constant, well-localized pain. On rare occasions, it can be explosive. Many patients report that the pain is worse at night. Although the pain is usually unilateral, it may also be bilateral. Pain is classically confined to the temples. Between 70% to 90% of patients with giant cell (temporal) arteritis complain of headache [127,128].

Clinical Manifestations

The typical presentation is a new-onset headache in patients older than 50 years of age. Incidence is higher in women than men (ratio 3.7:1), as well as in persons of northern European descent. It represents the most common vasculitis in adults. Nearly 50% of patients with polymyalgia rheumatica also have giant cell arteritis [127].

On exam, the affected scalp artery is sometimes prominent. It may be tender and is often pulseless. The scalp itself is usually tender as well. Depending upon the progression, visual field defects and decreased acuity may be noted, although the patient does not usually exhibit focal neurologic deficits. Typically, the headache occurs in someone who is febrile, has malaise, and feels aches in the back and shoulders. Claudication of the jaw occurs commonly and is virtually pathognomonic for this condition when present during talking or chewing [127].

Giant cell arteritis involves not only the arteries of the scalp causing headache, but also other vessels, including those supplying the eye and occasionally the brain. Nearly half of patients with giant cell arteritis develop blindness, if untreated, due to ischemia of the optic nerve or retina. Because blindness can be prevented by immediate steroid treatment, prompt and accurate diagnosis is critical [126,127].

Medical Management

When ocular symptoms exist, emergency medical treatment is necessary. High-dose corticosteroids are an effective treatment. Headache usually resolves or greatly improves within three days of high-dose steroid treatment [126,127]. A maintenance dose of prednisone may be required to be administered for one to two years in some patients [127].

LYME DISEASE

Lyme disease is the leading arthropod zoonosis reported in the United States [129]. The primary agent of Lyme disease is the spirochetal organism Borrelia burgdorferi; however, in the United States, there are at least one other bacteria (Borrelia mayonii), two other known genospecies, and as many as 40 disease-causing subspecies of Borrelia [130,131,132]. The primary Lyme disease vectors are the ticks Ixodes scapularis or Ixodes dammini in the eastern United States and Ixodes pacificus in the West [129]. Other Ixodes spp. ticks, also known as deer ticks, can carry the organism in some of the less disease-prevalent areas [133,134].

Clinical Manifestations

The first signs of Lyme disease are usually flu-like symptoms and joint pain, which is why it is considered a rheumatic disease. In an elderly person, pre-existing arthritis may complicate early diagnosis. Three distinct stages have been described in patients with untreated infections [135]. Stage 1 (early localized stage) occurs 3 to 30 days after the tick bite and is associated with the appearance of the characteristic "bull's-eye" skin lesion of erythema migrans. Various sources estimate that approximately 70% to 80% of the documented infections will have the characteristic expanding rash [129]. This initial stage may show the nonspecific clinical signs of malaise, headache, arthralgia, fever, myalgia, and regional lymphadenopathy. If they never see a rash, many patients will not consider Lyme disease as the source of their symptoms.

Stage 2 (early disseminated stage) develops through hematogenous spread and is evident after days to weeks post-tick bite [129,136]. Possible manifestations include subtle encephalitis with headache and cognitive difficulty, stiff neck, cranial neuropathy (with facial palsy being a common finding), cerebellar ataxia, motor and sensory radiculoneuritis, myelitis, and visual disturbances. This stage is associated with acute neuroborreliosis in a significant number of cases [129,136]. Most patients with neuroborreliosis are affected by meningitis, facial nerve palsy, and/or radiculitis, with only a limited number having parenchymal spinal cord or brain involvement [137].

Stage 3 (late disseminated stage) is the chronic phase, which may appear months to years after the initial infection [129]. Various names for this stage have been proposed and are currently used, including post-Lyme syndrome, post-Lyme disease syndrome, post-treatment chronic Lyme disease, or chronic Lyme disease [137]. One of the most common findings in this stage is oligoarthritis, with the knee being the most frequently affected joint, although other joints can become inflamed [129,136]. Pain is usually out of proportion to the swelling [129]. Musculoskeletal pain, spinal radiculopathy with paresthesias, encephalopathy, and the symptom complex of fibromyalgia or chronic fatigue syndrome may be present. This stage is associated with chronic borreliosis; consequently, cardiac arrhythmias, respiratory compromise, and spread to the entire nervous system are liable to occur. It is suspected that fibromyalgia may be a long-term sequela to chronic Lyme disease. If untreated, chronic expression results in potentially crippling arthritic changes as well as organ system involvement. The organism can establish itself in the bladder wall and reoccur with another exposure or stress from another illness [133].

Many of the symptoms of Lyme disease are caused by the body's immune system. Because the spirochete infects the cartilage cells intracellularly, the neutrophils concentrate in the region, resulting in a pain similar to the pain of rheumatoid arthritis. Damage to the cartilage cells and subsequent pain is caused by neutrophils attacking both infected and healthy cells. The amount of discomfort and joint destruction varies among patients depending upon their individual immune response.

Diagnosis

Clinical suspicion from history, signs, and symptoms is paramount in the diagnosis of Lyme disease [129]. Patients can present with a variety of clinical findings, and not all classic signs or symptoms are present in those with active Lyme disease. If patients have a rash and recognize it as visceral migrans, it may be too early for other symptoms to be noted or for testing to yield positive results. Additionally, early but inadequate antibiotic treatment may prevent full antibody development in patients who are still clinically ill [138]. Varying severity and expression can make Lyme disease difficult to diagnose in some patients. The criteria as set by the Centers for Disease Control and Prevention (CDC) do not always fit the signs, symptoms, and test results. This can be very frustrating for patients as well as medical professionals. A few good diagnostic procedures are available, although they require diligent interpretation.

The first test should include an ELISA or, rarely, an indirect immunofluorescence assay (IFA); however, false positives occur with cross reactions to other spirochetes, such as syphilis, mononucleosis, some autoimmune diseases, and oral cavity flora. If the first step is positive or indeterminate, the second step should be performed. The second step, the Western blot test, identifies antibodies for the different spirochetes [129]. The most definitive diagnosis is made with a combination of positive ELISA and specific Western blot results [129,133].

Medical Management

Evidence Based Practice Recommendation

According to the International Lyme and Associated Diseases Society, clinicians should promptly offer antibiotic prophylaxis for known Ixodes tick bites in which there is evidence of tick feeding, regardless of the degree of tick engorgement or the infection rate in the local tick population. The preferred regimen is 100–200 mg of doxycycline, twice daily for 20 days. Other treatment options may be appropriate on an individualized basis.

https://www.tandfonline.com/doi/full/10.1586/14787210.2014.940900

Last Accessed: October 25, 2019

Strength of Recommendation/Level of Evidence: Recommendation, very low-quality evidence

Prompt and complete treatment with antibiotics is important to prevent the development of chronic Lyme disease and/or chronic neuroborreliosis and their troublesome sequelae. The International Lyme and Associated Diseases Society (ILADS) suggests that Lyme disease should be treated with doxycycline as the antibiotic of choice for prophylaxis following an Ixodes tick bite with known feeding, irrespective of the amount of tick engorgement or the local tick population infection rate [139]. Where doxycycline is contraindicated, antibiotics known to be effective for treating Lyme disease, such as amoxicillin, azithromycin, or cefuroxime, may be substituted. The recommended adult dose and prophylactic regimen is 100–200 mg doxycycline twice daily for 20 days [139].

Nursing Management

Patients with Lyme disease can frequently be frustrated with the long-term nature of the treatment and will need support, especially to maintain the antibiotic regimens. The long-term effects can also be very discouraging for the unfortunate patients who eventually develop the syndrome, which mimics fibromyalgia or chronic fatigue syndrome. Fortunately, it appears that early treatment, and in most cases even late treatment, can prevent or eliminate these sequelae [129,133].

As with any disease, prevention is paramount. Educating people about how the disease is transmitted and its early signs will help reduce the overall incidence and lessen the severity in those who receive early treatment. The following advice should be given to patients, family, and friends.

