94150 • The Coronavirus Disease (COVID-19) Pandemic

Table of Contents

94150 • The Coronavirus Disease (COVID-19) Pandemic

How to Receive Credit

NetCE 2 Hour Course #94150 • The Coronavirus Disease (COVID-19) Pandemic

94150 • The Coronavirus Disease (COVID-19) Pandemic

1. BACKGROUND

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

3. CLINICAL MANIFESTATIONS OF COVID-19

4. COVID-19 IN CHILDREN

5. DIAGNOSTIC TESTING FOR SARS-COV-2

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

9. OTHER AVAILABLE RESOURCES

Works Cited

94150 • The Coronavirus Disease (COVID-19) Pandemic

John M. Leonard, MD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

94150 • The Coronavirus Disease (COVID-19) Pandemic

Expiration Date: 02/28/2022

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.

94150 • The Coronavirus Disease (COVID-19) Pandemic

John M. Leonard, MD

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the current outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale. In response to a 13-fold increase in the number of reported cases within the span of two weeks and active cases in more than 100 countries, the WHO reached a decision that the COVID-19 outbreak should be characterized as a pandemic.

Table of Contents

94150 • The Coronavirus Disease (COVID-19) Pandemic

Course Overview

Attention

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

Implicit Bias in Health Care

1. BACKGROUND

CORONAVIRUS

HUMAN CORONAVIRUS INFECTION

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

3. CLINICAL MANIFESTATIONS OF COVID-19

SEVERITY AND PROGRESSION OF ILLNESS

SYSTEMIC COMPLICATIONS OF COVID-19

RECOVERY FROM COVID-19

LATE SEQUELAE OF COVID-19

4. COVID-19 IN CHILDREN

PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME

5. DIAGNOSTIC TESTING FOR SARS-COV-2

ANTIBODY TESTING

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

INVESTIGATIONAL THERAPEUTICS

COVID-19 VACCINES

DURATION OF IMMUNITY AND REINFECTION

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

WHO DAILY SITUATION REPORT

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

VARIANT STRAINS OF SARS-COV-2

CDC MONITORING AND GUIDANCE FOR HEALTHCARE PROFESSIONALS

9. OTHER AVAILABLE RESOURCES

Works Cited

94150 • The Coronavirus Disease (COVID-19) Pandemic

Education Category. Infection Control / Internal Medicine

Release Date. 02/01/2020

Review Date. 01/15/2023

Expiration Date. 02/28/2023

Course Overview

Widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the current outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale. In response to a 13-fold increase in the number of reported cases within the span of two weeks and active cases in more than 100 countries, the WHO reached a decision that the COVID-19 outbreak should be characterized as a pandemic.

Attention

This outbreak is ongoing. As the situation evolves, the course is being revised to reflect new information. The last update was done May 27, 2022.

Audience

This course is designed for physicians, nurses, and other healthcare professionals who may identify or educate patients regarding coronavirus infection.

Course Objective

The purpose of this course is to provide physicians, nurses, and other healthcare professionals an overview of the 2019–2020 global outbreak of novel human coronavirus (SARS-CoV-2) infection, including background epidemiology, clinical features, mode of transmission, epidemic potential, and the clinical and public health measures recommended to limit the spread of infection and control the outbreak.

Learning Objectives

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

1. Differentiate between the common, ubiquitous strains of human coronavirus and novel (outbreak) strains with respect to epidemiology, modes of transmission, spectrum of illness, and public health implications.

2. Characterize the clinical and public health experience gained from the two prior novel human coronavirus epidemics, SARS and MERS, and how that informs our understanding and response to the current pandemic.

3. Recognize clinical manifestations of COVID-19 and anticipate systemic complications associated with a dysregulated immune response, and discuss the dynamics of transmission and advise patients regarding prevention of infection and the role of COVID-19 vaccines, with special attention to those at risk for severe disease.

4. Implement guideline recommendations for diagnostic testing and management of patients with recent exposure to, suspected infection with, or newly diagnosed COVID-19.

Faculty

John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

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

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

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.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. BACKGROUND

CORONAVIRUS

Coronaviruses (a subfamily of Coronaviridae) are enveloped, single-stranded RNA viruses that are broadly distributed among humans, other mammals, and birds. Under electron microscopy, the outer envelope of the virion shows club-like surface projections that confer a crown-like appearance to the virus, which accounts for the name given to this family of viruses. The nucleocapsid is a long, folded strand that tends to spontaneous mutations and recombination of genomic material. When virus circulation (and replication) is high, the number of random changes within the genome grows, increasing the likelihood that such changes may impact transmissibility and pathogenicity.

In addition to four specific subtypes of coronavirus commonly found in humans, other strains are specific to many different species of animals, including bats, cats, camels, and cattle. On rare occasions, an animal coronavirus is responsible for zoonotic infection in humans, meaning that a new (novel) coronavirus is transmitted from an animal host to one or more humans, producing clinical illness that may result in secondary spread among persons in close contact. The wide distribution, genetic diversity, and frequent shifts in the genome, combined with unique human-animal interface activities, are considered important factors in the periodic emergence of new coronavirus outbreaks in human populations [1,2].

HUMAN CORONAVIRUS INFECTION

Common Strains

Human coronavirus (HCoV) was first identified in 1965, isolated from a patient with what was described as the common cold [3]. Subsequently, four types of HCoV have been detected commonly in respiratory secretions of children and adults in scattered regions of the globe, labeled HCoV-229E, -NL63, -OC43, and -HKU1. These agents are a cause of common mild-to-moderate upper respiratory illness, including the common cold, bronchitis, bronchiolitis in infants and children, and asthma exacerbation. Rarely, HCoVs have been implicated in cases of lower respiratory tract infection (viral pneumonia), a complication more common to persons with underlying cardiopulmonary disease or weakened immune systems.

Novel Coronavirus Outbreaks

In addition to the seasonal infections caused by the ambient, adaptive HCoVs described, widespread outbreaks of novel coronavirus infection have occurred in each of the past two decades, and the 2019–2020 Wuhan, China, outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale [1,4]. The epidemiologic feature common to these outbreaks is an initial point source cluster of zoonotic infection followed by secondary spread of the virus via human-to-human transmission. Among the factors thought to be conducive to the emergence of such outbreaks are the following: genomic recombination in an animal CoV capsid that renders the virus better adapted to human infection (and perhaps more virulent); and dietary practices and cultural determinants that bring humans into close contact with livestock or raw meat and carcasses of wild animals and birds, thereby facilitating transmission from an infected animal host to humans. After infection is established, secondary viral transmission occurs through close person-to-person contact by way of droplet nuclei propelled into the air during coughing and sneezing. The first two known novel coronavirus outbreaks, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, are considered to be zoonotic in origin and were associated with serious, sometimes fatal illness.

Severe Acute Respiratory Syndrome (SARS-CoV)

Infection with SARS-CoV was first recognized in China in November 2002, and signs of an outbreak in Asia were evident by February 2003 [3]. Epidemiologic investigation found that early cases of SARS-CoV were zoonotic infection involving transmission from civet cats to humans. Over the next several months, SARS-CoV spread to countries in North America, South America, Europe, and other parts of Asia before the global outbreak was contained later in the same year.

SARS-CoV infection began with fever, headache, malaise, and arthralgia/myalgia followed in two to seven days by cough, shortness of breath, and signs of pneumonia [3].

According to the World Health Organization (WHO), the 2002–2003 outbreak caused 8,098 probable cases of SARS worldwide and 774 deaths. Just eight cases were identified in the United States. Since 2004, there have been no additional known cases of SARS-CoV infection reported anywhere in the world [3].

In response to the 2003 global SARS outbreak, the Centers for Disease Control and Prevention (CDC), working in concert with the WHO, developed a strategy for controlling the epidemic that included the following elements [3]:

- Activated the Emergency Operations Center to provide around-the-clock coordination and response.

- Committed more than 800 medical experts and support staff to work on the SARS response and to assist with ongoing investigations around the world.

- Provided assistance to state and local health departments in investigating possible cases of SARS in the United States.

- Conducted extensive laboratory testing of clinical specimens from patients with SARS to identify the cause of the disease.

- Initiated a system for distributing health alert notices to travelers who may have been exposed to cases of SARS.

This experience informed the rapid public health response to the 2019–2020 coronavirus outbreak in China.

Middle East Respiratory Syndrome (MERS-CoV)

MERS-CoV was first reported in Saudi Arabia in 2012, and all cases to date have been linked to countries in or near the Arabian Peninsula. Travel-associated cases of MERS-CoV infection have been reported in many countries, including two imported cases diagnosed in the United States in 2014 involving unlinked healthcare providers recently returned from Saudi Arabia. Two modes of transmission have been identified: zoonotic infection from an animal reservoir to humans (with camels acting as the intermediate host), and person-to-person transmission via close contact with an index case, as described in association with a family case cluster and a nosocomial outbreak [5,6,7].

Most persons with confirmed MERS-CoV infection have had moderately severe respiratory illness manifest by fever, cough, and shortness of breath, often complicated by pneumonia and respiratory failure. The case-fatality rate approaches 40%. Most deaths have been in patients with pre-existing chronic conditions such as diabetes, cancer, or heart, lung, or renal disease. Sporadic cases of MERS-CoV continue to appear in various parts of the Middle East [3].

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

In December 2019, Chinese physicians in Hubei Province, China, began an investigation of a cluster of cases of severe viral pneumonia in area hospitals. In the weeks following, it became evident that a large outbreak of respiratory illness was rapidly emerging within Wuhan City and nearby communities, reaching the thousands by mid-January.

On January 24, Chinese scientists reported the results of viral diagnostic studies conducted on bronchoalveolar lavage specimens obtained from three Wuhan City patients hospitalized in December with severe bilateral interstitial, alveolar pneumonia [2]. The investigation identified a viral genome matched to lineage B of the genus betacoronavirus, showing more than 85% match with a SARS-like CoV genome previously described in bats. Ultrathin sections of infected human airway epithelial cells showed inclusion bodies filled with virus particles in membrane-bound vesicles in the cytoplasm. The morphology of the virion on electron microscopy is consistent with the Coronaviridae family.

This newly identified coronavirus, the etiologic agent responsible for the Wuhan outbreak, was named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease caused by the infection is referred to as COVID-19. Like SARS-CoV and MERS-CoV, SARS-CoV-2 is a betacoronavirus that likely had its origin in bats, with one or more animals serving as the intermediate host. The actual source and timing of initial human infection is unclear. According to CDC reports, virus sequences from initial imported cases in the United States were similar to the one posted by China, indicating emergence of this virus from a point-source in Wuhan, China [12].

The rapid accumulation of many new COVID-19 cases in Wuhan City during December 2019 and January/February 2020, combined with evidence of spread to nearby provinces in central China and reports of acute infection in healthcare workers, indicated that facile human-to-human transmission of SARS-CoV-2 was the key factor responsible for propagation of the outbreak. This has been proven true throughout the pandemic. During the first six months of 2020, outbreaks of COVID-19 spread to countries in every part of the world. As of May 2022, the global COVID-19 disease burden totaled 487 million confirmed cases and more than 6 million deaths, of which 80 million cases and more than 1 million deaths have been reported in the United States [132].

Despite the availability of effective COVID-19 vaccines beginning in December 2020, the scope of the pandemic remained undiminished in Europe and the United States throughout the summer and fall of 2021, primarily because of two complimentary developments: the slow rollout and limited acceptance of COVID-19 vaccines in certain regions and population groups, and the emergence of a SARS-CoV-2 variant strains that are three to four times more infectious and spread faster than the original virus strain. By July 2021, the SARS-CoV-2 Delta variant accounted for 99% of all COVID-19 cases reported in the United States; in December 2021, Delta was rapidly supplanted by the less severe but highly infectious Omicron variant [132].

A viral variant has one or more mutations within the genome that differentiate it from other strains of the virus. Closely genetically related variants derived from a common ancestor are designated a lineage. In response to concerns that emerging SARS-CoV-2 variants may have the potential to circumvent COVID-19 countermeasures, a SARS-CoV-2 Interagency Group (SIG) was established to characterize variants and monitor their impact on transmission, disease severity, risk of reinfection, and potential to evade vaccine-induced immunity [123]. The CDC’s national genomic surveillance program identifies SARS-CoV-2 variants by genetic sequencing and tracks the proportion and distribution of COVID-19 cases caused by variants. As of April 2022, the SARS-CoV-2 Omicron lineage (subvariants BA.1, BA.2, BA.3) accounts for an estimated 100% of new cases of COVID-19 in the United States [123,124].

3. CLINICAL MANIFESTATIONS OF COVID-19

The incubation period of SARS-CoV-2 infection is 5 to 7 days on average, with a range of 2 to 14 days. It is estimated that 97.5% of persons with COVID-19 who develop symptoms will do so within 11.5 days of infection [15,18]. The onset and progression of illness is variable, with most patients experiencing some combination of fever, cough, fatigue, anorexia, myalgias, and shortness of breath. Less common presenting symptoms include rhinorrhea, sudden loss of smell (anosmia) and/or taste (ageusia), and sore throat. Atypical presentations have been described whereby some patients experience diarrhea or nausea and vomiting prior to the onset of fever and respiratory symptoms and signs. As with other infections, elderly persons may present with weakness and confusion. Older adults and persons with medical comorbidities may have delayed onset of fever and respiratory symptoms [15].

In a study designed to better characterize the symptom profiles of patients with COVID-19 in the United States, especially among nonhospitalized patients, the CDC used an optional questionnaire to collect detailed information from a sample of confirmed COVID-19 cases reported from 16 participating states [60]. Among 164 symptomatic patients with onset of illness between January 14 and April 4, 2020, a total of 158 (96%) reported fever, cough, or shortness of breath. Of 57 hospitalized adult patients, 39 (68%) reported all three of these symptoms, compared with 25 (31%) of the 81 nonhospitalized adult patients. Each of the following symptoms was reported by more than half of patients: cough (84%), fever (80%), myalgia (63%), chills (63%), fatigue (62%), headache (59%), and shortness of breath (57%). Gastrointestinal symptoms were relatively common, most frequently diarrhea (38%) and least frequently vomiting (13%). Shortness of breath was more common in patients who required hospitalization (82%) than in nonhospitalized patients (38%). Anosmia and ageusia were reported by a higher percentage of nonhospitalized patients (22%) than hospitalized patients (7%) [60].

An array of cutaneous symptoms and signs has been described in patients with COVID-19. Although the exact frequency remains unknown, reports have ranged from 0.2%, early in the pandemic, to as high as 20.4% [15]. In addition to the exanthems common to many viral infections, pernio-like lesions have been described [105]. Pernio (chilblains) is a superficial inflammatory vascular response that occurs on acral skin, usually after cold exposure. In patients with COVID-19, these lesions appear as discolored edematous plaques on the toes and fingers. An international registry was organized early in the pandemic to characterize the diversity of dermatologic manifestations. In a study of 171 registry patients with confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%) [106]. Morbilliform rashes were often pruritic and involved the trunk. Pernio morphologies were often painful/burning and involved the hands/feet. Pernio-like lesions were generally observed in patients with mild disease, whereas retiform purpura was seen exclusively in critically ill patients. Cutaneous manifestations usually appeared at the onset of or after other COVID-19 symptoms. However, in 12% of cases skin lesions occurred before other COVID-19 symptoms or signs [106]. Images of cutaneous findings are available from the American Academy of Dermatology at https://www.aad.org/public/diseases/coronavirus/covid-toes.