If walking where ticks might be present, wear clothing that provides protection from tick exposure. Bare legs should not be exposed and socks should be pulled up over pant legs. Ticks are not able to get through clothing to exposed skin, but they can climb up socks and reach exposed skin if the pant legs are not inside the socks. Long-sleeve tops and having long hair under control will help as well. Clothing should be removed and washed on arrival home. A thorough tick check should be completed, especially in body creases such as the groin and the axilla (armpit) [129]. Many people have been fooled into thinking ticks were freckles and have not removed them before they became engorged. It is most important that embedded ticks be removed promptly. If the capitulum, or head, is broken off, it may cause a local reaction. Borrelia is actually in the body of the tick, so transmission likelihood will decrease the faster the body is removed. It takes at least 24 to 36 hours of contact by the tick for the disease to be transmitted.

6. IMMUNE SYSTEM DISORDERS

ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)

HIV infects people worldwide and results in destruction of the body's host defenses and immune system. HIV has infected more than 42 million people throughout the world, with an estimated five million people newly infected each year. The CDC has reported an overall increase in new diagnoses of HIV in the United States. The greatest increases have been noted in black (55%) and Hispanic (26%) Americans. HIV kills more people than any other infectious disease and ranks fourth among the leading causes of death worldwide [123,140].

For many years, because of a lack of understanding and effective treatment, HIV was considered a rapidly progressing fatal disease. Today, HIV infection is viewed as a chronic disease that can be controlled with appropriate health care. The cost of such health care ($12,000 yearly per person), however, can limit its accessibility. Because many parts of the world, such as Africa and Asia, lack adequate economic resources to treat this disease, HIV infection continues to be a rapidly progressing fatal illness in these areas [123,140].

Etiology

The etiologic agent associated with AIDS was first isolated by French scientists in 1983 and named lymphadenopathy-associated virus. One year later, an American scientist claimed the discovery of the etiologic agent and named it the human T-cell lymphotropic virus type III. However, both scientists had actually identified the same virus, causing confusion. In 1986, the International Society in the Taxonomy of Viruses renamed the virus, calling it HIV. That same year, a second and distinctly different strain of the virus was discovered in Africa. Since 1986, the scientific names to distinguish the two viruses have been HIV-1 and HIV-2 [123,140].

This was a major discovery because it was the first clue that HIV could change its appearance, or mutate, rapidly. This capability, called genetic promiscuity, has become the hallmark of the virus, creating a monumental challenge for scientists and researchers alike. HIV-1 is distributed worldwide but is most prevalent in Europe and the United States. HIV-2 is believed to be endemic to West Africa, although it is increasingly overtaken by HIV-1. A total of 242 cases of HIV-2 had been identified in the United States as of 2010; most of the cases were associated with immigration from, travel to, or a sexual partner from West Africa [123,140].

HIV-1 has also mutated several times. It has two major subtypes, which are designated as HIV-1 major (group M) virus, and HIV-1 outlier (group O) viruses [123,140].

Risk Factors

On the basis of newly reported cases, the transmission categories are [141]:

- Male-to-male sexual contact (MSM)

- Injecting drug users

- MSM who inject drugs

- Heterosexual contact

- Perinatal transmission

- Other (includes hemophilia, blood transfusion, and risk factor not reported or not identified)

The CDC has published guidelines for medical professionals to integrate HIV prevention into the regular medical care of those living with HIV. The three major components of the recommendation are: screening for HIV transmission risk behaviors and sexually transmitted infections; providing brief, behavioral risk-reduction interventions in the office setting and referring selected patients for additional prevention interventions and other related services; and facilitating notification and counseling for sex and needle-sharing partners of infected persons [142,143].

Pathophysiology

HIV, known formerly as human T cell lymphotropic virus, is a member of the retrovirus group and as such carries an RNA genome and a reverse transcriptase enzyme (RNA-directed DNA polymerase) that enables the virus to replicate within infected host cells. Susceptibility in humans is determined by the binding affinity of virion envelope proteins for a specific cell surface receptor molecule (CD4+) found on tissue dendritic cells, macrophages, and CD4+ T lymphocytes. The pathogenesis of infection, and the subsequent perpetuation of the disease state, involves a complex set of interactions by which HIV is able to take advantage of cellular pathways while avoiding or neutralizing various components of the immune system [144,145].

The most common mode of HIV infection is sexual transmission across exposed mucosal epithelium. Dendritic cells and macrophages are found beneath the mucosal epithelium of the anogenital and cervicovaginal tracts, as well as within tonsillar and adenoidal tissue. Studies in primates demonstrate that after the virus penetrates the mucosal epithelium, infection is initiated within nearby dendritic cells and macrophages. Infected dendritic cells then fuse with CD4+ T lymphocytes and the infection extends to deeper tissue and, shortly thereafter, to regional lymph nodes [145]. Within days, this proliferation of infected CD4+ T lymphocytes, combined with the migration of infected macrophages, leads to the appearance of viral RNA in the bloodstream. This is followed by widespread secondary amplification of infection within the lymphoid tissue of the gastrointestinal tract, spleen, and bone marrow.

After the virus enters the cell, it may replicate, induce cell fusion and propagation of infection, or lead to cell death [145]. The defining characteristic of HIV disease is the immune deficiency state caused by ongoing viral replication and cell-to-cell transmission within lymphoid tissue. With chronicity of infection there is a progressive depletion of CD4 (helper-inducer) lymphocytes, the very T lymphocyte cohort whose function it is to direct other cells in the immune system and to orchestrate the inactivation of virus antigen. The result is a depressed T lymphocyte functional capacity, characterized by depletion of helper T cells (T4), impaired killer T cell activity, and increased suppressor T cells (T8). In persons with intact lymphocyte immune systems, the normal number of CD4 T cells ranges from 600–1,200 cells/mcL, depending on the stage and duration of infection.

Clinical Manifestations and Disease Course

The clinical manifestations of HIV disease are determined by the stage of primary infection and the chronicity and degree of the resultant cellular immunodeficiency state. Acute, primary HIV infection may be asymptomatic, but most often it is manifest by a subacute viral syndrome of malaise and fatigue, fever, sore throat, rash, myalgia, headache, and lymphadenopathy—clinical features similar in many respects to that seen with Epstein-Barr virus mononucleosis, CMV, and certain types of herpes simplex infections [145]. A variety of atypical symptoms and signs may be seen, including aseptic meningitis syndrome, genital ulcers, and ulcerations involving the gingiva, palate, or buccal mucosa. The acute illness usually resolves in less than 14 days, but may follow a protracted course over many weeks [145].

Early in the chronic phase of HIV infection, when the CD4 lymphocyte population is only modestly depressed and declining slowly, patients are often asymptomatic or may exhibit generalized lymphadenopathy and recurrent oropharyngeal candidiasis (thrush). During this stage, a reservoir of HIV is established throughout the lymphoid tissue system, including the spleen. Gradually, wandering (infected) macrophages disseminate the virus to certain internal organs, notably the brain, kidney, and adrenal glands.

Chronic HIV disease follows a variable course but eventually leads to a variety of clinical manifestations, some of which are directly related to the impact of chronic infection on vital organs. Common syndromes include HIV encephalopathy and dementia, peripheral neuropathy, interstitial nephropathy, a variety of skin eruptions, and signs of adrenal insufficiency.

The late clinical manifestations of HIV disease are most frequently the result of AIDS that follows progressive depletion of CD4+ T lymphocytes to levels <200 cells/mcL. AIDS-defining illnesses include secondary, opportunistic infections and certain malignancies usually encountered only in clinical settings of severely impaired cellular immunity.

Opportunistic infections are very common in persons with undiagnosed or poorly treated chronic HIV infection and are of two types. The first type is infection newly acquired by exposure to micro-organisms normally nonpathogenic, or of low pathogenicity, for persons with a healthy immune system. Examples are Pneumocystis jiroveci, Cryptococcus neoformans, Histoplasma capsulatum, and atypical mycobacteria, all of which are commonly associated with inhalational exposures and transient colonization of the respiratory tract in healthy individuals. The second type is reactivation of latent infection acquired earlier in life, which typically remains dormant throughout life. Examples of this type are CMV, Toxoplasma gondii, Mycobacterium tuberculosis, and Histoplasma capsulatum. The advent of an opportunistic infection may serve as the herald sign of unrecognized, undiagnosed chronic HIV infection/AIDS.

Clinically, these infections tend to present in one of several distinct syndromes, with useful differential diagnosis considerations:

- Pneumonia: Pneumocystis jiroveci pneumonia, Mycobacterium avium complex (MAC), cryptococcosis, histoplasmosis

- Meningoencephalitis: Toxoplasmosis, cryptococcosis, tuberculosis

- Gastrointestinal disease (diarrhea): Common bacterial dysentery, cryptosporidium, fungal and atypical mycobacterial infection

- Fever of unknown origin (often with abdominal complaints, hepatosplenomegaly, and/or lymphadenopathy): CMV, MAC, tuberculosis, histoplasmosis

Late clinical manifestations related to HIV-induced malignancy include Kaposi sarcoma of the skin or respiratory tract and lymphoma presenting as lymphadenopathy, splenomegaly, or focal gastrointestinal disease.

Without satisfactory antiretroviral therapy, the usual patient with HIV/AIDS experiences a slow, inexorable wasting illness punctuated by periods of feverishness and diarrhea, becoming increasingly anorectic, malnourished, and lethargic. Late clinical signs include muscle wasting and weakness, anemia and thrombocytopenia, lymphadenopathy, pulmonary infiltrates, and neurologic abnormalities (such as dementia, peripheral neuropathy, and tremors). The median survival of patients with advanced HIV/AIDS (CD4 count <50 cells/mcL) is approximately 12 to 18 months. Patients succumb to complications of uncontrolled infection, malignancy, or critical organ failure (such as uremia or adrenal insufficiency).

Medical Management

With early combination antiretroviral therapy (cART) and prophylaxis for opportunistic infections, HIV disease shares features of other multisystem, chronic diseases characterized by acute exacerbations and end-stage manifestations. cART combines six major classes of agents: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), integrase strand transfer inhibitors (INSTIs), and chemokine (C-C motif) receptor 5 (CCR5) antagonists.

Initiated in 1995 in the United States, antiretroviral therapy regimens have been effective in dramatically decreasing HIV-related morbidity and mortality and should be considered for all HIV-infected persons who qualify for such therapy. In addition to combination therapy, the sequencing of drugs and the preservation of future treatment options are also important. Two types of combination regimens are recommended as initial therapy: INSTI-based regimens or a PI-based regimen. The goal of these regimens is to effectively reduce HIV-associated morbidity, prolong the duration and quality of survival, restore and preserve immunologic function, and prevent HIV transmission while also avoiding drug resistance [146]. A significant proportion of patients starting cART are infected with drug-resistant strains of HIV, which may lead to suboptimal virologic responses. Therefore, pretreatment genotypic resistance testing should be used to guide selection of the most optimal initial regimen [146]. Patient compliance may be improved with therapies that combine more than one drug into a single pill, making it easier for patients to comply with their medication regimen.

Evidence Based Practice Recommendation

According to the Panel on Antiretroviral Guidelines for Adults and Adolescents, antiretroviral therapy should be initiated in all patients with HIV infection regardless of CD4 count.

https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

Last Accessed: October 25, 2019

Strength of Recommendation: AI (Strong recommendation based on one or more randomized trials with clinical outcomes and/or validated laboratory endpoints)

The decision to initiate antiretroviral therapy is one that requires careful discussion with the patient, usually in consultation with an infectious disease specialist or other physician well versed in the use of cART. Physicians and patients alike should be aware of the advantages, potential toxicities, and complexity of monitoring therapy. At the present time, the most active triple-drug regimen in a previously untreated patient can be expected to reduce the viral load below detectable levels, increase CD4 counts by an average of 100–150 cells/mcL, reduce the risk of HIV-associated complications, and prolong survival. However, the ability to achieve this advantage depends on the patient's willingness to accept a complex medical regimen that requires "many pills," rigorous compliance, frequent follow-up, and moderate risk for drug toxicity. In reaching a decision it is helpful to bear in mind that prognosis is determined by viral load and the CD4 count. Patients having a viral load in excess of 60,000 copies/mL have a relatively rapid course and average survival of a little more than four years. In contrast, those with less than 6,000 copies/mL have an average survival of more than 10 years. The CD4 count is also a prognostic factor, as counts less than 350 cells/mcL indicate severe damage to immune function and corresponding risk for opportunistic infection.

Antiretroviral therapy should be initiated immediately for all patients infected with HIV in order to reduce the risk of disease progression and limit transmission [146]. There is growing evidence that early initiation of cART is effective in preventing clinical events (e.g., non-AIDS malignancies, infection, AIDS-defining illness) regardless of pre-treatment CD4 count [147,148]. Advances in the development of antiretroviral medications and combination tablets makes adherence to therapy more effective, more convenient, and better tolerated than regimens used in the past. Deferral of therapy may be considered in patients with high CD4 counts (e.g., more than 500 cells/mcL) if adherence will be very difficult or impossible, comorbidities complicate or prohibit antiviral therapy, or a patient is considered a long-term non-progressor [146].

For treatment-naïve patients, initial recommended therapy generally consists of two NRTIs in combination with a third active antiretroviral drug from one of three drug classes: an INSTI, an NNRTI, or a PI with a pharmacokinetic enhancer (cobicistat or ritonavir) [146]. These regimens result in maximum reduction of viral load for the longest period of time. When used as initial therapy, these regimens will achieve the goal of no detectable virus in the majority of patients after four to six months [146].

Prevention of Opportunistic Infections

Depending on the CD4 count and other risk factors, asymptomatic patients may benefit from treatment to prevent opportunistic infections. In many cases, cART is useful in the prevention and treatment of these infections. Antimicrobial prophylaxis of opportunistic infections should be conducted according to guidelines provided by the CDC, the National Institutes of Health, and the Infectious Diseases Society of America [149]. Prophylactic therapy for these conditions is strongly recommended because these infections are relatively common in patients with HIV, preventive therapy is simple and cost-effective, and efficacy has been established in clinical studies. In addition, all patients should be vaccinated with pneumococcal vaccine. Hepatitis B vaccination should be considered in patients whose serologic testing indicates susceptibility.

Nursing Management

To help a patient with HIV/AIDS adhere to health maintenance behaviors, nurses should not restrict assessments to the patient's immediate clinical status. Instead, focus on potential problems the patient may encounter during the illness. For example, it is of no value to tell patients they need regular health care follow-up if they have no insurance and no money to pay for it. In these cases, social work intervention is needed to find an alternative source of healthcare services, such as the federally funded AIDS Drug Assistance Program, which provides more than just drugs. If the patient lives alone and has no one willing to assist, he or she may need to be hospitalized if the illness progresses. As a coordinator of care, have information readily available to identify problems and plan ahead [150,151].

Before performing any teaching, evaluate the patient's existing level of knowledge about HIV infection. Some patients may know little, whereas others may be knowledgeable. Try to assess exactly what the patient does and does not know about transmission and health-promoting behaviors instead of making any assumptions [150].

The psychologic burden to HIV disease can be overwhelming. Crisis points at which the nurse can anticipate anxiety, fear, or depression include [150]:

- Time of the initial HIV diagnosis

- Changes in treatment

- Development of new manifestations

- Recurrence of problems or relapse

- Terminal illness

Psychologic conflicts that patients commonly experience include fear of transmitting HIV to others, constant worry about developing an infection, guilt about a previous lifestyle, and changes in personal relationships. Social stressors may include disclosure of one's HIV status, stigma related to that status, insecurity about employment and insurance, and loneliness and social isolation [151].

Patient Education

Health teaching should be ongoing and repeated at frequent intervals. Patients with HIV can adopt several behaviors that not only improve immune function but also increase a sense of well-being. Teaching health maintenance for these individuals should include stress management, exercise, safer sex practices, pregnancy and HIV infection, nutrition, infection prevention (e.g., handwashing, food and water safety), skin care, routine mouth care, limiting alcohol consumption, risks of injection drug use, travel safety, importance of health care follow-up, and understanding and interpreting viral load tests and CD4 cell counts [151].

It is important to carefully explain viral load test results, because many people misunderstand the results. When successful therapy begins, the viral load drops from high levels (e.g., 750,000 copies/mL), down to what are called "undetectable" levels. Most laboratory tests can detect HIV copies down to only 400 copies/mL; an "undetectable level" indicates success of a prescribed regimen, but it does not mean that the person no longer has HIV infection. Patients with HIV infection should not interpret an "undetectable" result as cure or evidence that they are no longer at risk of spreading HIV. Emphasize that patients should still practice safer sex, avoiding sharing needles, and engage in other practices to prevent transmission [151].