Although most symptomatic patients with COVID-19 experience a mild-to-moderate illness with slow convalescence, there is substantial risk of progression to bilateral pneumonia complicated by respiratory failure and death. In February 2020, the overall case fatality rate for confirmed cases of COVID-19 reported from China was approximately 3%. As the pandemic has progressed, reported case fatality rates have varied considerably among countries and regions, ranging from 3% to as high as 14%. Multiple factors account for this variance, including available health resources and access to care, differences in public health mitigation strategies, lack of uniformity in the way deaths are attributed to COVID, and the extent to which testing and contact tracing identifies asymptomatic infections. Based on reported cases and attributable deaths through mid-July 2020, the COVID-19 case fatality rate during the first six months of the pandemic was 3.6% in the United States [8]. It is more useful to consider age-adjusted case fatality rates, which range from less than 1% in persons younger than 20 years of age to more than 15% for those older than 75 years of age.

SEVERITY AND PROGRESSION OF ILLNESS

The first report describing the clinical features of hospitalized patients with COVID-19-related pneumonia in Wuhan City was published online January 24, 2020 [9]. As of January 2, 41 admitted patients had been identified as having laboratory-confirmed 2019-nCoV infection; 30 (73%) were men and 27 (66%) had been exposed to the open-air Huanan Seafood Market. The median age was 49 years, and fewer than half of the patients had a history of underlying chronic disease. Common symptoms at onset of illness were fever (98%), cough (76%), and myalgia or fatigue (44%). Dyspnea developed in 22 patients (55%), with a median time from illness onset to dyspnea of eight days. Common laboratory abnormalities included leukopenia, lymphopenia, and mild hepatic enzyme elevations. All 41 patients were reported to have pneumonia, and all save one had radiographic evidence of bilateral involvement. The typical findings on chest computed tomography (CT) images of intensive care unit (ICU) patients were bilateral multilobar and segmental areas of consolidation. Acute respiratory distress syndrome developed in 12 (32%) patients, 13 (32%) were admitted to an ICU, and 6 died (15%).

A larger retrospective study examined the clinical characteristics of COVID-19 in a cohort of 1,099 hospitalized patients in China during the first two months of the outbreak [17]. The most common symptoms were fever (43.8% on admission, 88.7% during hospitalization), cough (67.8%), and fatigue (38.1%) [17]. The most common patterns on chest CT were ground-glass opacification (36.4%) and bilateral patchy shadowing (51.8%). Some degree of radiographic or CT abnormality was evident in 82% of patients with nonsevere disease and 97% of patients with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Sixty-seven patients (6.1%) were admitted or transferred to the ICU, 2.3% required mechanical ventilation, and 1.4% died [17].

In a summary of 72,314 cases reported to the Chinese Center for Disease Control and Prevention, the severity of illness ranged from mild to critical with approximately the following distribution [15,23]:

- Mild to moderate (mild symptoms up to mild pneumonia): 81%

- Severe (dyspnea, hypoxia or >50% lung involvement on imaging): 14%

- Critical (respiratory failure, shock, or multiorgan dysfunction): 5%

The majority of cases (81%) were characterized as mild, with no or mild pneumonia [23]. The overall case-fatality rate was 2.3%, with higher rates among patient subgroups. Specifically, the case-fatality rate was 49% among critical patients, and all reported deaths occurred in critical patients [23].

Risk Factors

Risk factors for severe disease include advanced age, obesity (body mass index ≥30), and comorbidities such as hypertension, diabetes, cardiovascular disease, cancer, and chronic lung disease. Among more than 70,000 cases reported in China through February 11, 2020, 87% occurred in persons 30 to 79 years of age [23]. The proportion of case fatalities among patients 70 to 79 years of age was 8%, and among those 80 years of age or older, the rate was 14.8%. Case fatality for patients with comorbidities was elevated as well, specifically for those with cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6%), and cancer (5.6%). Only 2% of cases were in persons younger than 20 years of age, and no deaths were reported in those younger than 10 years of age.

Atypical presentations have been described, and older adults and persons with medical comorbidities may have delayed presentation of fever and respiratory symptoms [15]. Headache, confusion, rhinorrhea, sore throat, hemoptysis, vomiting, and diarrhea have been reported but are less common (<10%). Some persons with COVID-19 have experienced gastrointestinal symptoms such as diarrhea and nausea prior to developing fever and lower respiratory tract signs and symptoms. Anosmia or ageusia preceeding the onset of respiratory symptoms has been anecdotally reported, but more information is needed to understand its role in identifying COVID-19. Several studies have documented SARS-CoV-2 infection in patients who never develop symptoms (asymptomatic) and in patients not yet symptomatic (presymptomatic) [15].

In June 2020, the CDC issued an epidemiologic report on 1,320,488 laboratory-confirmed COVID-19 cases in the United States and territories, reported to CDC between January 22 and May 30, 2020 [55]. Cumulative incidence (403.6 cases per 100,000 persons) was similar among males (401.1) and females (406.0), highest among persons 80 years of age or older (902.0), and lowest among children younger than 9 years of age (51.1). Among 599,636 cases with known information on both race and ethnicity, 36% of persons were non-Hispanic white, 33% were Hispanic, 22% were black, 4% were Asian, and 1.3% were American Indian or Alaska Native. Among 287,320 cases with sufficient data on underlying health conditions, the most frequently reported were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Overall, 184,673 (14%) patients were hospitalized, 29,837 (2%) were admitted to an ICU, and 71,116 (5%) died. The hospitalized rate was six times higher among patients with a reported underlying condition (45.4%) than among those without reported underlying conditions (7.6%). The mortality rate was 12 times higher among patients with reported underlying conditions (19.5%) compared with those with none reported (1.6%). Approximately 4% of reported cases were asymptomatic. Among 373,833 cases with data on individual symptoms, 70% noted fever, cough, or shortness of breath; 36% reported muscle aches; and 34% reported headache. Overall, 31,191 (8%) persons reported loss of taste or smell [55].

During the course of the COVID-19 pandemic in the United States, obesity has emerged as an important independent risk factor for severe disease, especially among adult patients younger than 60 years of age. Multiple reports, ranging from single-center studies to analyses of records from large patient care networks, have consistently found that severe obesity (body mass index >35) is associated with higher rates of hospitalization, respiratory failure, and mortality from COVID-19 [77,78]. The risk varies directly with degree of obesity and is independent of obesity-associated comorbidities. The impact is more striking among men than women. There are multiple mechanisms by which obesity may contribute to adverse outcomes in patients with COVID-19. In addition to obstructive pulmonary physiology and sleep apnea, severe obesity is associated with immune dysfunction (depression of anti-inflammatory signaling and increased pro-inflammatory signaling), alterations in vascular endothelium, and renin-angiotensin stimulation, which together may worsen lung inflammation and alveolar damage [78].

Although the absolute risk of severe COVID-19 is low among people of child-bearing age, the risk of severe illness and complications is substantial when infection is acquired during pregnancy. Evidence for this comes from an analysis of 409,462 women (15 to 44 years of age) with symptomatic COVID-19 reported to the CDC between January 22 and October 3, 2020 [107]. Of the total, 23,434 women (5.7%) were pregnant at the time of infection. Pregnant patients were admitted to an ICU more frequently than nonpregnant patients (10.5 versus 3.9 per 1,000 cases) and were more likely to receive invasive ventilation (2.9 versus 1.1 per 1,000 cases) or extracorporeal membrane oxygenation (ECMO) (0.7 versus 0.3 per 1,000 cases). The mortality rate was 1.5 per 1,000 cases for pregnant women compared with 1.2 per 1,000 cases for nonpregnant women. Older pregnant patients (35 to 44 years of age) with symptomatic COVID-19 were nearly four times more likely to require invasive ventilation and twice as likely to die than were nonpregnant patients of the same age [107].

Following the emergence of the Delta variant and 2021 summer surge of COVID-19, the risk for unvaccinated pregnant individuals infected with SARS-CoV-2 became even more serious. A retrospective cohort study comparing COVID-19 outcomes among unvaccinated pregnant patients infected in the pre-Delta period with those infected during the Delta surge found that proportions of severe-critical illness and ICU admissions were three-fold higher among patients in the Delta cohort than those in the pre-Delta cohort [149]. The need for intubation and mechanical ventilation was also greater among those with Delta variant infection. Maternal COVID-19 from SARS-CoV-2 Delta infection also had an adverse effect on perinatal outcomes; rates of cesarean delivery, stillbirth, preterm birth, and neonatal intensive care unit admission were all higher during the period of Delta predominance [149].

SYSTEMIC COMPLICATIONS OF COVID-19

At the cellular level, infection by a virus requires some affinity of the virion for the host cell combined with a mechanism that facilitates attachment and entry into the cell. Cell entry of SARS-CoV-2 depends on binding of the viral surface spike protein to angiotensin-converting enzyme (ACE2) receptors and activation of the spike protein by host cell transmembrane protease serine 2 [30]. ACE2 is highly expressed by epithelial cells in the nasopharynx and type II alveolar cells in the lung. ACE2 is also expressed in the heart, kidney, vascular endothelium, and intestinal epithelium, which may explain, in part, the propensity for multiorgan dysfunction and vascular complications increasingly recognized in patients with severe COVID-19. In an autopsy series of 27 patients reported from Germany, SARS-CoV-2 was detected in multiple organs, including the lungs, pharynx, kidney, heart, liver, and brain [31]. In a further analysis of renal involvement, SARS-CoV-2 viral load was detected in all kidney compartments examined, with preferential targeting of glomerular cells.

Based upon recent reports from clinical centers caring for a high volume of hospitalized patients, renal and cardiac complications are relatively common in severe COVID-19. In a retrospective study from China, 251 of 333 (75%) hospitalized patients with COVID-19 pneumonia exhibited some degree of renal involvement, as evidenced by proteinuria or hematuria, and 35 (10%) met criteria for acute kidney injury [32]. In another case series of 138 hospitalized COVID-19 patients, 7% overall and 22% of those admitted to the ICU developed elevated troponin levels or electrocardiogram abnormalities indicative of myocarditis or cardiac injury some time during hospitalization [33]. Myocardial injury affects more than one-quarter of COVID-19 cases classified as critical and presents in two patterns: acute myocardial injury and dysfunction on presentation, and myocardial injury developing as illness severity intensifies [34]. While headache and confusion are seen in some patients presenting with severe COVID-19, there is no indication that SARS-CoV-2 causes primary infection of the central nervous system (e.g., encephalitis). In an autopsy series of 18 consecutive patients who died 0 to 32 days after onset of COVID-19, histopathologic examination of brain specimens did not show encephalitis or other specific brain changes referable to the virus [56].

Coagulopathy

Hospitalized patients with advanced COVID-19 may have laboratory signs of a coagulopathy and increased risk for arterial and venous thromboembolic complications [15,39,40]. The pathogenesis is unknown but likely involves some combination of systemic inflammation, endothelial dysfunction, platelet activation, immobility, and stasis of blood flow [40]. The earliest abnormalities are elevated D-dimer levels and mild thrombocytopenia; with disease progression, fibrin degradation products are elevated and prothrombin time becomes prolonged. Laboratory measure of coagulation factors in a patient hospitalized with COVID-19 provides a way to track disease severity. The presence of an elevated D-dimer on admission carries a poor prognosis and has been associated with increased risk of requiring mechanical ventilation, ICU admission, and mortality [40,41]. The most frequently reported complications of COVID-19 coagulopathy are deep venous thrombosis (DVT) and pulmonary emboli (PE). In a prospective study of 150 critically ill patients from two centers in France, 25 patients developed PE and 3 developed DVT despite prophylactic anticoagulation [42]. In a report of 184 patients with severe COVID-19 from three centers in the Netherlands, the cumulative incidence of venous thromboembolism was 27%, including PE in 80% of the cases affected [43]. Other centers have reported lower rates. Among 393 patients from New York, venous thromboembolism was diagnosed in only 13 patients (3.3%), 10 of whom were on mechanical ventilation [44]. These differences point to the need for studies that control for clinical severity, underlying comorbidities, prophylactic regimen, and COVID-19-related therapies. At present, there are limited data available to inform clinical management around prophylaxis or treatment of venous thromboembolic complications in patients with COVID-19 [15]. One source of interim guidance recommends regularly monitoring hemostatic markers—namely D-dimer, prothrombin time, and platelet count—in all patients presenting with COVID-19 and prophylactic use of low-molecular-weight heparin in all hospitalized patients, unless there are contraindications [40]. The National Institutes of Health has developed guidelines for antithrombotic therapy in patients with COVID-19, available at https://www.covid19treatmentguidelines.nih.gov/therapies/antithrombotic-therapy.

RECOVERY FROM COVID-19

Convalescence following SARS-CoV-2 infection follows a variable course, and symptomatic recovery from severe COVID-19 may take weeks to months. A report from Italy describes a cohort of 143 patients with moderate-to-severe COVID-19, 87% of whom had persistent symptoms two months or more after discharge from hospital [68]. The mean duration of hospitalization was 13.5 days; 73% had evidence of interstitial pneumonia, 15% received noninvasive respiratory support, and 5% required mechanical ventilation. Follow-up clinical assessment was conducted a mean of 60 days after onset of the first COVID-19 symptom. At evaluation, 18 (13%) were symptom free; of the remaining participants, 32% had one or two symptoms and 55% had three or more symptoms. The most common persistent symptoms were fatigue (53%), dyspnea (43%), joint pain (27%), and chest pain (22%). None had fever or signs of acute illness. Of the total, 44% reported persistence of the decline in quality of life imposed by COVID-19.

"Long COVID" is the term applied to the syndrome of persistent symptoms four weeks or later after recovery from acute COVID-19. The majority of reported cases are adults in the 35-to-69-year age group, and women are 30% more likely to get long COVID than men [133]. The range of complaints includes residual cough, fatigue, loss of smell or taste, shortness of breath, headache, and "brain fog." The prevalence of post-COVID-19 cognitive impairment and association with disease severity was investigated in 740 adult patients with no prior history of dementia. Study participants were 38 to 59 years of age, prior COVID severity ranged mild to severe, and evaluations were performed an average of 7.6 months after diagnosis. Deficits were found in processing speed (18%), executive functioning (16%), phonetic fluency (15%) and category fluency (20%), memory encoding (24%), and memory recall (23%) [134]. Executive functioning, processing speed, and memory encoding and recall impairments were predominant among hospitalized patients.

A multistate survey conducted by the CDC found that persistent symptoms three weeks after diagnosis of SARS-CoV-2 infection was common among outpatients with milder illness [69]. Of 270 respondents who were symptomatic at diagnosis, 95 (35%) had not returned to their usual state of health 14 to 21 days from the test date, including 26% of those 18 to 34 years of age and 47% of those older than 50 years of age. Among respondents reporting cough, fatigue, or shortness of breath at the time of COVID-19 diagnosis, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview [69].

A cohort study of long-term symptoms among healthcare professionals found that after mild COVID-19, 26% of participants reported at least one moderate-to-severe symptom lasting two months and 15% reported at least one moderate-to-severe symptom lasting eight months [108]. The most common symptoms were anosmia, fatigue, ageusia, and dyspnea. These studies show that low-risk adults with mild COVID-19 commonly experience a slow convalescence with diverse long-term symptoms that may disrupt work and social activity.

LATE SEQUELAE OF COVID-19

In addition to lingering functional impairments represented by long COVID syndrome, there is growing evidence that beyond acute infection, SARS-CoV-2 may have late adverse effects on critical organ function that increase the subsequent burden of cardiovascular disease and diabetes. The lung/vascular/heart involvement of acute-phase moderate-to-severe COVID-19 reflects the trophism of SARS-CoV-2 and is augmented by a dysregulated (hyperimmune) inflammatory response to infection; this can lead to multiple complications. Microvascular dysfunction and endothelial injury may precipitate thromboembolic events. Myocarditis may impair cardiac function; acute coronary syndromes from vasculitis and plaque instability may cause myocardial ischemic injury and heart failure. Parenchymal lung injury and microvascular thrombosis may lead to interstitial fibrosis and hypoxemia, adding to the cardiac workload and subsequent risk of clinical or subclinical heart failure [159].

The cardiovascular sequelae of post-acute COVID-19 were analyzed using the databases of the U.S. Department of Veterans Affairs to build a cohort of 153,769 individuals with COVID-19, as well as cohorts of contemporary and historical controls. The study was designed to estimate risks and one-year burdens of a set of prespecified incident cardiovascular outcomes. The analysis showed that beyond the first 30 days after infection, individuals with COVID-19 were at increased risk of subsequent cardiovascular diseases spanning several categories, including dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, and thromboembolic disease [160]. The increased risk and added burden were evident among hospitalized and nonhospitalized patients. Overall, the impact increased in graded fashion according to the clinical care setting. In a separate report, using the same database and study protocol, investigators also found that the risks and 12-month burdens of incident diabetes and antihyperglycemic use were increased among people who survived COVID-19, compared to a contemporary control group who had not contracted SARS-CoV-2 [161]. The post-acute diabetes risks and disease burdens increased in graded fashion according to severity of the acute phase of COVID-19.

Chronic, persistent SARS-CoV-2 infection following COVID-19 has been reported in patients with hematologic malignancies and immunodeficiency disorders. The common features are protracted virus shedding, fluctuating symptoms, and failure of humeral immunity many months after acute infection. In addition to the burden of ongoing symptoms and added cost of care, these patients often have to endure prolonged self-isolation and inability to resume productive lives. COVID-19 vaccines may be beneficial in such cases; in a reported case study, mRNA COVID-19 vaccination elicited humoral and cellular immune responses to SARS-CoV-2, which had failed in response to ongoing infection itself, followed by viral clearance [162].

4. COVID-19 IN CHILDREN

The CDC provides information for pediatric healthcare providers and guidance for the evaluation and care of neonates at risk for COVID-19 [45]. Acute SARS-CoV-2 infection in childhood tends to be asymptomatic or relatively mild, consisting of transient fever, cough, and other signs common to an upper respiratory viral syndrome. Severe manifestations of COVID-19 have been reported in children of all ages, though the incidence is far less common than in adults and fatalities following acute childhood infection are rare. Among more than 2,000 pediatric cases in China, 4% were asymptomatic, 51% had mild symptoms, 39% were moderately ill with some evidence of pneumonia, and 5% were severely ill with dyspnea, hypoxia, and central cyanosis [45]. Only 0.6% developed respiratory failure, shock, or multi-organ dysfunction.

Children younger than 18 years of age account for 22% of the U.S. population and represent 19% of cumulative COVID-19 cases reported since the onset of the pandemic [136]. As of April 2022, more than 12.8 million children have tested positive for COVID-19, including 7.8 million child cases added since September 2021. Severe illness from SARS-CoV-2 infection is uncommon. Among states reporting, children account for 1.2% to 4.6% of COVID-19-related hospitalizations and less than 1.5% of all child COVID-19 cases result in hospitalization. The childhood COVID-19 case fatality rate is less than 0.03% [46,136]. As in adults, children with underlying medical conditions and special healthcare needs, including genetic, neurologic, and metabolic disorders or congenital heart disease are at increased risk for severe illness from COVID-19.

Coinciding with increased circulation of the highly infectious SARS-CoV-2 Omicron variant, COVID-19-associated hospitalization rates increased rapidly among children 0 to 4 years of age, a group not yet eligible for vaccination. During the period December 2021 to February 2022, weekly hospitalizations among children 0 to 4 years of age peaked at 14.5 per 100,000, a level fivefold higher than that during the previous six months (Delta predominance) [163]. During Omicron predominance, 63% of hospitalized infants and children had no underlying medical conditions. Monthly ICU admission rates were approximately 3.5 times higher during the Omicron predominance peak in January 2022 than during the Delta predominance peak in September 2021 [163].

Long COVID has also been described in children, though to a lesser degree than in adults. Adolescents and teenagers account for the majority (70%) of reported cases [133]. In a study of 151 children with documented SARS-CoV-2 infection, 8% had post-acute COVID-19 symptoms lasting three to eight weeks [135]. The most common symptoms were residual cough and/or fatigue. On follow-up survey at six months, all 151 children had fully recovered.

PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME

Reports from the United Kingdom, Italy, and New York describe a serious inflammatory disorder in children linked to COVID-19, with many features common to Kawasaki disease and toxic shock syndrome [46,47,48]. The term applied to this condition is multisystem inflammatory syndrome in children (MIS-C). Kawasaki disease is an acute vasculitis of unknown cause that affects infants and young children, first described in Japan and thought to involve an aberrant immune response to an unidentified pathogen in persons with a genetic predisposition [47]. Children with COVID-related MIS-C present with signs of a diffuse inflammatory disorder, including persistent fever, abdominal complaints, rash, leukocytosis, elevated C-reactive protein, and evidence of single or multiple organ dysfunction [49]. Hypotension on presentation is common, and myocarditis and other cardiovascular changes (e.g., mitral regurgitation, coronary artery dilatation) may be seen. The majority of patients have tested positive for recent SARS-CoV-2 infection by molecular diagnostic and/or antibody testing. The onset of MIS-C may come days or weeks after what appears to have been an asymptomatic or mild case of COVID-19.

During a 10-day period in mid-April 2020, pediatricians at an intensive care hospital in England noted an unprecedented cluster of eight children with hyperinflammatory shock and other clinical features similar to atypical Kawasaki disease [47]. All had been previously well, and five of the children were boys. Four of the children had known family exposure to SARS-CoV-2. Clinical presentations were similar, with unrelenting fever, variable rash, conjunctivitis, peripheral edema, and warm shock refractory to volume repletion and eventually requiring vasopressors. No clinical or virologic evidence of lower respiratory involvement was observed. All patients were treated with IV immunoglobulin (IVIG); seven recovered and one died following arrhythmia, shock, and cerebral infarction. During the course of the COVID-19 epidemic in northern Italy, physicians in Bergamo observed 10 children (median age: 7.5 years) in the span of two months with a severe form of Kawasaki-like disease, a 30-fold increase in incidence when compared to the previous five years [48]. All were positive for recent SARS-CoV-2 infection. As of June 3, 2020, the New York State Department of Health was investigating 195 reported cases of MIS-C and 3 deaths in children. Of these patients, 28% are younger than 5 years of age and 69% are between 5 and 19 years of age [46]. Of the 195 cases, 93% have tested positive for COVID-19. A targeted surveillance for MIS-C in pediatric health centers across the United States identified 186 cases in 26 states during a five-week period between March and May [61]. The median age was 8.3 years, 165 (62%) were male, and 131 (70%) tested positive for SARS-CoV-2 infection by rT-PCR or serologic antibody test.

The clinical features in the MIS-C cases investigated by the New York Department of Health have been reported [62]. Of 191 patients in the study, all presented with fever and tachycardia, 80% were admitted to the ICU, and 62% required vasopressor support. Abdominal complaints and gastrointestinal symptoms were common (62%), as was rash (60%), conjunctival injection (56%), and mucosal changes (27%). Laboratory markers of inflammation included elevated levels of C-reactive protein in all patients, positive D-dimer (91%), and elevated troponin (71%). Evidence of myocarditis was present in 53% of patients. At least one echocardiogram was obtained for 93 patients (94%); 51 (52%) had some degree of ventricular dysfunction, 32 (32%) had pericardial effusion, and 9 (9%) had a documented coronary artery aneurysm. The majority of patients were treated with IVIG and/or glucocorticoids in addition to vasopressors. The median duration of hospitalization was six days. Two patients died. As in Italy, MIS-C cases in New York followed the peak of the COVID-19 epidemic in that state and nearly all patients tested seropositive for recent SARS-CoV-2 infection [62].

Early recognition of MIS-C and prompt referral to an inpatient unit of care is essential. Approximately 50% to 60% of children and adolescents with MIS-C present with signs of cardiovascular involvement leading to warm shock and a need for vasopressor support, compared with about 5% of children with Kawasaki's disease [61,62]. Cardiac abnormalities are common, including a 9% incidence of coronary artery aneurysm. Echocardiography is recommended in all patients presenting with MIS-C, and until more is known about long-term cardiac sequelae of MIS-C, providers should consider follow-up imaging at one to two weeks and four to six weeks after treatment [61]. Clinical evaluation should include inquiry as to recent COVID-19 illness or known exposure to persons with COVID-19. There are currently no published guidelines or CDC recommendations regarding treatment for MIS-C and no studies comparing efficacy of various treatment options. Based on published reports, principles of care include close observation, correction of hemodynamic instability, diagnostic evaluation to exclude serious bacterial infection (e.g., streptococcal or staphylococcal sepsis, toxic shock syndrome), and consideration of treatment with IVIG. The CDC recommends that patients younger than 21 years of age meeting MIS-C criteria be reported to local, state, and territorial health departments. The CDC case definition for MIS-C is [49]:

- An individual younger than 21 years of age presenting with fever (>38.0°C for at least 24 hours), laboratory evidence of inflammation (including, but not limited to, one or more of the following: an elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, or interleukin-6, elevated neutrophils, reduced lymphocytes, and low albumin), and evidence of clinically severe illness requiring hospitalization, with multisystem (at least two) organ involvement; AND

- No alternative plausible diagnoses; AND

- Positive for current or recent SARS-CoV-2 infection or exposure to a suspected or confirmed COVID-19 case within the four weeks prior to the onset of symptoms

All individuals should be reported if they meet the case definition for MIS-C, regardless of whether they fulfill criteria for Kawasaki disease. In addition, MIS-C should be considered in any pediatric death with evidence of SARS-CoV-2 infection.

The CDC tracks case reports of MIS-C associated with COVID-19. As of March 2022, the number of patients meeting the case definition of MIS-C in the United States totaled 7,885, with 66 deaths [137]. The median age of reported cases was 9 years, and half of children with MIS-C are 5 to 13 years of age. Of the total MIS-C cases reported, 58% are Hispanic/Latino or non-Hispanic Black, 60% are male, and 98% had a positive test for recent SARS-CoV-2 infection [137].

Vaccination with mRNA vaccine is highly effective in preventing COVID-19-associated MIS-C in children 12 to 18 years of age. A case-control study across 24 pediatric hospitals in 20 states comparing 124 patients with MIS-C with 181 hospitalized controls found that the estimated effectiveness against MIS-C following two doses of Pfizer-BioNTech vaccine was 91% [164]. Ninety-five percent of patients hospitalized with MIS-C were unvaccinated, and all 38 MIS-C patients requiring life support were unvaccinated.

5. DIAGNOSTIC TESTING FOR SARS-COV-2

There are two types of diagnostic tests for determining active SARS-CoV-2 infection: molecular tests that use the real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect viral RNA, and antigen tests that detect specific proteins on the surface of the virion. The most widely used and reliable of these is RT-PCR, which can be applied to mucus specimens from the upper or lower respiratory tracts and to serum samples. SARS-CoV-2 viral RNA can be detected more readily in secretions taken by swab from the nasopharynx than in samples obtained by throat swab [15]. RT-PCR testing of deep nasopharyngeal swab specimens has become the standard procedure for the laboratory diagnosis of active SARS-CoV-2 infection [79,80]. This test is highly accurate and results can be obtained within one or two days. Antigen tests for the diagnosis of active SARS-CoV-2 infection are also performed on nasal or throat swab specimens and have the advantage of providing results much faster than the RT-PCR test (often less than one hour) [80]. However, antigen tests are less sensitive than molecular tests, which detect viral nucleic acids, and the amount of antigen in a sample decreases as the duration of illness increases. Specimens collected more than seven days after onset of illness are considered more likely to be negative compared to a RT-PCR assay [80]. Thus, a positive antigen test result is highly reliable, but a negative test may need to be confirmed with RT-PCR. Updated CDC guidance for healthcare providers who order antigen tests, receive antigen test results, or perform point-of-care testing in the community is available online at https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html.

The availability of safe, reliable, and timely SARS-CoV-2 diagnostic testing is essential for effective public health measures to control the COVID-19 pandemic. The nasopharyngeal swab specimen collection method involves close interaction between healthcare workers and patients, requires personal protective equipment, and entails a measure of discomfort for the test subject—all disadvantages to community drive-through diagnostic testing and contact tracing. Self-collected saliva could prove to be a simple, less expensive alternative that alleviates the need for personal protective equipment. There is growing evidence that the molecular test detection rate in saliva specimens from symptomatic and asymptomatic SARS-CoV-2 infected individuals is comparable to deep nasopharyngeal swab specimens. Yale investigators found that among 70 inpatients with confirmed COVID-19 and 495 asymptomatic healthcare workers, the use of self-collected saliva specimens for SARS-CoV-2 molecular diagnostic testing compared favorably with nasopharyngeal swab specimens collected by personnel [81]. In another study of 354 patients presenting to a drive-through testing center with at least one symptom consistent with COVID-19, the SARS-CoV-2 positivity rate was 22.6% for nasopharyngeal swab specimens compared with 22.9% for salivary specimens [82]. Between nasopharyngeal swab specimens and salivary specimens, the positive percent agreement was 93.8% and the negative percent agreement 97.8%.

COVID-19 diagnostic testing in the United States is available at all state and local public health laboratories and at commercial laboratories authorized by the U. S. Food and Drug Administration (FDA) [16,80]. Although in some cases viral nucleic acid can be detected in nasopharyngeal specimens for weeks after infection, studies show that SARS-CoV-2 viral cultures are usually negative within 8 to 10 days after onset of infection. Shedding of live virus may persist longer in severely ill, hospitalized patients (median range of viral shedding: 12 to 20 days) [15]. Information on specimen collection, handling, and storage is available online at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html.

ANTIBODY TESTING

SARS-CoV-2 antibody assays are useful for epidemiologic investigation of prevalence in the general population and to identify groups at risk for infection. Unlike RT-PCR and antigen detection tests that identify acute infection, antibody tests determine whether there is evidence of prior infection, even if the person being tested never developed symptoms. The FDA has not authorized the use of serology to detect active SARS-CoV-2 infection, and the CDC does not recommend antibody testing for routine diagnosis of acute infection [79]. However, antibody testing in conjunction with viral RT-PCR may be used to support clinical assessment of persons who present late in the course of COVID-19, or a patient suspected of having a post-infectious syndrome caused by recent SARS-CoV-2 infection (e.g., MIS-C).

Following SARS-CoV-2 infection, IgM and IgG antibodies appear almost simultaneously in the serum within two to three weeks after symptom onset, at which time infectiousness likely is greatly decreased and some degree of immunity from future infection has developed [83]. Thus, early IgM assay without IgG testing is of little value. The duration of detectable antibody is unknown, and the absence of detectable IgM or IgG antibodies does not necessarily rule out previous infection. Several commercially marketed serologic assays for SARS-CoV-2 have emergency use authorization (EUA) by the FDA, which has independently reviewed their performance. A list of all tests authorized for emergency use under EUA is maintained on the FDA website [84]. All currently authorized tests are qualitative (providing a result that is positive, negative, or indeterminate) rather than quantitative (providing a quantitative assessment of antibody levels). It is important to minimize false-positive test results by choosing an assay with high specificity and by testing individuals with an elevated likelihood of previous exposure to SARS-CoV-2 [83].

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

There is no simple, safe, and highly effective antiviral therapy for the routine treatment of COVID-19. Care is supportive and should be provided in a controlled environment under Isolation Precautions. Effective vaccines for prevention of SARS-CoV-2 began distribution at the end of 2020.

After China published the viral genome on a public database in mid-January 2020, the National Institutes of Health immediately began research efforts to improve diagnostics, identify effective treatments, and develop vaccines against SARS-CoV-2 [10]. As noted, the CDC and commercial laboratories developed a reliable diagnostic test based on genetic sequencing of the virus. Two antiviral agents—remdesivir, a drug tried unsuccessfully in the Ebola outbreak, and lopinavir/ritonavir (Kaletra), a combination antiviral used for treatment of human immunodeficiency virus (HIV)—were provided on a compassionate use basis in China. However, one study of hospitalized patients with COVID-19 in China found no difference in time to clinical improvement or outcome with lopinavir/ritonavir treatment [20].