Some patients may opt to try alternative or complementary treatments, including spiritual or psychologic interventions (e.g., guided imagery, mediation, faith healing), nutritional alternatives, (e.g., macrobiotic diet), drug and biologic therapies (e.g., homoeopathy, oxygen, ozone therapy), and physical therapies (e.g., acupuncture, acupressure, massage therapy). In most cases, these choices can have a positive effect on the person's emotional well-being with no adverse effects. But some approaches can be detrimental. For example, a macrobiotic diet can lead to vitamin and mineral deficiencies as well as weight loss. Herbal remedies may cause nausea, vomiting, diarrhea, or CNS depression [151].

Initiating and Maintaining Antiretroviral Therapy

One of the most important aspects of providing nursing care to patients with HIV is helping with the antiretroviral regimen. Studies suggest that, in general, patients with chronic diseases take their prescribed drugs about 50% of the time [151]. In contrast, to sustain the durability and efficacy of antiretroviral therapy, patients must maintain about a 95% compliance rate. This places high expectations on both the patient and his or her healthcare providers. Because therapy may last for many years, it is vital that the patient understand the potential benefits and drawbacks of any regimen and the potential consequences of not adhering to therapy. Benefits of cART include [151]:

- Control of HIV replication and mutation, with reduction in viral load

- Prevention of destruction of the immune system and loss of CD4 T helper cells

- Delayed progression to AIDS-defining illnesses

- Decreased risk for development of HIV resistance to drugs

- Decreased risk for drug toxicity

- Increased survival with HIV disease

Potential risks include [151]:

- Reduced quality of life from adverse drug effects and the inconvenience of a complex regimen

- A limited number of drugs available to respond to drug resistance

- Unknown long-term toxicity

- Unknown duration of the effectiveness of current therapies

The decision of whether to take cART is ultimately up to the patient. The regimen ordered is commonly complex and requires the patient to take many pills daily (although combination agents are addressing this issue), often at exactly spaced intervals and with differing requirements as to timing the pills related to food. All antiretrovirals have side effects and may interact with numerous other drugs. These drug-drug interactions are usually not life-threatening [151].

Evaluation of a patient's ability to adhere to a prescribed drug regimen includes both subjective and objective techniques. Subjective evaluation is by self-report; patients and their care partner describe the patient's ability to take all prescribed medications. Objective analysis of the success of the plan of care is by laboratory evaluation of CD4 cell counts and viral load. "Pill counting" should only be performed if the patient wants this intervention and participates. In the past, pill counts have been used as a sort of policing activity, but today the practice is generally considered to be a waste of time, with leftover pills often simply discarded prior to the count [150].

Caring for the Patient with AIDS

In advanced HIV disease, the goal of nursing care is to diagnose and treat human responses to an actual or potential health problems related to the development of clinical manifestations and the diagnosis of AIDS. All efforts are directed at controlling manifestations. Issues that often arise include fever, fatigue, weight loss, nausea, diarrhea, dry and painful mouth, dry skin, skin lesions, pain, dyspnea, cough, impaired cognition, impaired vision, insomnia, and sexual dysfunction [32,152]. Assessment of clinical manifestations should include both subjective and objective data. All clinical manifestations should be quantified [32,152].

Because of the underlying immunodeficiency and impaired inflammatory responses, clinical manifestations of infection, including fever, may be greatly muted. Nonpharmacologic interventions include keeping the patient in a warm room to avoid shivering and applying a sheet and a light blanket. Avoid fanning the bed covers, exposing skin, or removing clothing, all of which might cause chilling [23]. Counterproductive treatments should be avoided, such as tepid water sponge bathing, which causes defensive vasoconstriction and has not been shown to be an effective coolant in fever [23].

Increase caloric and fluid intake by providing a plan for six feedings distributed over 24 hours and high-protein, high-calorie nutritional supplements, especially if the patient has anorexia. Provide 2–2.5 L of fluids daily. Maintain comfort and safety by providing dry clothes and bed linens made of natural fibers. Emollient creams may be useful for dry skin. Mental status should be monitored frequently, especially when the patient has a fever. Evaluate the patient's need for assistance with activities of daily living.

PRIMARY IMMUNE DEFICIENCY DISEASES

Primary immune deficiency diseases (PIDDs) are inherited genetic disorders and tend to cause chronic susceptibility to infection. There are more than 300 PIDDs, and almost all are considered rare (affecting fewer than 200,000 people in the United States) [153,154]. They may result from altered immune signaling molecules or the complete absence of mature immune cells. For instance, X-linked severe combined immunodeficiency is caused by a mutation in a signaling receptor gene, rendering immune cells insensitive to multiple cytokines. Without the growth and activation signals delivered by cytokines, immune cell subsets, particularly T and natural killer cells, fail to develop normally.

Medical Management

Because there are many PIDDs, treatment options are targeted toward the specific immune defects [154]. Options include transplantation (e.g., bone marrow, stem cell, thymus), immunoglobulin replacement, preventive antibiotics, strategies to manage autoimmune disease, and in some cases, gene therapy.

SEPSIS

Sepsis is a systemic pathophysiologic and clinical syndrome caused by infection and manifest by signs of inflammation, host immune response, and organ dysfunction. The causes of sepsis are myriad, and the scope of illness is broad. Most cases of sepsis syndrome arise from bacterial infection, but certain viral (e.g., Ebola and other hemorrhagic fevers) and fungal (e.g., candidiasis, histoplasmosis) infections induce a sepsis syndrome as well.

Evidence Based Practice Recommendation

According to the National Institute for Health and Care Excellence, risk factors for sepsis include very young (younger than 1 year) and older (older than 75 years) age; frailty; impaired immune systems and/or function; administration of chemotherapy, long-term steroids, or immunosuppressant drugs; history of surgery or other invasive procedures in the past six weeks; any breach of skin integrity; injection drug use; and indwelling lines or catheters.

https://www.nice.org.uk/guidance/ng51

Last Accessed: October 25, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Sepsis is defined clinically as a systemic inflammatory response arising from known or suspected infection, leading to widespread tissue injury and manifested by two or more of the following conditions [155,156]:

- Fever (temperature greater than 38.3°C [100.6°F])

- Hypothermia (core temperature less than 36°C [96.8°F])

- Tachycardia (heart rate greater than 90 beats per minute in adults)

- Tachypnea (respiratory rate greater than 20 breaths per minute)

- Altered mental status

- Hyperventilation (partial pressure of carbon dioxide less than 32 mm Hg)

- Leukocytosis (leukocyte count greater than 12,000 cells per mm^3)

- Leukopenia (leukocyte count less than 4,000 cells per mm^3)

Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.

Medical Management

The Society of Critical Care Medicine guideline emphasizes that sepsis and septic shock are medical emergencies; treatment and resuscitation should begin immediately upon recognition. Intravenous fluid resuscitation of a patient with sepsis-induced shock (defined as tissue hypoperfusion) should be initiated as soon as the hypoperfusion is recognized (i.e., not delayed pending admission to an intensive care unit).

Intravenous antimicrobial therapy should be started as early as possible, ideally within the first hour of recognition of sepsis or septic shock. If hypotension persists after intravascular volume repletion, then vasopressors may be required to restore and maintain adequate blood pressure and tissue perfusion (goal mean arterial blood pressure ≥65 mg Hg). Such patients are considered to have the combination of vasodilation and reduced cardiac contractility, a condition best managed with a combined inotrope-vasopressor agent. In order to monitor arterial pressure accurately, it is suggested that all patients requiring vasopressors have an arterial catheter placed as soon as practical, if resources are available [157].

The Hour-1 Bundle consists of five elements that are intended to be initiated within the first hour after the time of triage in the emergency department or, if referred from another care location, from the earliest chart annotation consistent with all elements of sepsis or septic shock. The five elements are [158]:

- Measure lactate level. Re-measure if initial lactate is >2 mmol/L.

- Obtain blood cultures prior to administration of antibiotics.

- Administer broad-spectrum antibiotics.

- Rapidly administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L.

- Apply vasopressors if patient is hypotensive during or after fluid resuscitation to maintain mean arterial blood pressure ≥65 mm Hg.

More than one hour may be required for resuscitation to be completed, but initiation of resuscitation and treatment should begin immediately [158]. The Hour-1 Bundle, based on the 2016 guideline, is evidence-based and intended for use by emergency department, hospital, and intensive care unit staff as a tool for improving the care of patients with sepsis and septic shock.