Following successful development and clinical trials of vaccines against SARS-CoV-2 in the summer and fall of 2020, an accelerated effort was launched in the United States and other countries to implement an immunization strategy against COVID-19.

INVESTIGATIONAL THERAPEUTICS

Antiviral Therapy

Remdesivir is the only drug approved by the FDA for the treatment of COVID-19. Ritonavir-boosted nirmatrelvir (Paxlovid), molnupiravir, and certain SARS-CoV-2 monoclonal antibodies have received EUA from the FDA for treatment of COVID-19. The NIH Treatment Guidelines Panel provides updated information on these and other drugs of interest for the management of COVID-19, including recommendations for patient selection and use of specific anti-viral regimens [57].

Remdesivir

Remdesivir, an investigational antiviral drug that inhibits viral RNA polymerases, has been shown to have in-vitro activity against SARS-CoV-2 [15]. An early report described the clinical outcomes for a cohort of patients with COVID-19 who were treated with a 10-day course of intravenous remdesivir as part of a compassionate use program [26]. The study enrolled patients from the United States, Canada, Europe, and Japan who were hospitalized with confirmed SARS-CoV-2 infection and signs of lower respiratory tract disease severe enough to require some degree of oxygen supplementation and/or ventilatory support. Of 53 patients with sufficient data for analysis, 32 (68%) showed significant improvement in oxygen support status with use of remdesivir; the overall mortality was 13% over a median follow-up of 18 days, including 18% among those who were receiving invasive ventilation and 5% among those who were receiving noninvasive oxygen support. The authors observed that while there was no randomized control group and the patients in this study are not directly comparable, the observed mortality was considerably less than that reported contemporaneously in other COVID-19 case series and reports [26].

On October 22, 2020, the FDA approved remdesivir for use in adult and pediatric patients 12 years of age and older (weighing at least 40 kg) for the treatment of COVID-19 when hospitalization is required [90]. In April 2022, this approval was expanded to include children 28 days of age and older weighing at least 3 kilograms [177]. The approval was supported by an analysis of three randomized, controlled clinical trials that showed remdesivir shortens the time to recovery and decreases progression of respiratory illness in adult patients hospitalized with COVID-19 [90]. The data analysis included final results from an NIH-sponsored study, a double-blind, placebo-controlled remdesivir trial involving hospitalized patients with moderate-to-severe COVID-19 [35]. In this study, a total of 1,062 patients were randomized to receive intravenous remdesivir or placebo for 10 days. The primary outcome was time to recovery, defined by discharge from hospital or resolution of need for clinical care (hospitalization for infection-control purposes only). The median time to recovery was 10 days for the remdesivir group, compared with 15 days for the placebo group. In an analysis of secondary outcomes, patients who received remdesivir were more likely than those who received placebo to have clinical improvement at day 15. The proportion of serious adverse events related to respiratory failure and the need for higher levels of respiratory support were lower among patients in the remdesivir group. Kaplan-Meier estimates of mortality showed a trend in favor of the treatment group: 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% versus 15.2% by day 29 [35].

The NIH Treatment Guidelines Panel (NIH Panel) recommends remdesivir for treatment of COVID-19 in hospitalized patients with SpO2 <94% on ambient air or those who require supplemental oxygen, and in patients who need any form of mechanical ventilatory support [57]. The recommended duration of treatment and the advisability of combining remdesivir with a glucocorticoid vary in relation to severity of illness and level of ventilatory support. For patients who require supplemental oxygen but have no need for delivery of oxygen through a high-flow device, the recommended regimen is remdesivir 200 mg IV for one day, followed by 100 mg daily for four days or until hospital discharge, whichever comes first. The duration of remdesivir therapy may be extended up to 10 days when there is no substantial clinical improvement by day 5.

A three-day course of remdesivir has received FDA approval for use in nonhospitalized COVID-19 patients in settings where intravenous therapy and close patient monitoring are feasible. In a randomized, placebo-controlled clinical trial among nonhospitalized adults (mean age: 50 years) with symptomatic COVID-19 and at least one risk factor for disease progression, a three-day course of remdesivir resulted in an 87% lower risk of hospitalization or death than placebo [165]. COVID-19-related hospitalizations and deaths from any cause occurred in 2 patients (0.7%) in the remdesivir group and 15 patients (5.3%) in the placebo group.

Oral Anti-SARS-CoV-2 Agents

Two oral antiviral drugs, molnupiravir and nirmatrelvir-ritonavir, have received FDA EUA for early treatment of nonhospitalized patients with mild-to-moderate COVID-19 who are at risk of disease progression. Mulnupiravir is the prodrug of a ribonucleoside with broad antiviral activity against RNA viruses. Uptake by viral RNA-dependent RNA polymerases causes mutations that are lethal to the virus. In clinical trials, 800-mg molnupiravir twice daily for five days reduced the rate of hospitalization or death among patients with COVID-19 by 30% compared with placebo [57]. Molnupiravir is not recommended for use in pregnant patients due to concerns about potential fetal toxicity. The NIH Panel recommends using molnupiravir only when nirmatrelvir-ritonavir, remdesivir, and selective monoclonal antibody therapy are not available or cannot be used, because molnupiravir has lower efficacy than the other options [57].

Nirmatrelvir is a protease inhibitor active against a constitutive protein (protease) essential for virus replication. It has demonstrated antiviral activity against all human coronaviruses [57]. Nirmatrelvir is used in combination with ritonavir, a pharmacokinetic booster required to increase nirmetrelvir concentration into therapeutic range. Because ritonavir is a potent P450 3A4 inhibitor, nirmatrelvir-ritonavir has significant potential drug-drug interactions; the patient’s concomitant medications should be reviewed before clinical use. The available formulation (Paxlovid) uses nirmatrelvir 300 mg plus ritonavir 100 mg orally twice daily for five days in those older than 12 years of age and weighing more than 40 kg. Treatment should be initiated as soon as possible and within five days of symptom onset. Paxlovid is indicated for early treatment of select patients who are at high risk of severe disease and complications from COVID-19 [57]. In a randomized, placebo-controlled clinical trial of nirtrelvir-riyonavir among symptomatic, unvaccinated, nonhospitalized adults at risk for severe disease, the incidence of progression to severe COVID-19 (hospitalization or death) was 89% lower in the treatment group than in the placebo group [166]. The incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths.

There is some evidence of a COVID-19 recurrence following treatment with nirmatrelvir-ritonavir [176]. Limited information currently available from case reports suggests that persons treated with ritonavir-boosted nirmatrelvir who experience COVID-19 rebound have had mild illness; there are no reports of severe disease. There is currently no evidence that additional treatment is needed in cases where COVID-19 rebound is suspected. Patients with a COVID-19 recurrence should be advised to re-isolate for at least five days to prevent further transmission of the virus.

Hydroxychloroquine

In-vitro studies show that chloroquine phosphate and hydroxychloroquine sulphate (commonly used to treat malaria) interfere with the replication cycle of coronaviruses, including SARS-CoV-2, and thus may offer some therapeutic efficacy for treatment of COVID-19 [21]. Randomized controlled clinical trials of hydroxychloroquine are underway in the United States. Based on small case studies and anecdotal reports of possible efficacy, many clinicians have been inclined to administer hydroxychloroquine to patients with COVID-19 who are so ill as to require hospitalization and having risk factors for severe disease (i.e., age older than 65 years, underlying medical conditions, and/or signs of viral pneumonia). On March 28, 2020, the FDA issued an EUA that allowed chloroquine phosphate or hydroxychloroquine sulphate to be used for the treatment of patients hospitalized with COVID-19 when clinical trials are not available or participation is not feasible [36]. However, this letter was revoked in June 2020 [58]. If used, hydroxychloroquine is generally preferred as it is better tolerated. The suggested dosage regimen is hydroxychloroquine sulphate administered orally in a loading dose of 400 mg twice daily (for one day) then 200 mg twice daily for four days [22]. Potential adverse effects include cardiac conduction QT-prolongation and a number of drug-drug interactions.

An observational study examined the association between hydroxychloroquine use and clinical outcomes, analyzing data from 1,376 consecutive patients with COVID-19 admitted to a clinical center in New York City between March 7 and April 8, 2020 [37]. To assess potential benefit or detrimental effect, the primary end point selected was a composite of intubation or death in a time-to-event analysis, comparing outcomes in patients who received hydroxychloroquine with those who did not. A total of 811 patients (59%) were treated with hydroxychloroquine for a median of five days, 60% of whom also received azithromycin. After adjusting for severity of illness, the investigators found no significant difference in the rate of the composite end point of intubation or death over a median follow-up of 22.5 days. Thus, the risk of intubation or death was not significantly different among hospitalized patients with COVID-19 who received hydroxychloroquine than among those who did not [37].

Randomized, controlled clinical trials to assess efficacy of hydroxychloroquine in patients hospitalized with COVID-19 have not shown a benefit. A multicenter study of hospitalized patients with mild-to-moderate COVID-19 found that hydroxychloroquine, alone or in combination with azithromycin, was no more effective than standard care in improving clinical status at 15 days [70]. Preliminary analysis of data from a multicenter, randomized trial in the United Kingdom found no reduction in 28-day mortality among those treated with hydroxychloroquine when compared with the control group [71]. Hydroxychloroquine use was associated with increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation. An NIH-sponsored, controlled clinical trial was halted (after the fourth interim analysis) because hydroxychloroquine was found unlikely to be beneficial to hospitalized patients with COVID-19 [72]. As of November 2021, multiple randomized, controlled trials have failed to demonstrate any significant benefit for hydroxychloroquine in outpatient treatment of mild COVID-19 or as primary or secondary prophylaxis against SARS-CoV-2 infection.

On June 15, 2020, the FDA revoked the EUA that allowed for chloroquine and hydroxychloroquine donated to the Strategic National Stockpile to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was not available or feasible [58]. This decision was based on an ongoing analysis of emerging data indicating that these drugs are unlikely to be effective for patients hospitalized with COVID-19. As of July 2020, the NIH Panel recommends against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 except in a clinical trial [57].

Ivermectin

Ivermectin is an antiparasitic drug approved by the FDA for the treatment of several tropical diseases (e.g., onchocerciasis, helminthiases, scabies) and under investigation for the prevention of malaria transmission. Ivermectin is poorly absorbed from the intestinal tract, which enhances its effectiveness against parasitic infections confined largely to the intestinal tracts of humans and large mammals (e.g., sheep, cattle, horses). Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host's antiviral response. In addition, ivermectin docking may interfere with the attachment of the SARS-CoV-2 spike protein to the human cell membrane. Although ivermectin inhibits SARS-CoV-2 replication in vitro (cell culture), the effect is dose-dependent, meaning that inhibition is observed when the concentration of ivermectin is raised to a certain level. Furthermore, the ivermectin concentration required for in vitro inhibition of SARS-CoV-2 is 50 to 60 times higher than can be achieved in humans by standard oral doses of the drug. Pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold higher than those approved for use in humans.

In 2021, ivermectin dispensing by retail pharmacies increased dramatically, as did the use of available over-the-counter veterinary formulations not intended for human consumption. The number of ivermectin prescriptions dispensed in the United States increased from 3,600 per week at the pre-pandemic baseline to more than 88,000 per week in August 2021 [167]. During the same period, state poison control centers across the country reported a fivefold increase in consultations for human exposures to ivermectin [167,168]. Misuse of prescription ivermectin by excess dosage or duration can have adverse effects. Veterinary formulations intended for use in horses and cattle are often highly concentrated and unsafe for ingestion by humans. Clinical signs of ivermectin toxicity include gastrointestinal upset, confusion, ataxia, hypotension, disturbances of vision, hallucinations, seizures, and coma.

Ivermectin is not authorized or approved by FDA for prevention or treatment of COVID-19. Clinical studies regarding the use of ivermectin to treat or prevent COVID-19 have been conflicting, and many studies had incomplete information and significant methodological limitations. Among 400 patients with mild COVID-19, a double-blind, randomized, placebo-controlled trial of ivermectin 300 mg/kg twice daily for five days found that ivermectin had no significant effect on time to resolution of symptoms compared with placebo [169]. A larger, double-blind, randomized, placebo-controlled trial of early ivermectin treatment for COVID-19 (679 patients in each comparator group) found that ivermectin did not lower incidence of admission to hospital (progression of disease) or duration of time required for emergency department observation [170]. In a randomized, placebo-controlled trial among patients hospitalized with mild-to-moderate COVID-19, treatment with ivermectin on admission had no beneficial effect on the rate of disease progression (21.6%) compared with standard care (17.3%) [171]. The rates of COVID-19-associated ICU admission, mechanical ventilation, and mortality were not significantly different for the ivermectin group than the control group. Due to the lack of reliable and accurate data, the NIH Panel does not recommend either for or against the use of ivermectin for the treatment of COVID-19 [57].

Baricitinib

In May 2022, the FDA issued an EUA for baricitinib to treat COVID-19 in hospitalized pediatric patients 2 to 17 years of age requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO [175]. The recommended dosage of baricitinib under the EUA is 4 mg once daily for patients 9 years of age and older or 2 mg once daily for patients 2 to 8 years of age. Treatment should continue for 14 days or until hospital discharge, whichever occurs first [175].

Before initiating therapy, baseline glomerular filtration rate, liver enzyme level, and complete blood count should be assessed, as modifications in approach are necessary with abnormalities in any of these values. Baricitinib is not recommended for patients with active tuberculosis, who are on dialysis, have end-stage renal disease, or have acute kidney injury [175].

Other Agents

Several other approaches to antiviral therapy have been explored for the treatment of COVID-19, with poor results. The NIH guidelines for the treatment of COVID-19 recommend against the use of nitazoxanide, lopinavir/ritonavir, and other HIV protease inhibitors to manage or prevent COVID-19 outside of clinical trials [57].

Approaches to Disease Modification

Severe SARS-Cov-2 infection results in progressive interstitial-alveolar pneumonia and respiratory failure. The disease process is closely linked to activation of the innate immune system and dysregulation of adaptive immune responses, with release of proinflammatory cytokines and chemokines. Death from COVID-19 is often preceded by signs of a hyperimmune inflammatory response ("cytokine storm") that leads to ARDS, multi-organ dysfunction, and circulatory collapse. Laboratory markers of heightened inflammation include elevated C-reactive protein, ferritin, and interleukin-6. Novel approaches to disease management seek to modify disease progression and prevent or ameliorate pulmonary and systemic complications of cytokine storm, in hope of reducing mortality from COVID-19.

COVID-19 Convalescent Plasma

Passive immunization with plasma obtained from surviving patients has been used in the past to treat life-threatening infections absent specific therapy. There is emerging evidence that intravenous transfusion of convalescent plasma with high-titer antibody directed against SARS-CoV-2 is effective in reducing mortality in hospitalized patients with COVID-19 pneumonia. In a preliminary, uncontrolled case series of five critically ill Chinese patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in clinical status, including resolution of ARDS in four patients at 12 days after transfusion [27].

Convalescent plasma treatment has been widely utilized in the United States since early April 2020 under the Mayo Clinic's Expanded Access Protocol (EAP). A report from the Mayo EAP involving 35,322 registered patients found that plasma infusion is relatively safe and may reduce COVID-19 mortality when administered early after hospitalization [76]. A subset analysis showed a gradient of mortality in relation to IgG antibody levels in transfused plasma. The risk of dying from COVID-19 was lower among patients who received convalescent plasma units containing high titer anti-SARS-CoV-2 antibody than among those who received plasma containing low antibody levels. The pooled relative risk reduction among patients transfused with high antibody level plasma units versus low-level antibody plasma was 35% at 7 days and 23% at 30 days. The Mayo EAP report is an analysis of registry data and not a randomized controlled study.

On August 23, 2020, the FDA granted an EUA to COVID-19 convalescent plasma for treatment of patients hospitalized with COVID-19 [73]. This decision was based on historical evidence derived from the use of plasma in prior outbreaks of respiratory virus infection, small case series, and non-randomized clinical trials conducted during the current outbreak. As of December 2020, the only double-blind, placebo-controlled clinical trial of convalescent plasma did not demonstrate a reduction in mortality or improvement in other clinical outcomes [93]. In this study, 333 patients with severe COVID-19 pneumonia were randomized in a 2:1 ratio to receive convalescent plasma (228 subjects) or placebo (105 subjects). Of the total, 68% were men and 65% had a coexisting condition at entry into the trial. The median time from onset of COVID-19 symptoms to enrollment was eight days. More than 90% were receiving oxygen and glucocorticoids at the time of entry into the trial. The infused convalescent plasma had a median titer of 1:3,200 of total SARS-CoV-2 antibodies. At 30 days, the clinical status of patients in the convalescent plasma group did not differ significantly from that of patients in the placebo group. The proportion of ICU admissions and invasive ventilatory support requirements were similar in both groups. Overall mortality was 11.43% in the placebo group and 10.96% in the convalescent plasma group. In a subset analysis, no differences favoring convalescent plasma were noted in a group of 39 patients who received the intervention within 72 hours of symptom onset [93]. Of note, all patients in this study had signs of severe pneumonia; thus, no firm conclusion can be drawn as to the potential efficacy of COVID-19 convalescent plasma initiated earlier in the disease. At present, IDSA and NIH guidelines recommend that convalescent plasma therapy be used only in the context of a clinical trial [10,57].

Although convalescent plasma therapy has no clear benefit for hospitalized patients with COVID-19 pneumonia, treatment with high-titer convalescent plasma early in the course of illness has been shown to reduce the risk of progression to severe disease. Evidence for this comes from a randomized, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 administered to older adults within 72 hours after onset of mild COVID-19 symptoms. In the cohort of patients who received high-titer plasma therapy, 13 of 80 (16%) patients progressed to severe respiratory disease, compared with 25 of 80 patients (31%) who received placebo [109]. This corresponds to a relative risk reduction of 48%. The study population consisted of adults 75 years of age or older, or between 65 and 74 years of age with at least one coexisting condition.

The FDA provides a COVID-19 convalescent plasma fact sheet with guidance for healthcare providers [73]. Patients recovering from COVID-19 who wish to donate convalescent plasma can also find information at the FDA website [28]. Persons who have fully recovered from COVID-19 are candidates for plasma donation. COVID-19 convalescent plasma can only be collected from recovered individuals if they are eligible to donate blood. A potential donor must have had a prior diagnosis of COVID-19 documented by a laboratory test and meet other donor criteria. Complete resolution of symptoms for at least 28 days is required before an individual may donate plasma, or alternatively have had no symptoms for at least 14 days prior to donation and have a negative lab test for active COVID-19 disease [28]. Persons interested in becoming donors should contact the American Red Cross or ask the local blood center about options to donate convalescent plasma in their area.

On April 10, 2020, the FDA granted EUA for an extracorporeal blood purification system to treat adult patients with COVID-19 admitted to an ICU with confirmed or imminent respiratory failure [29]. This device filters the blood for removal of cytokines and other inflammatory mediators associated with cytokine storm, then returns filtered blood to the patient.

Monoclonal Antibody to SARS-CoV-2

Modern immunologic techniques enable the identification of pathogen-specific memory B cells and recovery of immunoglobulin genes that can be expressed to produce monoclonal antibodies [85]. The clinical application of monoclonal antibodies has been relatively safe. FDA-approved monoclonal antibody products are available to treat or prevent respiratory-syncytial virus, anthrax, and Clostridioides difficile. Several laboratories have used B cells from patients recovering from COVID-19 to produce neutralizing monoclonal antibodies to SARS-CoV-2. These antibodies are directed against surface spike glycoprotein, preventing entry of virus into host cells. Passive immunization with monoclonal antibodies has potential for preventing COVID-19 in vulnerable people and for early augmentation of the immune response (to block disease progression) in COVID-19 patients at risk for severe illness. Given the long half-life of immunoglobulin (approximately three weeks), a single infusion of monoclonal antibodies to SARS-CoV-2 should suffice for either prevention or treatment of COVID-19 [85]. In a phase 2 randomized clinical trial involving outpatients with mild or moderate COVID-19, a single infusion of bamlanivimab (a monoclonal neutralizing antibody) was associated with rapid decline in viral load and reduced need for further medical attention [94]. Subsequent COVID-related hospitalization or visit to an emergency room was required in 1.6% of patients in the monoclonal antibody group, compared with 6.3% in the placebo group.

As of March 2022, three monoclonal antibody products (bamlanivimab plus etexevemab, casirivimab plus imdevimab, and sotrovimab) have received EUAs from the FDA for the treatment of nonhospitalized patients with mild-to-moderate COVID-19 who are at high risk of progressing to severe disease. In placebo-controlled clinical trials for these agents, anti-SARS-CoV-2 monoclonal antibodies reduced the risk of hospitalization or death by 70% to 85% [57]. At present, sotrovimab is recommended over the other two products because in vitro studies indicate that only sotrovimab exhibits acceptable activity against the Omicron variant, the predominant SARS-CoV-2 variant in all regions of the United States as of May 2022 [57]. Outpatient monoclonal antibody therapy is reserved for at-risk symptomatic patients and should be administered soon after confirmation of SARS-CoV-2 infection, within 7 to 10 days of symptom onset. Patients with symptomatic COVID-19 who meet one of the following criteria are eligible for treatment:

- Body mass index >35

- Diabetes

- Chronic kidney disease

- Immunosuppressive disease or current immunosuppressive treatment

- Age 65 years or older or 55 years or older with underlying cardiovascular disease, hypertension, or chronic lung disease

Specific guidance that addresses patient selection criteria, authorized dosage, and treatment precautions, is provided at the NIH Panel website [57,96].

Dexamethasone

Preliminary results of a large multicenter therapeutic trial show that dexamethasone (a glucocorticoid) improves survival in patients hospitalized with COVID-19 who require some degree of respiratory support [63]. In this ongoing study platform, patients are randomly assigned to a group of different therapies and efficacy is assessed using a single end-point: mortality within 28 days after randomization. A total of 2,104 patients were assigned to receive dexamethasone at a dose of 6 mg daily, and 4,321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1,110 patients (25.7%) in the usual care group died within 28 days after randomization. The observed differences in mortality varied according to the level of respiratory support patients required upon entry to the study. Among patients receiving mechanical ventilation, the 28-day mortality was significantly lower in the dexamethasone group (29.3%) than that in the usual care group (41.4%). Among patients receiving supplemental oxygen without mechanical ventilation, the observed benefit was less pronounced but also significant, 23.3% in the dexamethasone group and 26.2% in the usual care group. There was no demonstrable benefit from dexamethasone treatment in patients who did not require oxygen.

The NIH Panel recommends using dexamethasone (at a dose of 6 mg per day for up to 10 days) for the treatment of COVID-19 in patients who are mechanically ventilated and in patients who require supplemental oxygen but not mechanical ventilation [57]. If dexamethasone is not available, equivalent doses of another glucocorticoid may be used, such as prednisone 40 mg/day or methylprednisolone 32 mg/day. Dexamethasone is the preferred glucocorticoid to use in pregnant women with COVID-19 who require respiratory support, because of the potential benefit of decreased maternal mortality and the known low risk of fetal adverse effects associated with short-course maternal dexamethasone therapy [57]. Patients receiving dexamethasone at the time of hospital discharge should be given a prescription to complete the specified 10-day course. The Panel recommends against using dexamethasone for the treatment of COVID-19 in patients who do not require supplemental oxygen.

Potential adverse effects of glucocorticoid use include hyperglycemia and opportunistic infection. Clinicians should be aware that Strongyloides hyperinfection syndrome has been reported as a complication of modest-dose and short-duration dexamethasone regimens [75]. Patients who may be at risk are those who have previously resided in South America, the Caribbean, the Middle East, Africa, or Asia. Clinical clues to subclinical or unrecognized Strongyloides infection include peripheral eosinophilia and unexplained gram-negative bacteremia [75].

Tocilizumab

Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been used to mitigate cytokine storm syndrome associated with COVID-19. A retrospective cohort study of hospitalized patients who required ICU support found that treatment with tocilizumab was associated with reduced mortality [74]. Of 630 patients selected for analysis, 358 (57%) died—102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. The primary multivariable Cox regression analysis showed an association between receiving tocilizumab and decreased hospital-related mortality. This association was also noted among subgroups requiring mechanical ventilation and with baseline C-reactive protein of 15 mg/dL or higher. In contrast to findings from this and other observational studies of COVID-19 pneumonia, randomized clinical trials have not reported a mortality benefit from tocilizumab therapy [91]. Tocilizumab has been reported to reduce the requirement for mechanical ventilation in some patient populations, thereby alleviating the demand on ICU-level care for management of severe COVID-19. A published editorial assessment concluded that newly released randomized trials suggest a potential role for tocilizumab in COVID-19 but do not show clear evidence of efficacy [91]. As of August 2021, the NIH Panel guidelines recommend adding IV tocilizumab for the treatment of hospitalized patients with evidence of systemic inflammation and who require delivery of oxygen through a high-flow device or either noninvasive or mechanical ventilation [57]. Tocilizumab should only be used in combination with dexamethasone, as trials have shown the clinical benefit of tocilizumab was seen among patients who were receiving this agent in combination with a glucocorticoid [57]. Clinicians may consider assessing the patient's response to dexamethasone before deciding whether adding tocilizumab is necessary.

COVID-19 VACCINES

The effort to develop vaccines against coronavirus began following the 2002–2004 SARS outbreak, but was halted when SARS-CoV began to disappear from the human population. These earlier preclinical studies did clarify the antigenic target for coronavirus and laid the groundwork for current SARS-CoV-2 vaccine development. Coronaviruses encode for one large surface glycoprotein, the spike protein, which is responsible for receptor binding and membrane fusion [97]. As noted, SARS-CoV-2 spike protein binds to ACE2 receptors on host cells and facilitates release of the viral genome into the cytoplasm for replication of new virions. Antibodies that bind to the spike protein prevent attachment and neutralize the virus [97]. On the basis of these observations, the spike protein is an antigenic target for development of vaccines against SARS-CoV-2.

As of December 2020, more than 180 potential vaccines were in preclinical studies worldwide, and several candidate vaccines had entered into clinical trials designed to assess immunogenicity and safety. The range of vaccine platforms includes inactivated-virus and live-virus vaccines, recombinant protein vaccines, vectored vaccines, and novel RNA and DNA vaccines [97]. Three vaccines showed promising early results and were advanced to phase 3 clinical trials in August 2020; two are messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna, and the third is an adenovirus-vectored vaccine developed by Astra-Zeneca and the University of Oxford. Pfizer and the German company BioNTech have reported preliminary results of an ongoing phase 1 mRNA vaccine trial in 45 healthy adults 18 to 55 years of age. Participants received one of three vaccine doses (25, 100, or 250 mcg) given as two inoculations 28 days apart [64]. All participants developed an immune response. Following the second dose, antibody titers increased and serum neutralizing antibody activity was comparable to levels measured in a control panel of SARS-CoV-2 convalescent serum. Adverse events such as fatigue, myalgia, feverishness, and pain at injection site were reported in half the participants, more commonly after the second injection and at the highest dose. The study group concluded that immunogenicity and safety findings supported expansion of the trial to include older adults and advancement of this vaccine to later-stage clinical trials. In a follow-up report of 40 older adults (50% 56 to 70 years of age and 50% older than 70 years of age) administered the mRNA vaccine, the safety profile and immunogenicity were comparable to results in the younger cohort of participants [86]. Enrollment in a phase 3 trial began in late July 2020.

A report from the University of Oxford described early results of a clinical trial using a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCov-19) that expresses a full-length version of the SARS-CoV-2 spike protein [65]. In a phase 1/2 randomized controlled trial, 1,077 healthy adults received either the candidate vaccine or a meningococcal conjugate vaccine as control. Following a single dose, ChAdOx1 nCoV-19 elicited spike-specific T-cell responses that peaked on day 14 and measurable anti-spike IgG antibody by day 28. Strong humoral and cellular immune responses persisted at day 56 of the ongoing trial. Neutralizing antibody was detected in 32 (91%) of 35 participants after a single dose, and in 10 (100%) of 10 participants who received a booster dose. Adverse events such as discomfort at injection site, fever, malaise, and headache were common but mild or moderate and self-limiting. There were no serious adverse reactions. Progression into phase 2 and 3 trials is underway, recruiting older age groups with comorbidities, healthcare workers, and those at higher risk for SARS-CoV-2 exposure [65].

COVID-19 mRNA Vaccines

COVID-19 mRNA vaccine represents a new vaccine technology that has important public health advantages. The vaccine can be produced completely in vitro, which enables facile purification and rapid production of individual vaccine doses. The COVID-19 mRNA vaccine consists of a nucleoside-modified messenger RNA inside a lipid-laden nanoparticle. The vaccine mRNA encodes for SARS-CoV-2 surface spike protein. The lipid envelope not only facilitates vaccine delivery into host cells but also enhances stability and may augment the immune response. Following intramuscular inoculation, host myocytes utilize vaccine mRNA to express SARS-CoV-2 antigen on cell surfaces, which in turn elicits neutralizing antibody and cellular immune responses to SARS-CoV-2. The vaccine mRNA does not enter the host cell nucleus and cannot become part of the vaccinee's own DNA.

Preliminary results of phase 3 clinical trials demonstrate that both the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines are safe and 94% to 95% effective [98,99]. In the Pfizer-BioNTech vaccine trial, 43,448 adults were randomized to receive vaccine (21,720 participants) or placebo (21,728 participants) in two doses 21 days apart [98]. The primary outcomes were safety and the incidence of symptomatic COVID-19 at least seven days after the second dose. The interim analysis included the first 170 cases of symptomatic COVID-19 diagnosed in the study population and covered a median of two months of safety data. Of the total, eight cases of COVID-19 were observed in the vaccine group and 162 cases in the placebo group. This corresponds to a vaccine efficacy of 95.0%. Vaccine efficacy was similar across subgroups defined by age, sex, race, body mass index, and coexisting medical conditions. Ten cases of severe COVID-19 occurred with onset after the first dose, of which nine were in placebo recipients. Post-vaccination reactions included mild-to-moderate localized pain at the injection site and transient systemic reactions such as fatigue, fever, and headache. Systemic reactions occurred more commonly in younger vaccine recipients (16 to 55 years of age) and after the second dose [98]. The Moderna phase 3 vaccine trial results were equally favorable [99]. In this trial, 30,420 adult participants were randomly assigned to receive either two doses of vaccine or placebo 28 days apart. Of 196 confirmed cases of symptomatic COVID-19 with onset at least 14 days after the second inoculation, 185 cases were in the placebo group and 11 in the vaccine group, a vaccine efficacy of 94.1%. Severe COVID-19, including one fatality, occurred in 30 participants, all of whom were in the placebo group. Transient local and systemic post-vaccination reactions occurred commonly; no safety concerns were identified [99]. In mid-December 2020, following independent verification of safety and efficacy data, the FDA issued an EUA to the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines for use in adults and older adolescents.