7. CONCLUSION

With knowledge of the immune system and function and the dynamic pathology that intrudes and impedes normal function, nurses are able to readily provide quality and often lifesaving actions. The awareness of pathology underlying symptoms leads to quicker reporting of changes in the patient's condition. Nurses can also perform immediate interventions based on standing orders and a recognition of appropriate actions to provide safe, quality care. This knowledge elevates technical care to professional care through use of decision-making skills built upon the knowledge of pathophysiology.

8. CASE STUDIES

SYSTEMIC LUPUS ERYTHEMATOSUS

Patient A is a married black woman, 47 years of age, with two children and an 18-year history of systemic lupus erythematosus. She has no known allergies. The patient takes an occasional naproxen for joint pain and antacid for heartburn, but reports no other prescription or over-the-counter medications. She neither smokes nor drinks alcohol. Except for lupus, the patient's medical history is unremarkable.

Patient A is 5 feet 5 inches in height and weighs 102 pounds, a decrease in weight of 23 pounds since her last physical exam nearly one year ago. She has four brothers and three sisters. An older sister has rheumatoid arthritis, an aunt has pernicious anemia, and her deceased mother had hyperthyroidism (Graves disease).

At presentation, the patient's blood pressure is 110/70 mm Hg, heart rate is 70 beats per minute, and oral temperature is 99.9°F. Her respiration is unlabored at 15 breaths per minute.

Medical History

Eighteen years ago, Patient A complained to her primary care provider of multiple rashes that developed on her arms and legs whenever she went out into the sun. She also complained of several small patches of hair loss on her head that she attributed to stress and anxiety experienced during an airplane trip (as she has a fear of flying). Furthermore, she mentioned at that time she lacked energy, became tired very easily, and always needed to take at least one nap each day. She reported mild arthritic pain in her fingers and elbows, but attributed the joint discomfort to "growing old." Her erythrocyte sedimentation rate was 25 mm/hour.

Patient A had been aware of these problems for approximately four months. A physical examination was conducted, during which the primary care provider noted multiple rash-like lesions on sun-exposed areas of the body, primarily on the arms and legs. A tissue biopsy of one of the lesions was taken and microscopic examination of the tissue revealed vasculitis (white blood cells within the walls of blood vessels). An ANA test was positive. The lungs were clear to auscultation, heart sounds were normal with a prominent S_1 and S_2, and there was no evidence of enlarged lymph nodes. Blood tests revealed a hematocrit of 23% and a red blood cell count of 3.5 million/mcL. She was also slightly jaundiced, with some yellowing within the sclera. Microscopic examination of a peripheral blood smear revealed that red blood cells were normal in shape, size, and color, ruling out iron, folate, and vitamin B12 deficiencies. The total white blood cell count was 5,500/mcL, and her pitted erythrocyte count was 350,000/mcL. Urinalysis was normal. She was placed on prednisone for two months, during which time all signs and symptoms of disease resolved.

Five years ago, Patient A presented again to her primary care provider, this time complaining of a productive cough and stiffness and pain in her hands and feet that seemed to come and go and to affect different joints (migratory polyarthritis). She was afraid that she was developing rheumatoid arthritis like her older sister.

Her blood pressure at this time was 140/90 mm Hg and heart rate 105 beats per minute, and she had a temperature of 100°F. Auscultation of the lungs revealed abnormal lung sounds, suggesting that she had bronchitis. A chest x-ray revealed mild pulmonary edema but no white blood cell infiltrates in the terminal airways. The primary care provider was concerned about susceptibility for developing pneumonia. Axillary and inguinal lymph nodes were slightly enlarged. Blood tests revealed a hematocrit of 43%, a platelet count of 330,000/mcL, and a total white blood cell count of 1,200/mcL. A urinalysis was essentially normal.

The patient was given a 10-day course of antibiotic therapy to prevent pneumonia and placed on prednisone again. All signs and symptoms resolved within three months.

Today, Patient A returns to her primary care provider complaining of fatigue, anorexia, weight loss, and significant swelling in the abdomen, face, and ankles. The primary care provider notes that a "butterfly-shaped" rash is present across the bridge of her nose and cheeks. Blood tests reveal a hematocrit of 24%. The white blood cell count is 2,400/mcL. A dipstick examination of the urine reveals an abnormal protein concentration, and microscopy shows the presence of significant numbers of red and white blood cells. A 24-hour urine protein collection reveals excretion of 2.5 g protein/24 hours.

Study Questions

1. What is the relevance of the current information to her disease?

2. What is the significance of the patient's family history?

3. Explain the pathophysiology that underlies hair loss in this patient and the relevance of the abnormal erythrocyte sedimentation rate.

4. What might have caused the lack of energy in this patient, and what type of tests might be ordered to support this conclusion?

5. Vasculitis in lupus results from the trapping of antigen-antibody complexes in blood vessel walls followed by an intense inflammatory response to the immune complexes. Why is prednisone effective in relieving vasculitis?

6. What is the most likely cause of jaundice in this patient?

7. What is the pathophysiology that underlies lymph node enlargement in this patient?

8. Which of the three blood test results would be of most concern? Give a likely cause for the abnormality.

9. The patient's white blood cell differential was 75% neutrophils, 15% lymphocytes, 5% monocyte/macrophages, 4% eosinophils, and 1% basophils. Which one of these five white blood cell types has been specifically targeted by the patient's immune system?

10. Give a reasonable explanation for the cause of tachycardia and elevated blood pressure in this patient.

11. Patients with systemic lupus erythematosus should receive an influenza vaccination every year and a pneumococcal vaccination every five years. Why?

12. Why is hypocomplementemia consistent with a diagnosis of systemic lupus erythematosus?

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

A white man, 32 years of age, presents to the emergency department with a fever of 102.5°F. He was diagnosed with HIV infection approximately three years previously, when he presented to his primary care provider with oral thrush. He was offered cART and stayed on this regimen until approximately 10 months ago, when he lost his job and insurance and could no longer pay for the drugs and discontinued all treatment. He has felt more "run down" recently. For the past two to three weeks, he has had fever, a nonproductive cough, and shortness of breath with mild exertion, such as when cleaning his house. On examination, his blood pressure is 134/82 mm Hg, pulse 110 beats per minute, and respiratory rate 28 breaths per minute. His oxygen saturation on room air at rest is 89% but drops to 80% when he walks 100 feet, and his breathing becomes quite labored. His lungs are clear to auscultation, but white patches cover his buccal mucosa. Otherwise, his examination is unremarkable. Laboratory testing shows a leukocyte count of 2,800 cells/mcL. Serum lactic (acid) dehydrogenase is 540 IU/L.

Study Questions

1. What is the most likely diagnosis?

2. What is your next step?

3. What other diagnoses should be considered?

IMMUNE THROMBOCYTOPENIC PURPURA

A Hispanic woman, 26 years of age, presents to the emergency department on a Saturday afternoon with complaints of bleeding from her nose and mouth since the previous night. She also noticed small, reddish spots on her lower extremities when she got out of bed in the morning. She denies fever, chills, nausea, vomiting, abdominal pain, or joint pain. The patient reports she had developed an upper respiratory infection two weeks prior to the visit, but the infection has now resolved. She denies significant medical problems. Her menses have been normal, and her last menstrual period was approximately two weeks ago. She denies excessive bleeding in the past. Prior to this episode, she never had epistaxis, easy bruisability, or bleeding into her joints. There is no family history of abnormal bleeding. The patient does not take any medications.

On examination, the patient is alert, oriented, and somewhat anxious. Her blood pressure is 110/70 mm Hg, her heart rate is 90 beats per minute, and she is afebrile. No pallor or jaundice is noted. There is bright red oozing from the nose and the gingiva. Skin examination reveals multiple 1-mm flat, reddish spots on her lower extremities. The rest of the examination is normal. There is no lymphadenopathy or hepatosplenomegaly. Her complete blood count is normal, except for a platelet count of 18,000/mcL. Prothrombin time and partial thromboplastin time are normal.

Study Questions

1. What is your most likely diagnosis?

2. What is the best initial treatment?

Works Cited

1. Copstead-Kirkhorn LEC, Banasik JL. Study Guide for Copstead and Banasik Pathophysiology. 4th ed. St. Louis, MO: Saunders Elsevier; 2010.

2. Nowak T, Gordon Hanford A. Pathophysiology: Concepts and Applications for Health Care Professionals. 3rd ed. New York, NY: McGraw-Hill; 2004.

3. Hall JE. Guyton and Hall Textbook of Medical Physiology. 13th ed. Philadelphia, PA: Elsevier; 2016.

4. Grossman S, Porth CM. Porth's Pathophysiology: Concepts of Altered Health States. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014.

5. Bruyere HJ. 100 Case Studies in Pathophysiology. 1st ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009.

6. McCance KL, Huether SE. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 8th ed. St. Louis, MO: Elsevier; 2019.

7. Dembic Z. The Cytokines of the Immune System: The Role of Cytokines in Disease Related to Immune Response. San Diego, CA: Academic Press; 2015.

8. Zouali M. The Epigenetics of Autoimmune Diseases. 1st ed. Hoboken, NJ: John Wiley & Sons; 2009.

9. Mitchell RN, Kumar V, Fausto N, Abbas AK, Aster JC. Pocket Companion to Robbins & Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Elsevier; 2017.

10. Huether SE, McCance KL. Understanding Pathophysiology. 6th ed. St. Louis, MO: Elsevier; 2017.

11. Rose NR, Mackay IR. The Autoimmune Diseases. 5th ed. San Diego, CA: Academic Press; 2014.

12. Bullock BL, Henze RL. Focus on Pathophysiology. Philadelphia, PA: Lippincott Williams and Wilkins; 2000.

13. Corwin EJ. Handbook of Pathophysiology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.

14. Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th ed. Maryland Heights, MO: Mosby; 2002.

15. Mahmoudi M. Challenging Cases in Rheumatology and Diseases of the Immune System. New York, NY: Springer; 2013.

16. American Medical Association. The American Medical Association: Essential Guide to Asthma. New York, NY: Pocket Books; 1998.

17. Velasquez-Manoff M. An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases. New York, NY: Scribner; 2012.

18. Upton E. Sorting Out Autoimmune Disease: Your Roadmap to Wellness, Naturally. Beverly Hills, CA: Fifth Element Press; 2018.

19. Weil A. The Autoimmune Solution: Learn How to Prevent and Overcome Inflammatory Disease. Scotts Valley, CA: CreateSpace Independent Publishing; 2015.

20. Markovchick VJ, Pons PT, Bakes KA. Emergency Medicine Secrets. 5th ed. St. Louis, MO: Elsevier; 2011.

21. Langwith J. Perspectives on Diseases & Disorders: Autoimmune Disease. Farmington Hills, MI: Greenhaven Press; 2011.

22. Aaseng N. Autoimmune Diseases. London: Franklin Watts; 1995.

23. Gulanick M, Myers JL. Nursing Care Plans: Diagnoses, Interventions, and Outcomes. 9th ed. St. Louis, MO: Elsevier; 2017.

24. O'Bryan T. The Autoimmune Fix: How to Stop the Hidden Autoimmune Damage That Keeps You Sick, Fat, and Tired Before It Turns Into Disease. Emmaus, PA: Rodale; 2016.

25. Langwith J. Perspectives on Diseases & Disorders: Autoimmune Disease. Farmington Hills, MI: Greenhaven Press; 2011.

26. Merck Manual. Asthma. Available at https://www.merckmanuals.com/professional/pulmonary-disorders/asthma-and-related-disorders/asthma. Last accessed October 22, 2019.

27. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma. Available at https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf. Last accessed October 22, 2019.

28. Smith AD, Cowan JO, Brassett, KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment of chronic asthma. N Engl J Med. 2005;352(21):2163-2172.

29. Ackley BJ, Ladwig GB, Makic MF. Nursing Diagnosis Handbook: An Evidence-Based Guide to Planning Care. 11th ed. St. Louis, MO: Elsevier; 2017.

30. Alexander L. Autoimmune Diseases. Roseville, CA: NetCE; 2017.

31. Colbert D. The Bible Cure for Autoimmune Diseases. Lake Mary, FL: Siloam; 2004.

32. Ignatavicius DD, Workman ML. Medical-Surgical Nursing: Patient-Centered Collaborative Care. 8th ed. St. Louis, MO: Elsevier; 2016.

33. Bope ET, Kellerman RD. Conn's Current Therapy 2017. 1st ed. Philadelphia, PA: Elsevier; 2017.

34. Mansoor DK, Sharma HP. Clinical presentations of food allergy. Pediatr Clin N Am. 2011;58:315-326.

35. Burks W. Skin manifestations of food allergy. Pediatrics. 2003;111(6 Pt 3):1617-1624.

36. Cleveland Clinic. Urticaria (Hives) and Angioedema. Available at https://my.clevelandclinic.org/health/diseases/8630-urticaria-hives-and-angioedema. Last accessed October 21, 2019.

37. LexiComp Online. Available at https://online.lexi.com. Last accessed October 21, 2019.

38. Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report. Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol. 2006;117(2):391-397.

39. Simons FE, Ardusso LR, Bilò MB, et al. World allergy organization anaphylaxis guidelines: summary. J Allergy Clin Immunol. 2011;127(3):587-593.

40. Campbell RL, Hagan JB, Manivannan V, et al. Evaluation of national institute of allergy and infectious diseases/food allergy and anaphylaxis network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol. 2012;129(3):748-752.

41. Sampson HA. Anaphylaxis and emergency treatment. Pediatrics. 2003;111(6 pt 3):1601-1608.

42. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis—a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115(5):341-384.

43. Chipps BE. Update in pediatric anaphylaxis: a systematic review. Clin Pediatr (Phila). 2013;52(5):451-461.

44. Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 Suppl):S1-S58.

45. Ross MP, Ferguson M, Street D, Klontz K, Schroeder T, Luccioli S. Analysis of food-allergic and anaphylactic events in the National Electronic Injury Surveillance System. J Allergy Clin Immunol. 2008;121(1):166-171.

46. Rudders SA, Banerji A, Clark S, Camargo Jr CA. Age-related differences in the clinical presentation of food-induced anaphylaxis.J Pediatr. 2011;158(2):326-328.

47. Simons FE, Ardusso LR, Bilò MB, et al. 2012 update: world allergy organization guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol. 2012;12(4):389-399.

48. Prince BT, Mikhail I, Stukus DR. Underuse of epinephrine for the treatment of anaphylaxis: missed opportunities. J Asthma Allergy. 2018;11:143-151.

49. Decker WW, Campbell RL, Manivannan V, et al. The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project. J Allergy Clin Immunol. 2008;122(6):1161-1165.

50. Lieberman P, Camargo Jr CA, Bohlke K, et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma, and Immunology epidemiology of anaphylaxis working group. Ann Allergy Asthma Immunol. 2006;97(5):596-602.

51. Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol. 2006;97(1):39-43.

52. Järvinen KM, Sicherer SH, Sampson HA, Nowak-Wegrzyn A. Use of multiple doses of epinephrine in food-induced anaphylaxis in children. J Allergy Clin Immunol. 2008;122(1):133-138.

53. Russell WS, Farrar JR, Nowak R, et al. Evaluating the management of anaphylaxis in U.S. emergency departments: guidelines vs. practice. World J Emerg Med. 2013;4(2):98-106.

54. Lieberman P. Anaphylactic reactions during surgical and medical procedures. J Allergy Clin Immunol. 2002;110(2 Suppl):S64-S69.

55. Choo KJ, Simons FE, Sheikh A. Glucocorticoids for the treatment of anaphylaxis. Cochrane Database Syst Rev. 2012;(4):CD007596.

56. Sheikh A, Shehata YA, Brown SG, Simons FE. Adrenaline for the treatment of anaphylaxis: Cochrane systematic review. Allergy. 2009;64(2):204-212.

57. Campbell RL, Li JT, Nicklas RA, Sadosty AT, Members of the Joint Task Force, Practice Parameter Workgroup. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol. 2014;113(6):599-608.

58. Gupta RS, Springston EE, Warrier MR, et al. The prevelance, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9-e17.

59. Acker WW, Plasek JM, Blumenthal KG, et al. Prevalence of food allergies and intolerances documented in electronic health records. J Allergy Clin Immunol. 2017;140(6):1587-1591.

60. Jackson KD, Howie LD, Akinbami LJ. Trends in allergic conditions among children: United States, 1997–2011. NCHS Data Brief. 2013;(121):1-8.