COVID-19 Adenovirus Vector Vaccine

In February 2021, Johnson and Johnson (Janssen Pharmaceuticals) received an EUA for use of the Janssen COVID-19 vaccine in adults [110]. This is a recombinant, replication-incompetent adenovirus vector vaccine encoded for the SARS-CoV-2 prefusion spike glycoprotein. Based on interim data from an international phase 3 clinical trial, a single dose of Janssen COVID-19 vaccine is highly effective in preventing COVID-19-associated hospitalization and death [110]. The phase 3 study enrolled 43,783 participants across three regions, 44% from United States, 41% from Latin America, and 15% from South Africa. One-third of the participants were older than 60 years of age and 41% had underlying chronic health conditions. At 14 days following vaccination, the Janssen vaccine was 66% effective in preventing symptomatic COVID-19. After 28 days, the vaccine was 85% effective against severe disease and 93% effective in preventing hospitalization. Among participants in South African, where 95% of COVID-19 cases were caused by the B.1.351 variant, vaccine efficacy against severe disease was 89%. There were no COVID-19 deaths in the vaccine group compared with seven in the placebo group. Vaccine administration side effects were mild-to-moderate, and adverse events were rare and manageable; no anaphylaxis was encountered [110].

COVID-19 Protein Subunit Vaccine

In July 2022, the FDA issued an EUA for the Novavax COVID-19 Vaccine, Adjuvanted for individuals 18 years of age and older [178]. The vaccine contains purified SARS-CoV-2 spike protein and Matrix-M adjuvant. The vaccine was the subject of an ongoing randomized, blinded, placebo-controlled study conducted in the United States and Mexico. The effectiveness of the vaccine was assessed in clinical trial participants 18 years of age and older who did not have evidence of SARS-CoV-2 infection through six days after receiving the second vaccine dose. Among these participants, approximately 17,200 received the vaccine and approximately 8,300 received saline placebo. Overall, the vaccine was 90.4% effective in preventing mild, moderate, or severe COVID-19, with 17 cases of COVID-19 occurring in the vaccine group and 79 cases in the placebo group [178]. No cases of moderate or severe COVID-19 were reported in participants who received the vaccine, compared with nine cases of moderate COVID-19 and four cases of severe COVID-19 reported in placebo recipients. In the subset of participants 65 years of age and older, the vaccine was 78.6% effective. However, it is important to note that the clinical trial was conducted prior to the emergence of Delta and Omicron variants [178].

Vaccine Distribution

Because initial supplies of vaccine were limited, the Advisory Committee on Immunization Practices (ACIP) and the CDC have provided interim recommendations for allocation of COVID-19 vaccines, updated January 1, 2021 [100]. The recommended plan called for prioritization of vaccine distribution based upon risk of exposure to SARS-CoV-2 and potential for severe illness. In Phase 1a, healthcare workers and residents and staff of long-term care facilities were offered vaccination. The next priority group (Phase 1b) consisted of front-line essential workers (e.g., first-responders, teachers, Postal Service employees, grocery workers) and people older than 75 years of age. In Phase 1c, vaccine was offered to persons 65 to 74 years of age and 14 to 64 years of age with high-risk conditions, and other essential workers. Phase 2 included all other persons 16 years of age and older who were not offered the vaccine in Phase 1.

The ACIP has issued interim considerations for the use of Pfizer-BioNTech, Moderna, and Janssen (Johnson & Johnson) COVID-19 vaccines, available at the CDC website [101]. This guidance includes vaccine dose, timing of second inoculation, contraindications, anticipated side effects, and COVID-19 vaccination of pregnant persons and those with underlying medical conditions. Adolescents 16 to 17 years of age were included among those initially eligible to receive the Pfizer-BioNTech COVID-19 vaccine under the EUA. Following review of efficacy and safety data in spring 2021, Pfizer mRNA COVID-19 vaccine received FDA EUA for use in adolescents 12 to 18 years of age. In November 2021, FDA issued a EUA and CDC/ACIP recommended Pfizer COVID-19 vaccine use, at reduced dosage, in children 5 to 11 years of age. Providers should counsel vaccine recipients to expect local reactions (e.g., injection site pain, swelling, erythema, localized axillary lymphadenopathy) and systemic symptoms such as fever, fatigue, headache, or myalgias. Most post-vaccination symptoms are mild-to-moderate and resolve within one to three days of onset.

Data from clinical trials indicate that it is safe to offer vaccination to persons with evidence of a prior SARS-CoV-2 infection, and the CDC recommends doing so 90 days or more after infection [101]. Interestingly, the natural immunity that follows SARS-CoV-2 infection is greatly enhanced by vaccination. In one study, anti-spike antibody titers increased more than 140-fold from peak pre-vaccine levels following a single dose of mRNA vaccine [111]. In a small cohort of persons previously infected, a single dose of vaccine was also shown to substantially increase neutralizing activity against the important SARS-CoV-2 variants circulating in the United States [112].

COVID-19 Vaccine Booster Dose

Following initial rollout in December 2020, COVID-19 vaccines were nearly 100% effective against severe disease, hospitalization, and death, and about 95% effective in preventing SARS-CoV-2 infection. Six months later, and coinciding with emergence of the Delta variant in May/June 2021, protection against severe illness and hospitalization remained strong (92% to 95%) while efficacy against infection had declined to about 70%. An analysis of reported COVID-19 hospitalizations during the period January to May 2021, during which 100 million persons were vaccinated against SARS-CoV-2, found that 600 vaccinated adults had developed breakthrough COVID-19 severe enough to require hospitalization. Of this group, 74% were older than 65 years of age and 130 died (all deaths were patients 71 to 89 years of age) [154].

In fall 2021, the CDC noted that vaccine effectiveness against SARS-CoV-2 infection and mild illness was gradually diminishing among healthcare and other frontline workers, most likely because of decreased immune protection and greater infectiousness of the Delta variant. Small clinical trials demonstrated that booster doses of COVID-19 vaccines enhanced the anti-SARS-CoV-2 immune response in participants who were immunized months earlier [155]. In response, the CDC recommended everyone 5 years of age and older receive an interval-appropriate booster after completing the initial COVID-19 vaccine series. The recommended timing is six months after completion of Pfizer or Moderna mRNA vaccination or two months after Johnson & Johnson vaccination. The choice of vaccine booster is open, meaning that one may “mix and match” dosing for booster shots. One of the two mRNA vaccines is preferred. Effective April 1, 2022, the CDC has authorized a second booster dose of COVID-19 vaccine for persons older than 50 years of age and those at high risk of severe illness because of underlying medical conditions. Updated guidance and COVID-19 vaccine schedules are provided at the CDC website.

As of April 2022, COVID-19 vaccines have been in use in the United States for 16 months; more than 560 million COVID-19 vaccine doses have been administered and 217.6 million people are fully vaccinated, comprising 65.5% of the total population and 85.3% of those 65 years of age and older [124]. About 50% of those fully vaccinated have received an interval-appropriate booster dose. Vaccine efficacy in reducing the incidence of SARS-CoV-2 infection and protecting against severe outcomes (hospitalization and death) has been demonstrated in clinical trials and confirmed by real-world observational studies. One such study, which analyzed data from a multistate hospital network comprising 7,544 patients enrolled between March 11, 2021, and January 24, 2022, found that receipt of two or three doses of COVID-19 mRNA vaccine conferred 90% protection against COVID-19-related invasive mechanical ventilation or in-hospital death [172]. Vaccine effectiveness was consistent throughout the periods of Delta and Omicron predominance; protection against mechanical ventilation and death was higher (94%) among those who received a third (booster) dose during the period of Omicron predominance.

COVID-19 Vaccine Safety

COVID-19 Vaccines and Pregnancy, Lactation, and Fertility

As noted, observational data demonstrate that pregnant persons have an increased risk of severe illness and complications from COVID-19, including ICU admission and mechanical ventilation [107]. Related concerns include the possibility that COVID-19 during pregnancy may increase the risk for adverse pregnancy outcomes (e.g., pre-eclampsia, coagulopathy, preterm birth) [101]. Any currently authorized COVID-19 vaccine can be administered to pregnant or lactating people; the ACIP does not state a product preference [101,149].

Vaccination reduces the risk of getting COVID-19 and protects patient and fetus from severe consequences. Vaccination while pregnant has the added benefit of providing transplacental maternal antibody protection to the newborn for some months after delivery. Studies show that maternal neutralizing antibodies directed against SARS-CoV-2 are present in umbilical cord blood of newborn infants and in breast milk [138].

There was no expectation that COVID-19 vaccines would pose a risk to pregnant persons or the fetus based on current knowledge of human coronaviruses and the science of COVID-19 vaccine development. The authorized COVID-19 vaccines in use are non-replicating vaccines; they do not contain intact virus and cannot cause infection in either the mother or fetus [101]. No reproductive, fetal developmental, or safety concerns were demonstrated in preclinical vaccine studies in animals, nor were any adverse pregnancy-related outcomes, including fetal outcomes, determined to be related to previous use of an adenovirus vector platform in a large-scale Ebola virus vaccine trial [101].

The CDC has three national surveillance programs in place to monitor the safety and efficacy of COVID-19 vaccination in pregnant persons [139]. As of October 25, 2021, more than 169,000 participants enrolled in the CDC v-safe Health Checker indicated they were pregnant when vaccinated against COVID-19. The COVID-19 Vaccination Registry, a subset of 5,100 participants enrolled within 30 days of vaccination, provides direct contact and detailed surveillance, including access to medical records. To date there are no reports of increased risk of pregnancy loss, adverse effects on fetal growth and development, or other safety concerns among pregnant or lactating individuals. An analysis of outcomes among registry participants vaccinated before 20 weeks' gestation found no increased risk of miscarriage in association with COVID-19 vaccine use early in pregnancy [140]. A case-control analysis of outcomes from Norwegian registries on first-trimester pregnancies also found no evidence of an increased risk for early pregnancy loss after COVID-19 vaccination [141]. In general, there is no difference in the incidence of pregnancy loss, preterm birth, delayed gestational growth, congenital abnormalities, and neonatal death among pregnant persons who have received mRNA vaccine compared with the known background incidence of these events in unvaccinated pregnant persons.

The Academy of Breastfeeding Medicine does not recommend cessation of breastfeeding for individuals who are vaccinated against COVID-19 [142]. The Academy considers it unlikely that vaccine lipid would enter the blood stream and reach breast tissue, and if it did, even less likely that either the intact nanoparticle or mRNA would transfer into milk. In the unlikely event mRNA is present in milk, it would be digested by the child and be unlikely to have any biological effects. In a study of seven breastfeeding mothers who received either Pfizer or Moderna COVID-19 vaccine, analysis of 13 samples of breastmilk obtained 4 to 48 hours after vaccination found no detectable mRNA or any other vaccine-related particles in any of the samples tested [143].

On September 14, 2021, the Society for Maternal and Fetal Health and the American College of Obstetrics and Gynecology, along with 18 other professional organizations representing nurse practitioners, nurse-midwives, pediatricians, infectious disease specialists, and public health professionals, issued a joint Statement of Strong Medical Consensus for Vaccination of Pregnant Individuals Against COVID-19 [144]:

As the leading organizations representing experts in maternal care and public health professionals that advocate and educate about vaccination, we strongly urge all pregnant individuals—along with recently pregnant, planning to become pregnant, lactating, and other eligible individuals—to be vaccinated against COVID-19.

A conversation between the patient and clinical team may assist with decisions about the selection and timing of a COVID-19 vaccine during pregnancy, though a discussion with a healthcare provider is not required before vaccination [101]. When making a decision, patient and provider should consider the level of SARS-CoV-2 community transmission, the patient's personal risk of contracting COVID-19, the risks of COVID-19 to the patient and potential risks to the fetus, the efficacy and side effects of the vaccine, and current data about the COVID-19 vaccine use during pregnancy [101]. Pregnant persons who choose to receive COVID-19 vaccine are encouraged to enroll in the CDC's v-safe registry, established to follow outcomes among people who are vaccinated [113].

Concerning infertility, there is no scientific basis for COVID-19 vaccines having any impact on fertility, and no scientific evidence that these vaccines cause sterility in either women or men. Claims that vaccine-derived antibodies directed against SARS-CoV-2 spike protein would cross-react with uterine syncytin-1 protein and cause damage to the developing trophoblast, thereby preventing embryo implantation, are unfounded. A study comparing implantation and sustained pregnancy success rates among individuals receiving frozen embryo transfer found no differences among vaccine seropositive, infection seropositive, and seronegative participants. Rates of sustained embryo implantation for seronegative, vaccine seropositive, and infection seropositive patients were 52.3%, 65.7%, and 47.4%, respectively, and were consistent with pre-COVID-19 success rates [150]. Seropositivity to the SARS-CoV-2 spike protein, derived from either vaccination or infection, had no adverse effect on embryo implantation or early pregnancy development.

There are no studies showing COVID vaccination reduces sperm concentration or motility. Among 45 volunteers for baseline and post-vaccination measure of sperm parameters, no significant differences in semen volume, sperm counts, or sperm motility were found after two doses of mRNA COVID-19 vaccine [151]. On the other hand, male sexual dysfunction and related fertility issues have been reported as potential late complications of symptomatic COVID-19 [152].

Adverse Reactions to COVID-19 mRNA Vaccines

Early side effects, such as soreness at injection site, fatigue, and headache, occur in about 50% of vaccine recipients; feverishness is less common, and all side effects usually resolve in 12 to 36 hours. Immediate, severe allergic reactions (anaphylaxis) do occur rarely within 15 minutes after injection, as with influenza vaccine. Anaphylaxis was not observed during clinical trials, in part because potential participants who had experienced reactions to vaccines were excluded. However, according to a review of SARS-CoV-2 vaccine safety, several cases of anaphylaxis associated with the Pfizer mRNA vaccine were reported following vaccination of 2 million healthcare workers in the United States [102]. For most vaccines in common use, vaccine-associated anaphylaxis has been a rare event, at about one case per million injections. The estimated risk of anaphylaxis associated with use of the Pfizer mRNA vaccine is 1 in 100,000 inoculations—10 times higher [102]. The explanation for this is unclear. One component unique to mRNA vaccines is a polyethylene glycol (PEG) 200 lipid conjugate used to stabilize the nanoparticle carrier system. PEG is a stabilizing compound commonly used in medications and other products and has been implicated in IgE-mediated reactions and recurrent anaphylaxis [102]. This has raised concern that individuals sensitized by past exposure to PEG (or its polysorbate derivative) in commercial products may be at risk of anaphylactic reactions from mRNA vaccination. Anaphylaxis is an acute allergic reaction that can lead to upper airway obstruction, bronchospasm, and circulatory collapse. Prompt recognition and treatment with epinephrine is necessary to prevent life-threatening complications.

A detailed discussion of contraindications and precautions to be observed with mRNA vaccine administration is included in the guidance provided by the CDC [101]. The history of any one of the following reactions is considered a contraindication to vaccination with either the Pfizer-BioNTech or Moderna COVID-19 vaccines [101]:

- Severe allergic reaction (e.g., anaphylaxis) after a previous dose of an mRNA vaccine or any of its components

- Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including PEG)

- Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive hypersensitivity with the vaccine ingredient PEG)

Persons with an immediate allergic reaction to the first dose of an mRNA vaccine should not receive additional doses of either of the mRNA COVID-19 vaccines [101]. Healthcare providers who participate in mRNA vaccine administration should be familiar with signs and symptoms of hypersensitivity reactions and have access to medications and supplies needed for assessing and managing anaphylaxis. The CDC has provided interim guidance on preparation for the potential management of anaphylaxis after COVID-19 vaccination [103].

Delayed-onset local reactions have been reported after mRNA vaccination in some individuals beginning a few days through the second week after the first dose [101,114]. The suspected cause is delayed-type or T-cell-mediated hypersensitivity, and reactions resolve within a few days. In a small series report, the recurrence rate following the second dose was less than 50% [114]. Vaccinees with only a delayed-onset local reaction (e.g., erythema, induration, pruritis) around the injection site do not have a contraindication or precaution to the second dose of vaccine. The CDC recommends these individuals receive the second dose using the same vaccine product as the first dose at the recommended interval, preferably in the opposite arm [101].