61. Gupta R, Warren C, Blumenstock J, Kotowska J, Mittal K, Smith B. OR078 The prevalence of childhood food allergy in the United States: an update. Ann Allergy Asthma Immunol. 2017;119(5):S11.

62. Centers for Disease Control and Prevention. National Health Interview Survey. Available at https://www.cdc.gov/nchs/nhis/shs/tables.htm. Last accessed October 22, 2019.

63. Food Allergy Research & Education. Facts and Statistics. Available at https://www.foodallergy.org/life-with-food-allergies/food-allergy-101/facts-and-statistics. Last accessed October 22, 2019.

64. Turner PJ, Jerschow E, Umasunthar T, Lin R, Campbell DE, Boyle RJ. Fatal anaphylaxis: mortality rate and risk factors. J Allergy Clin Immunol Pract. 2017;5(5):1169-1178.

65. Patel DA, Holdford DA, Edwards E, Carroll NV. Estimating the economic burden of food-induced allergic reactions and anaphylaxis in the United States. J Allergy Clin Immunol. 2011;128(1):110-115.

66. Burks AW, Tang M, Sicherer S, et al. ICON: food allergy. J Allergy Clin Immunol. 2012;129(4):906-920.

67. Liu AH, Jaramillo R, Sicherer SH, et al. National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol. 2010;126(4):798-806.

68. Sicherer SH, Wood RA, American Academy of Pediatrics Section on Allergy and Immunology. Allergy testing in childhood: using allergen-specific IgE tests. Pediatrics. 2012;129(1):193-197.

69. Bischoff S, Crowe SE. Gastrointestinal food allergy: new insights into pathophysiology and clinical perspectives. Gastroenterology. 2005;128(4):1089-1113.

70. Mayer L. Mucosal immunity. Pediatrics. 2003;111(6 pt 3):1595-1600.

71. Fleischer DM, Perry TT, Atkins D, et al. Allergic reactions to foods in preschool-aged children in a prospective observational food allergy study. Pediatrics. 2012;130(1):25-32.

72. Gupta RS, Warren CM, Smith BM, et al. Prevalence and severity of food allergies among U.S. adults. JAMA Netw Open. 2019;2(1):e185630.

73. Gupta RS, Springston EE, Smith B, Pongracic J, Holl JL, Warrier MR. Parent report of physician diagnosis in pediatric food allergy. J Allergy Clin Immunol. 2013;131(1):150-156.

74. Vargas PA, Sicherer SH, Christie L, et al. Developing a food allergy curriculum for parents. Pediatr Allergy Immunol. 2011;22(6):575-582.

75. Eigenmann PA, Zamora SA. An Internet-based survey on the circumstances of food-induced reactions following the diagnosis of IgE-mediated food allergy. Allergy. 2002;57(5):449-453.

76. Kim JS, Sicherer SH. Living with food allergy: allergen avoidance. Pediatr Clin North Am. 2011;58(2):459-470.

77. Steinman HA. "Hidden" allergens in foods. J Allergy Clin Immunol. 1996;98(2):241-250.

78. Centers for Disease Control and Prevention. FastStats: Asthma. Available at https://www.cdc.gov/nchs/fastats/asthma.htm. Last accessed October 22, 2019.

79. McMillan JA, Feigin RD, DeAngelis C, Jones Jr MD. Oski's Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.

80. National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Available at https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Last accessed October 22, 2019.

81. BlueCross BlueShield of Texas. 2018 Clinical Practice Guidelines: Asthma. Available at https://www.bcbstx.com/provider/pdf/asthma_cpg_2018.pdf. Last accessed October 22, 2019.

82. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention (2018 Update). Available at https://ginasthma.org/wp-content/uploads/2018/04/wms-GINA-2018-report-tracked_v1.3.pdf. Last accessed October 22, 2019.

83. Centers for Disease Control and Prevention. Common Asthma Triggers. Available at https://www.cdc.gov/asthma/triggers.html. Last accessed October 22, 2019.

84. Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising? Results from Olmstead County, Minnesota, 1955–2007. Arthritis Rheum. 2010;62(6):1576-1582.

85. Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2005;72(6):1037-1047.

86. Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. In: Firstein GS, Budd RC, Gabriel SE, McInnes IB, O'Dell JR (eds). Kelley and Firestein's Textbook of Rheumatology. 10th ed. Philadelphia, PA: Elsevier; 2017: 1115-1166.

87. Goldring SR. A 55-year-old woman with rheumatoid arthritis. JAMA. 2000;283(4):524-531.

88. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580-1588.

89. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Rheumatoid Arthritis. Available at https://www.niams.nih.gov/health-topics/rheumatoid-arthritis. Last accessed October 22, 2019.

90. O'Dell J. Rheumatoid arthritis. In: Goldman L, Schafer AI (eds). Goldman-Cecil Medicine. 25th ed. New York, NY: Elsevier; 2015.

91. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.

92. Jurgens MS, Welsing PM, Jacobs JW. Overview and analysis of treat-to-target trials in rheumatoid arthritis reporting on remission. Clin Exp Rheumatol. 2012;30(4 Suppl 73):S56-S63.

93. Singh JA, Saag KG, Bridges Jr SL, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26.

94. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146(6):406-415.

95. Pincus T, O'Dell JR, Kremer JM. Combination therapy with multiple disease-modifying antirheumatic drigs in rheumatoid arthritis: a preventive strategy. Ann Intern Med. 1999;131(10):768-774.

96. Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med. 2004;350(21):2167-2179.

97. Wells G, Li T, Maxwell L, MacLean R, Tugwell P. Determining the minimal clinically important differences in activity, fatigue, and sleep quality in patients with rheumatoid arthritis. J Rheumatol. 2007;34(2):280-289.

98. van Gestel AM, Prevoo ML, van't Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Arthritis Rheum. 1996;39(1):34-40.

99. Falvo D, Holland BE. Medical and Psychosocial Aspects of Chronic Illness and Disability. 6th ed. Burlington, MA: Jones & Bartlett Learning; 2017.

100. National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases. Lupus: A Patient Care Guide for Nurses and Other Health Professionals. Bethesda, MD: The Institute; 2006.

101. Wallace DJ. The Lupus Book: A Guide for Patients and Their Families. 6th ed. New York, NY: Oxford; 2019.

102. Phillips RH. Coping with Lupus: A Practical Guide to Alleviating the Challenges of Systemic Lupus Erythematosus. New York, NY: Penguin Group; 2012.

103. Mayo Clinic. Lupus. Available at https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789. Last accessed October 22, 2019.

104. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Systemic Lupus Erythematosus (Lupus). Available at https://www.niams.nih.gov/health-topics/lupus. Last accessed October 22, 2019.

105. Medscape. Drug-Induced Lupus Erythematosus. Available at https://emedicine.medscape.com/article/1065086-overview. Last accessed October 22, 2019.

106. Lupus Foundation of America. Lab Tests for Lupus. Available at https://www.lupus.org/resources/lab-tests-for-lupus. Last accessed October 22, 2019.

107. Lab Tests Online. Complement. Available at https://labtestsonline.org/tests/complement. Last accessed October 22, 2019.

108. U.S. Food and Drug Administration. FDA Approves First Treatment for Pediatric Patients with Lupus. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-pediatric-patients-lupus. Last accessed October 22, 2019.

109. Collins CE, Dall'Era M, Kan H, et al. Response to belimumab among patients with systemic lupus erythematosus in clinical practice settings: 24-month results from the OBSErve study in the USA. Lupus Sci Med. 2016;3(1):e000118.

110. Touma Z, Sayani A, Pineau CA, et al. Belimumab use, clinical outcomes and glucocorticoid reduction in patients with systemic lupus erythematosus receiving belimumab in clinical practice settings: results from the OBSErve Canada Study. Rheumatol Int. 2017;37(6):865-873.

111. Kassan SS, Moutsopoulos HM. Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med. 2004;164(12):1275-1284.

112. Garcia-Carrasco M, Ramos-Casals M, Rosas J, et al. Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore). 2002;81(4):270-280.

113. Al-Hashimi I, Khuder S, Haghighat N, Zipp M. Frequency and predictive value of the clinical manifestations in Sjögren syndrome. J Oral Pathol Med. 2001;30(1):1-6.

114. Harboe E, Tjensvoll AB, Maroni S, et al. Neuropsychiatric syndromes in patients with systemic lupus erythematosus and primary Sjögren syndrome: a comparative population-based study. Ann Rheum Dis. 2009;68(10):1541-1546.

115. Mellgren SI, Göransson LG, Omdal R. Primary Sjögren syndrome associated neuropathy. Can J Neurol Sci. 2007;34(3):280-287.

116. Sánchez-Guerrero J, Pérez-Dosal MR, Cárdenas-Velázquez F, et al. Prevalence of Sjögren syndrome in ambulatory patients according to the American-European Consensus Group criteria. Rheumatology. 2005;44(2):235-240.

117. Ramos-Casals M, Tzioufas AG, Stone JH, Sisó A, Bosch X. Treatment of primary Sjögren syndrome: a systematic review. JAMA. 2010;304(4):452-460.

118. American Academy of Ophthalmology. Dry Eye Syndrome PPP-2018. Available at https://www.aao.org/preferred-practice-pattern/dry-eye-syndrome-ppp-2018. Last accessed October 22, 2019.

119. Kruszka P, O'Brian RJ. Diagnosis and management of Sjögren syndrome. Am Fam Physician. 2009;79(6):465-470.

120. Ship JA. Diagnosing, managing, and preventing salivary gland disorders. Oral Dis. 2002;8(2):77-89.

121. Singh JA, Guyatt G, Ogdie A, et al. Special article: 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis. Arthritis Rheumatol. 2019;71(1):5-32.

122. Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2016;68(2):282-298.

123. Gerson C. Healing "Auto-Immune" Diseases: The Gerson Way. Carmel, CA: Gerson Health Media; 2017.

124. Genetic and Rare Diseases Information Center. Behçet Disease. Available at https://rarediseases.info.nih.gov/diseases/848/behcet-disease. Last accessed October 21, 2019.

125. Genetic and Rare Diseases Information Center. Kawasaki Disease. Available at https://rarediseases.info.nih.gov/diseases/6816/kawasaki-disease. Last accessed October 21, 2019.

126. International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia.2013;33(9):629-808.

127. Medscape. Giant Cell Arteritis (Temporal Arteritis). Available at https://emedicine.medscape.com/article/332483-overview. Last accessed October 22, 2019, 2019.

128. Carter J. Evidence-Based Guidelines for Migraine Headache in the Primary Care Setting: Pharmacological Management of Acute Attacks. Available at http://www.jasoncartermd.com/resources/pdf/Migraine%20Guidelines.pdf. Last accessed October 22, 2019.

129. Centers for Disease Control and Prevention. Lyme Disease: Data and Surveillance. Available at https://www.cdc.gov/lyme/datasurveillance/index.html. Last accessed October 22, 2019.

130. Semantic Scholar. Will There Ever Be An Accurate Test for Lyme Disease? Available at https://pdfs.semanticscholar.org/a964/f1f40b94ea9ff1f8d5eef865d27f174e470b.pdf. Last accessed October 22, 2019.

131. Lin T, Oliver JH Jr, Gao L, Kollars TM Jr, Clark KL. Genetic heterogeneity of Borrelia burgdorferi sensu lato in the southern United States based on restriction fragment length polymorphism and sequence analysis. J Clin Microbiol. 2001;39(7):2500-2507.

132. WebMD. New Lyme Disease Bacteria Discovered: CDC. Available at https://www.webmd.com/arthritis/news/20160209/new-lyme-disease-bacteria-discovered-in-upper-midwest-cdc. Last accessed October 22, 2019.

133. Steere AC. A 58-year old man with a diagnosis of chronic Lyme disease. JAMA. 2002;288(8):1002-1010.

134. Spielman A, Wilson ML, Levine JF, Piesman J. Ecology of Ixodes dammini-borne human babesiosis and lyme disease. Annu Rev Entomol. 1985;30:439-460.

135. Steere AC, Coburn J, Glickstein L. The emergence of Lyme disease. J Clin Invest. 2004;113(8):1093-1101.

136. DePietopaolo DL, Powers JH, Gill JM, Foy AJ. Diagnosis of Lyme disease. Am Fam Physician. 2005;72(2):297-304.

137. Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2007;69(1):91-102.

138. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease: dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med. 1988;319(22):1441-1446.

139. Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther. 2014;12(9):1103-1135.

140. Volpe R. Autoimmune Diseases of the Endocrine System. Boca Raton, FL: CRC Press; 1990.

141. Centers for Disease Control and Prevention. HIV Surveillance Report. Volume 29. Available at https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2017-vol-29.pdf. Last accessed October 22, 2019.

142. Centers for Disease Control and Prevention. Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings. Available at https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm. Last accessed October 22, 2019.

143. Centers for Disease Control and Prevention. Recommendations for HIV Prevention with Adults and Adolescents with HIV in the United States, 2014: Summary for Clinical Providers. Available at https://stacks.cdc.gov/view/cdc/44065. Last accessed October 22, 2019.

144. Simon V, Ho DD, Karim QA. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet. 2006;368(9534):489-504.

145. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med. 1998;339(1):33-39.

146. 146.U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Available at https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/37/whats-new-in-the-guidelines-. Last accessed October 22, 2019.

147. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373(9):795-807.

148. TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373(9):808-822.

149. Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR. 2009;58(RR):1-207.

150. Gulanick M, Myers JL. Nursing Care Plans: Diagnoses, Interventions, and Outcomes. 9th ed. St. Louis, MO: Elsevier; 2017.

151. Ladwig GB, Ackley BJ, Flynn Makic MB. Mosby's Guide to Nursing Diagnosis. 5th ed. St. Louis, MO: Elsevier; 2017.

152. LeMone PT, Burke KM. Medical-Surgical Nursing: Critical Thinking in Client Care. 4th ed. Upper Saddle River, NJ: Prentice Hall; 2007.

153. National Institute of Allergy and Infectious Diseases. Disorders of the Immune System. Available at https://www.niaid.nih.gov/research/immune-system-disorders. Last accessed October 21, 2019.

154. American Academy of Allergy, Asthma, and Immunology. Primary Immunodeficiency Disease. Available at https://www.aaaai.org/conditions-and-treatments/primary-immunodeficiency-disease. Last accessed October 21, 2019.

155. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. Chest. 1992;101:1644-1655.

156. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med. 2003;29:530-538.

157. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for managing sepsis and septic shock 2016. Intensive Care Med. 2017;43(3):304-377.

158. Society of Critical Care Medicine. SSC Hour-1 Bundle. Available at http://www.survivingsepsis.org/Bundles. Last accessed October 21, 2019.

Evidence-Based Practice Recommendations Citations

1. Nicholson PJ, Cullinan P, Burge PS, Boyle C. Occupational Asthma: Prevention, Identification and Management: Systematic Review and Recommendations. London: British Occupational Health Research Foundation; 2010. Available at https://www.bohrf.org.uk/downloads/OccupationalAsthmaEvidenceReview-Mar2010.pdf. Last accessed October 25, 2019.

2. Jacobson JA, Roberts CC, Bencardino JT, et al. ACR Appropriateness Criteria: Chronic Extremity Joint Pain, Suspected Inflammatory Arthritis. Reston, VA: American College of Radiology; 2016. Available at https://acsearch.acr.org/docs/3097211/Narrative. Last accessed October 25, 2019.

3. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797-808. Available at https://www.rheumatology.org/Portals/0/Files/ACR%20Guidelines%20for%20Screening,%20Treatment,%20and%20Management%20of%20Lupus%20Nephritis.pdf. Last accessed October 25, 2019.

4. Singh JA, Guyatt G, Ogdie A, et al. 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis. Arthritis Rheumatol. 2019;71(1):5-32. Available at https://www.rheumatology.org/Portals/0/Files/PsA-Guideline-2018.pdf. Last accessed October 25, 2019.

5. Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther. 2014;12(9):1103-1135. Available at https://www.tandfonline.com/doi/full/10.1586/14787210.2014.940900. Last accessed October 25, 2019.

6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Bethesda, MD: Department of Health and Human Services; 2016. Available at https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Last accessed October 25, 2019.

7. National Guideline Centre. Sepsis: Recognition, Diagnosis and Early Management. London: National Institute for Health and Care Excellence; 2016. Available at https://www.nice.org.uk/guidance/ng51. Last accessed October 25, 2019.