Immune Thrombotic Thrombocytopenia and Adenovirus-Vectored Vaccines

On April 13, 2021, after more than 6.8 million doses of the Janssen COVID-19 vaccine had been administered in the United States. the FDA placed a pause on use of this vaccine while the CDC investigated six reports of severe intravascular clotting events that occurred within two weeks following vaccination [127]. In these cases, a rare form of blood clot (cerebral venous sinus thrombosis) combined with thrombocytopenia was observed between the 6th and 13th day after vaccination. All cases were women 18 to 48 years of age, one of whom died. The pause was for purposes of further analysis and so health professionals could become familiar with the diagnostic and management implications. Treatment of this type of clotting disorder is different from treatment that might typically be administered to patients with thrombosis. Usually, the anticoagulant drug heparin is used to treat blood clots. However, in this setting the administration of heparin may be dangerous, and alternative therapies are needed [127]. The risk of cerebral venous thrombosis following Jenssen COVID-19 vaccination is approximately 1 in 1,000,000 vaccinees.

AstraZenica COVID-19 vaccine, the other primate adenovirus-vectored vaccine used in Europe, has also been linked to thrombotic events in vaccinees. In two separate reviews (11 cases from Germany and Austria, and 5 cases from Norway), patients presented 5 to 16 days after vaccination with thrombocytopenia and signs of vascular thrombosis at unusual sites [128,129]. In patients with one or more thrombotic events, there were 13 instances of cerebral venous thrombosis, 4 of splanchnic-vein thrombosis, 2 of pulmonary embolism, and 4 involving other sites. The patient age range was 22 to 54 years, and 13 of 16 cases were women. The timing of events and character of clinical features were similar to that observed in cases of severe autoimmune heparin-induced thrombocytopenia, suggesting an antibody-mediated thrombotic thrombocytopenia triggered by the vaccine. All patients in each series had high levels of antibodies directed against antigenic complexes of platelet factor 4 (PF4). None of the patients had previously received heparin. This disorder is thought to represent vaccine-induced immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4 [128,129].

These reports, and the action taken by the FDA and the CDC, have important implications for health professionals. The few cases among millions of vaccine doses administered indicates the incidence is rare and the risk low. The risk may be highest in women younger than 50 years of age. Vaccinees who are beyond three weeks from date of vaccination are not considered at risk for thrombotic complications. Individuals who develop any of the following new-onset symptoms within three weeks of vaccination should be evaluated for severe headache, abdominal pain, swelling or pain in the leg, chest pain, or shortness of breath. The evaluation should include a platelet count and imaging studies appropriate to clinical exam findings. Patients with thrombocytopenia and suspicion of a thrombotic event should not be treated initially with a heparin product. A diagnostic screening immunoassay for antibodies against PF4-heparin, or an enzyme-linked immunosorbent assay for antibodies against PF4-polyanion should be ordered. Hematology consultation is advisable. Potential treatment options include high-dose immunoglobulins and certain non-heparin anticoagulants [128,130].

Another rare adverse event reported after Janssen COVID-19 vaccination is Guillain-Barré syndrome (GBS). As of June 30, 2021, approximately 12.6 million doses of Janssen COVID-19 vaccine had been administered in the United States, with 100 reports of GBS with disease onset 3 to 42 days after vaccination [145]. The median age of reported cases was 57 years, and 61 were male. The GBS reporting rate for all recipients was 7.8 cases per million doses administered; among men 50 to 64 years of age, the rate is 15.6 cases per million doses [145].

Myocarditis/Pericarditis and mRNA COVID-19 Vaccines

Myocarditis and pericarditis have been reported more frequently than expected following receipt of either the Pfizer or Moderna mRNA COVID-19 vaccine, usually within seven days after the second dose of vaccine. The majority were male adolescents or young adult, and most cases were mild, responded well to treatment, and improved rapidly without evident long-term effects. Because a background level of seasonal myocarditis/pericarditis is associated with several common viral infections, at issue is whether and how many additional (excess) cases are precipitated by COVID vaccination. Following a nationwide vaccination program, a one-to-one comparison study with 800,000 subjects each in the vaccinated and control groups found that mRNA COVID-19 vaccine was associated with an excess risk of myocarditis (2.7 events per 100,000 persons) [146]. SARS-CoV-2 infection in the same time period was associated with a higher incidence of myocarditis (11 events per 100,000 persons). In a follow-up report, the estimated incidence of vaccine-associated myocarditis among males 16 to 29 years of age was 10 events per 100,000 vaccinees; among females 16 to 29 years of age, 0.3 events per 100,000 vaccinees; and among males 30 years of age of older, 2 events per 100,000 [153].

Data from a network of 40 healthcare systems (subserving 15 million people) found the risk of cardiac complications (myocarditis/pericarditis) was significantly higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination in all age groups evaluated. For example, among males 12 to 17 years of age, the incidence rate of myocarditis/pericarditis was 50 to 65 cases per 100,000 after infection, 2 to 3 cases per 100,000 after the first dose of vaccine, and 22 to 36 after the second dose; among males 18 to 29 years of age, the corresponding incidence rates (cases per 100,000) were 55 to 100 after infection, to -8 after the first and 7 to 15 after the second dose of vaccine. Among young children 5 to 11 years of age, the incidence of myocarditis/pericarditis was considerably lower. After infection, the rate was 13 to 18 cases per 100,000 among males and 5 to 11 cases per 100,000 among females; after COVID-19 vaccination, the rate was 0 to 4 cases per 100,000 among males and 0 cases among females [173]. These findings show that the risk of myocarditis/pericarditis in adolescent and young adult males is 5 to 8 times higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination.

On July 22, 2021, the ACIP reviewed updated benefit-risk analyses after Janssen and mRNA COVID-19 vaccination and concluded that the benefits of COVID-19 vaccination outweigh the risks for rare serious adverse events after COVID-19 vaccination [145]. In reaching this conclusion, the ACIP reviewed population-level considerations, including that COVID-19 cases were rising in the United States, the predominance of the highly transmissible Delta variant, and the importance of providing options for the type of COVID-19 vaccines offered in relation to epidemiologic considerations. The Department of Health and Human Services, American Academy of Pediatrics, American Heart Association, and other health professional organizations issued a joint statement concurring with the ACIP findings and recommended COVID-19 vaccination of all eligible persons [147].

DURATION OF IMMUNITY AND REINFECTION

More than two years into the COVID-19 pandemic, there is limited information on duration of immunity following SARS-CoV-2 infection and COVID-19 vaccination. Despite the scope of the pandemic and burgeoning number of COVID-19 cases, reports of reinfection were uncommon before the emergence of SARS-CoV-2 variants. Natural immunity to SARS-CoV-2 appears to be quite durable for protection against reinfection by the original infecting strain, but less robust or predictable for protection against reinfection by variant strains of the virus.

As with most viral infections, pathogen-specific IgG antibody assays in the weeks following onset of COVID-19 are useful for diagnostic purposes but not for measuring the durability of immunity provided by (unmeasured) neutralizing antibody and memory T-cell immune responses, which often persist for months to years. In a population-based study designed to assess durability of humoral immune responses to SARS-CoV-2, serum samples from 1,107 seropositive persons were collected up to four months after diagnosis of COVID-19. Antiviral Ig-antibody titers increased during the first two months and had not declined four months after infection [116]. In a longitudinal study of healthcare workers at the University of Oxford Hospitals undergoing periodic SARS-CoV-2 testing, the presence of antibodies in persons with previous asymptomatic or symptomatic COVID-19 substantially reduced the risk of reinfection [117]. Workers were offered nasopharyngeal SARS-CoV-2 PCR testing every two weeks and antibody testing at two-month intervals. Among 11,364 workers who were initially seronegative, 223 subsequently acquired SARS-CoV-2 infection, evidenced by a positive PCR. Among 1,265 workers who were seropositive, 2 subsequently developed an asymptomatic reinfection, evidenced by a positive PCR. During eight months surveillance, no symptomatic SARS-CoV-2 reinfections were detected among workers who had serologic evidence of prior SARS-CoV-2 infection [117].

Population-based studies also indicate that reinfection with SARS-CoV-2 is uncommon and occurs in less than 1% of individuals who have previously tested positive by SARS-CoV-2 PCR. Using a PCR-test data set from 4 million inhabitants of Denmark, researchers analyzed infection rates across separate surges of COVID-19 to estimate the degree of protection afforded by natural immunity against SARS-CoV-2 reinfection more than seven months later [118]. Among 11,068 persons who tested PCR-positive during the first COVID-19 surge (March to May 2020), 72 (0.65%) tested positive again during the second surge (September to December 2020). By comparison, the rate of infection among uninfected persons who became PCR-positive during the second surge was 3.27%. Thus, the estimate of protection against SARS-CoV-2 reinfection was 80.5%. However, protection against reinfection among persons older than 65 years of age was lower (47%). The authors note the limitations of this study, including absence of information about severity of infection and the possibility individuals infected during the first COVID-19 surge may have altered subsequent behavior affecting exposure risk. These estimates of protection do highlight the importance of administering SARS-CoV-2 vaccines to previously infected individuals, especially the elderly [118].

Durable protective immunity after SARS-CoV-2 infection or COVID-19 vaccination consists of a repertoire of immune responses referred to collectively as "immunological memory" [119]. Measurable components of immune memory include pathogen-specific antibody level, memory B cells, CD4+ T cells, and/or memory CD8+ T cells. Immune memory against SARS-CoV-2 provides the basis of protection against reinfection and determines the quality and duration of vaccine efficacy. An analysis of 254 blood samples from 188 COVID-19 cases, including some samples up to eight months after infection, found that substantial immune memory involving all four types of immune response was retained in 95% of subjects over the six- to eight-month period of observation [119]. Antibodies against SARS-CoV-2 spike and receptor binding domains declined over eight months, and memory B cell activity increased between one month and eight months after infection. Circulating antibody titers were not predictive of memory T-cell activity. The authors concluded that simple serologic tests for SARS-CoV-2 antibodies do not reflect the quality and durability of immune memory to the virus [119].

COVID-19 vaccines also produce durable cellular immunity against SARS-CoV-2 infection. Studies show persistence of memory B cells and strong CD4+ T cell immune responses at least six to eight months after mRNA COVID-19 vaccination [156]. Furthermore, vaccine-induced cellular immune responses impacting cell binding with SARS-CoV-2 variants are superior to infection-induced natural immunity. This may explain in part the epidemiologic evidence that COVID-19 vaccination provides greater protection against subsequent Delta variant COVID-19 than prior SARS-CoV-2 infection. An analysis of hospitalizations for COVID-19-like illness during January–September 2021 found the adjusted odds of laboratory-confirmed COVID-19 were five-fold higher among unvaccinated patients with documented previous SARS-CoV-2 infection than among mRNA COVID-19 vaccinated patients with no previous SARS-CoV-2 infection [157].

Natural immunity augmented by COVID-19 vaccination against SARS-CoV-2 may provide the strongest, most durable protection against subsequent COVID-19. In a retrospective cohort study, using data from national health registries subserving the entire population of Sweden, investigators analyzed the impact of natural immunity on risk of SARS-CoV-2 reinfection and COVID-19 hospitalization, and potential further benefit from COVID-19 vaccination (hybrid immunity). Natural immunity from SARS-CoV-2 infection was associated with a 95% lower risk of reinfection and 87% lower risk of COVID-19 hospitalization up to 20 months follow-up. One- and two-dose hybrid immunity was associated with a lower risk of SARS-CoV-2 reinfection than natural immunity up to nine months follow-up. One-dose hybrid immunity conferred a 94% lower risk of subsequent COVID-19 hospitalization than natural immunity alone, though differences in absolute numbers were small [174].

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

WHO DAILY SITUATION REPORT

Beginning in January 2020, and in association with travel to and from China, cases of confirmed SARS-CoV-2 infection began to be reported from multiple countries around the world, including the United States. In the initial weeks of the outbreak, cases reported in countries outside China were occurring primarily in returning travelers who had visited Wuhan City or nearby locales in central China. Soon, however, the extent of person-to-person transmission unrelated to travel became increasingly clear from contact tracing and rapid community spread. By November 2021, 224 countries and territories around the world had been impacted by the COVID-19 pandemic, SARS-CoV-2 infections were on the increase in 53 countries, and the global case report total exceeded 250 million, with more than 5 million deaths [120].

The WHO monitors developments and tracks the progress of the epidemic, providing daily Situation Reports at its website [8]. In an effort to curb the spread of infection, the WHO and national agencies have developed public health measures and clinical criteria to guide the evaluation and management of persons with significant exposure and/or compatible illness.

Advice to the Public

The WHO has posted standard recommendations for the general public designed to reduce exposure to, and transmission of SARS-CoV-2 [11]. In addition, the CDC has developed guidelines for the public on how to best protect themselves and others [24]:

- Wash hands often with soap and water for at least 20 seconds, especially after having been in a public place or after coughing, sneezing, or blowing your nose. If soap and water are not readily available, a hand sanitizer that contains at least 60% alcohol may be used.

- Avoid touching eyes, nose, and mouth with unwashed hands.

- Avoid close contact with people who are sick, and stay home as much as possible

- Put distance (at least 6 feet) between yourself and other people.

- Cover your mouth and nose with a cloth face cover when around others (i.e., in public). Note: This recommendation does not apply to children younger than 2 years of age, persons with breathing difficulties, or those who are unable to remove the mask unassisted.

- Cover coughs and sneezes.

- Clean and disinfect frequently touched surfaces daily, including tables, doorknobs, light switches, countertops, handles, desks, phones, keyboards, toilets, faucets, and sinks.

WHO and CDC guidance on the use of a face covering, whether by prefabricated mask or fashioned from cloth, is predicated on the growing evidence that asymptomatic and presymptomatic individuals infected with SARS-CoV-2 can transmit the virus to others in close proximity [54]. Therefore, anyone out in public should consider that he or she could, unwittingly, be an agent of transmission to others. The simple act of coughing, sneezing, talking, singing, or forceful breathing can release virus-laden droplets and respiratory particles into the air and onto nearby environmental surfaces. Multi-layered cloth masks block 50% to 70% of fine droplets and particles and limit the forward spread of those not captured [104]. Although the primary function of a face covering is to prevent inadvertent transmission to others ("source control"), it may also provide a degree of barrier protection for the one wearing it. The CDC recommends wearing cloth face coverings in public settings in which other social distancing measures are difficult to maintain (e.g., grocery stores, pharmacies), especially in areas experiencing significant community-based transmission. Detailed guidance on the construction, proper usage, and cleaning of cloth face coverings is provided on the CDC website [12].

As public health restrictions are lifted, professional and social interactions in the community present more opportunities for spread of SARS-CoV-2. The risk of transmission varies in proportion to how closely a person interacts with an infected individual and for how long. In a scientific brief updated November 20, 2020, the CDC summarized the experimental and epidemiologic data supporting community masking to reduce the spread of SARS-CoV-2 and concluded that the prevention benefit of masking is derived from the combination of source control and personal protection for the mask wearer [104]. Studies confirm that wearing face masks or double-layer cloth face coverings reduces the risk of transmission for medical personnel, patients, and the general public when in social and community settings, especially when social distancing is not possible [66,67]. A CDC report of a contact investigation involving a hair salon where universal face covering was practiced is illustrative. Two stylists with COVID-19 symptoms had worked closely with 139 clients over an eight-day period before learning of the COVID-19 diagnosis, yet there was no evidence of secondary transmission [67]. None of the clients developed COVID-19 symptoms and of 67 individuals tested for SARS-CoV-2, all were negative. Both stylists and 98% of of the clients interviewed had followed posted company policy and city ordinance requiring face coverings by employees and clients in businesses providing personal care services.

The CDC issued an order, effective February 1, 2021, requiring passengers to wear a mask on all public conveyances (e.g., airplanes, ships, ferries, subways, buses, taxis, ride-shares) when traveling into, within, or out of the United States [121]. Masks are required upon entering or while on the premises of a transportation hub and when waiting, boarding, and disembarking from public conveyances. People must wear masks that completely cover the mouth and nose.

Although highly effective in preventing severe illness, hospitalization, and death, COVID-19 vaccines are not 100% effective at preventing SARS-CoV-2 breakthrough infection. Most breakthrough infections in immunized individuals are asymptomatic or mild, having little public health import unless local transmission rates are high. In order to reduce such risks, the CDC website provides updated public health recommendations for vaccinated people [131]. As of October 2021, the CDC recommends fully vaccinated persons wear a mask indoors in public if local SARS-CoV-2 transmission is sustained or high, and get tested for COVID-19 if experiencing symptoms or within five to seven days after exposure to someone with known or suspected COVID-19. Vaccinated people may resume domestic and international travel and refrain from testing before and after travel and from self-quarantine after travel [131].

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

The rapidity with which the outbreak spread locally in China provided early evidence that human-to-human transmission from close contact with persons having mild, nonspecific symptoms is the primary means by which SARS-CoV-2 spreads within the community. Epidemiologic studies suggest that infected droplet nuclei expelled during coughing, sneezing, loud talking, or singing is the primary mode of transmission. Sustained close personal contact (being within 6 feet for at least 15 minutes) with an infected person increases the risk of transmission. Limiting the time and lengthening the distance reduces the risk [87]. Recovery of replication-competent virus from the upper respiratory tract begins to decline after onset of symptoms. For patients with mild-to-moderate COVID-19, replication-competent virus has not been recovered after 10 days following symptom onset [88]. Recovery of replication-competent virus between 10 and 20 days after symptom onset has been documented in some patients with severe COVID-19.

Unlike the 2003 SARS-CoV, whereby replication occurred mostly in the lower respiratory tract and virus shedding is temporally associated with symptom onset, SARS-CoV-2 is characterized by high levels of replication and virus shedding was the upper respiratory tract, even during the pre-symptomatic phase of infection [38]. Newly infected individuals are most infectious one to two days before and for a few days after the onset of symptoms. This means that persons with asymptomatic and pre-symptomatic SARS-CoV-2 infection may have high viral loads in nasopharyngeal secretions that render them efficient vectors of person-to-person transmission. Therefore, a strategy for prevention that relies solely on symptom-based detection and isolation of COVID-19 cases is likely to have limited effectiveness. In a study of skilled nursing facility residents infected with SARS-CoV-2 from a healthcare worker, half were asymptomatic or pre-symptomatic at the time of contact tracing evaluation and testing [15].

These considerations have important public health implications. Close personal contact implies touching and the sharing of common utensils; it is also defined by a proximity of 6–8 feet—the distance respiratory droplets travel after coughing or sneezing. As noted, the risk of infection is greatest for persons who have prolonged, unprotected close contact (i.e., within 6 feet for 15 minutes or longer) with someone recently diagnosed with SARS-CoV-2 infection, regardless of whether the patient has symptoms [89]. A CDC contact investigation demonstrated that even brief periods of unprotected close contact, if repeated and cumulative (exceeding 15 minutes) over the course of a day, significantly increases the risk [92]. This highlights the importance of avoiding congregate settings (e.g., assisted living facilities, college dormitories, family gatherings, indoor dining and bars) because of the increased likelihood of repetitive or sustained close contact. People can reduce the community spread of SARS-CoV-2 by practicing social distancing, wearing face coverings in public, and washing their hands.

On October 21, 2020, the CDC definition of "close contact" was revised for purposes of contact investigation [59]. Close contact describes someone who was within 6 feet of an infected person for a cumulative total of 15 minutes within a 24-hour period starting from two days before illness onset (or, for asymptomatic patients, two days prior to test specimen collection) until the time the patient is isolated. The cumulative 15-minute exposure refers to any combination of individual exposures (e.g., three 5-minute exposures) over a 24-hour period. Factors to consider when assessing close contact include proximity, duration of exposure, whether the individual has symptoms (as the period around onset of symptoms is associated with highest levels of viral shedding), whether the infected person was likely to generate aerosols (e.g., was coughing, shouting, singing), and other environmental factors (e.g., crowding, adequacy of ventilation, whether exposure was indoors or out of doors) [59].

Several emerging reports and epidemiologic studies indicate that children younger than 10 years of age may play only a small role in transmission of SARS-CoV-2. An investigation of 36 childhood COVID-19 cases in China found that 89% acquired the infection from exposure to an older household family member [50]. A population-based surveillance study in Iceland, drawing from a nationwide random sample, found that of 848 children younger than 10 years of age, none tested positive for SARS-CoV-2, whereas 100 of 12,232 (0.8%) adolescents and adults tested positive [51]. Contact tracing in relation to a cluster of COVID-19 among family and friends in France revealed that despite several days of potential exposure to a symptomatic pediatric case, there was no evidence of secondary transmission among 172 school contacts [52]. One possible explanation for these observations is the finding that gene expression of ACE2 in nasal epithelium is age-dependent; it is significantly lower in young children and increases as one develops into adulthood [53]. Lower ACE2 expression in children relative to adults could impact transmission dynamics and may help explain why COVID-19 is less prevalent in children.

Assumptions about childhood transmission of COVID-19 have been tempered somewhat since emergence of the highly transmissible SARS-CoV-2 Delta and Omicron variants in 2021. Compared with original strain infection, nasal and pharyngeal virus shedding is significantly higher; persons with Delta or Omicron infection are two and four times more infectious, respectively. Consequently, transmission now occurs more readily among children and from child to adult. Because most children were unvaccinated, symptomatic childhood infection has increased and with it the need for hospitalization. COVID-19-associated hospitalization rates among children and adolescents in the United States increased five-fold from June 2021 to mid-August 2021 [148]. Hospitalization rates were 10 times higher among unvaccinated than among vaccinated adolescents.

The stability of SARS-CoV-2 on environmental surfaces has been studied in an effort to assess whether surface contamination (fomites) could play a role in virus transmission. After application of aerosols containing a standard dose of SARS-CoV-2, viable virus was detected up to 72 hours on plastic and stainless steel, though the virus titer was greatly reduced; on cardboard, no viable SARS-CoV-2 was measured after 24 hours [19]. These data should be interpreted with caution, as it is unclear to what extent environmental detection of virus in much reduced titer at a given interval, experimentally, can be equated with actual risk of transmission from common environmental surfaces. In an April 2021 scientific brief, a CDC analysis of quantitative microbial risk assessment studies concluded the risk of SARS-CoV-2 infection via the fomite transmission route is less than 1 in 10,000, which means that each contact with a contaminated surface has less than a 1 in 10,000 chance of causing an infection [122].

The public health strategy of mitigation (preventing spread within communities) has become paramount in order to decisively limit spread and blunt the COVID-19 epidemic curve, pending development and distribution of effective vaccines. These measures include the following: suspension or cancellation of events having large public gatherings, such as cinema, theatre, concerts, and collegiate and professional sports competition; closure of schools and cancellation of classes at colleges and universities; the practice of social distancing in smaller venues such as restaurants and churches; the wearing of masks or cloth face coverings at indoor commercial venues and social gatherings. By slowing the degree and pace of virus transmission, effective mitigation helps to protect those most vulnerable and to ensure that the clinical case load does not overwhelm local hospital and critical care resources.

VARIANT STRAINS OF SARS-COV-2

In late 2020, variant strains of SARS-CoV-2 began to appear in countries with high COVID-19 case rates. Widespread circulation of SARS-CoV-2 combined with spontaneous mutations in the genome increases the probability that mutations affecting transmissibility will lead to emergence of a variant strain. As indicated, the CDC’s national genomic surveillance program identifies SARS-CoV-2 variants and tracks the proportion and distribution of COVID-19 cases attributable to variants [123,124]. SARS-CoV-2 variants circulating in the United States are characterized as variants of concern (VOC) or variants of interest (VOI). In spring 2021, three VOCs accounted for 40% of COVID-19 cases in the United States: B.1.1.7, B.1.351, P.1, and California (B.1.351, 427/429) [123]. The defining characteristics of VOC include increased transmission (B.1.1.7), increased disease severity (B.1.1.7), and decreased neutralization by monoclonal antibody therapeutics (P.1, B.1.351, 427/429). By June/July 2021, these variants had been superseded by a single highly transmissible VOC: B.1.617.2 (Delta) variant [132].

Delta Variant

Compared with the original SARS-CoV-2 strain, Delta variant is more infectious, spreads faster, and causes more severe illness in unvaccinated people than previous variants [132]. First detected in December 2020, the Delta variant spread rapidly to 43 countries across six continents. In spring 2021, the COVID-19 surge in the United States had receded to the lowest point of the pandemic; the seven-day moving average of daily new cases was 12,000. By mid-July, the daily average of new cases had again surged to more than 60,000, of which 98% were caused by the SARS-CoV-2 Delta variant [132].

During the period of Delta predominance, breakthrough infection (usually asymptomatic or mild) occurred in vaccinated persons, but the majority of hospitalizations and deaths caused by Delta variant COVID-19 were in unvaccinated people. During the summer COVID-19 surge in Los Angeles County, unvaccinated individuals were five times more likely to acquire Delta variant infection and 29 times more likely to be hospitalized than persons who had been fully vaccinated [158]. The principal risk of secondary household and community transmission was also attributable to unvaccinated people, who were much more likely to become infected and thus shed the virus. Fully vaccinated individuals with breakthrough Delta infection did spread virus to others, but to a lesser degree and for a shorter period of time [132]. An investigation of virologic characteristics among healthcare workers with Delta variant breakthrough COVID-19 found that illness was uniformly mild; shedding of virus from the nose and throat was either unmeasurable or rapidly dissipated within one to three days [115].

Omicron Variant

In mid-November 2021, a new SARS-CoV-2 strain (the Omicron variant) emerged in South Africa among children, college students, and international travelers. Within 10 to 14 days’ time, cases of Omicron variant COVID-19 were identified in 50 countries, indicating a high level of transmission. Early clinical reports indicated that Omicron-associated COVID is mild (characterized mainly by nasal congestion, cough, and fatigue). with rates of hospitalization less than half that seen with the Delta variant. Cases of SARS-CoV-2 Omicron were first reported in the United States in December; by end of that month, Omicron had replaced Delta as the predominant variant and principal cause of COVID-19 in the United States [123,124].

Omicron is unique because of the number of genomic mutations and substitutions identified--50 overall and more than 30 in the spike protein, some of which are known to be associated with reduced susceptibility to monoclonal antibody therapeutics or reduced neutralization by convalescent and vaccinee sera [123]. Omicron is highly transmissible and spreads two to four times more rapidly than the original SARS-CoV-2 and Delta variant. COVID-19 cases tend to be less severe, though this can be misleading, as many patients are children or vaccinated adults, groups expected to experience mild illness. Health providers should expect the Omicron COVID-19 clinical profile to be similar to that associated with previous strains; the risk of serious illness is lower but still significant for unvaccinated persons, especially the elderly and those with underlying health conditions.

It was expected that the Omicron variant might evade immune protection gained from prior SARS-CoV-2 infection or COVID-19 vaccination. There is a three- to eightfold increased risk of Omicron reinfection among people who have had prior COVID-19. Studies show the initial two-dose mRNA vaccines (Pfizer, Moderna) lose their effectiveness against Omicron infection after four to six months (though protection against severe illness and hospitalization is largely preserved). Evasion of vaccine immunity is reversed following a booster dose in people who previously received the primary COVID-19 vaccine series; an interval-appropriate third (booster) dose increases neutralizing antibody levels 25- to 60-fold, reduces risk of breakthrough infection by 75%, and provides more than 90% protection against severe illness and hospitalization.

Rapid, wide-spread circulation has led to emergence of Omicron subvariants, one of which (BA.2) is more transmissible than the parent variant and slowly becoming the predominant version. Apart from heightened transmissibility, severity of illness appears to be unchanged and the benefit derived from previous natural and boosted vaccine immunity appears to be as robust as that against the parent variant.

The emergence of Delta and Omicron demonstrates that SARS-CoV-2 variants can impact transmission, disease severity, risk of reinfection, and vaccine efficacy. At issue is the extent to which adaptive immunity (CD4+ and CD8+ T cell responses) in COVID-19 convalescent patients and vaccinees recognize (target) conserved epitopes on SARS-CoV-2 variants of concern. Fortunately, studies to date have demonstrated that SARS-CoV-2 T cell epitopes are not appreciably affected by the mutations found in newly described variants [125,126]. Overall, CD4+ and CD8+ T cell responses in convalescing COVID-19 patients or COVID-19 mRNA vaccinees remain effective against VOC presently circulating in the United States, including Delta and Omicron variants.

CDC MONITORING AND GUIDANCE FOR HEALTHCARE PROFESSIONALS

As of May 2022, more than 82 million cases and more than 1 million deaths from COVID-19 have been reported in the United States and territories [124]. Ethnic populations appear to be disproportionately affected. The CDC monitors COVID-19 epidemiologic data and provides updated clinical guidance for healthcare providers, laboratories, health facilities, and public health professionals [124]. Included are recommendations for the evaluation of persons/patients under investigation, laboratory specimen transport, and protection of healthcare workers. Recommendations for patient assessment and care in hospitals and other healthcare facilities emphasize the importance of strict adherence to patient isolation and barrier precautions, including the proper use of personal protective equipment (PPE).

Selected materials from the CDC website, including recommendations for travelers, interim guidance for healthcare professionals, infection control, and healthcare worker safety, are reproduced in the following sections. Please note that language and/or cultural barriers may impede assessment and education on the topic, and interpreters and translated materials are recommended, when appropriate.

COVID-19 Data Tracker

The CDC website maintains a COVID-19 Data Tracker and Weekly Review [124]. This site tracks the number of reported cases of SARS-COV-2 infection in the United States, prevalence of variant strains, rates of COVID-19 hospitalization, and vaccination status of the population. As of May 15, 2022, the seven-day moving average of daily new cases was 90,337 (2.4% increase). The CDC estimates the Omicron lineage (e.g., BA.1, BA.2) accounted for 100% of new cases. The seven-day daily average of new hospitalizations was 2,698 (8.3% increase). The seven-day moving average of daily new deaths remained stable over the prior week. Overall, about 581.8 million vaccine doses have been administered and about 221 million people (66.7% of the population) is fully vaccinated. Vaccination trends by age group show that 96.9% of people 65 or older have received at least one dose and 84.9% are fully vaccinated. About 102.3 million people (46.4% of the eligible population) have received an additional or booster dose of COVID-19 vaccine [124].

The CDC Data Tracker also monitors COVID-19 vaccine effectiveness. COVID-19 case rates and deaths among fully vaccinated and unvaccinated people are reported to the CDC from multiple jurisdictions. During the recent Omicron surge, adults who were vaccinated and boosted were 7 times less likely to be hospitalized and 21 times less likely to die from COVID-19 compared with those who were unvaccinated [124].

CDC Guidance on Travel During COVID-19

The CDC provides updated information and guidance on domestic and international travel based on SARS-CoV-2 vaccination status [13]. The CDC recommends delaying travel until fully vaccinated. Both vaccinated and unvaccinated individuals who must travel should observe the following precautions [13]:

- Avoid contact with sick people.

- Avoid touching your eyes, nose, or mouth with unwashed hands.

- Wash hands often with soap and water for at least 20 seconds or use an alcohol-based hand sanitizer that contains at least 60% to 85% alcohol.

- Avoid traveling if you are sick.

- Wear a cloth face covering in terminals and other public venues.

- Cover coughs and sneezes.

- Pick up food at drive-throughs, curbside restaurant service, or stores.

Unvaccinated persons should get a SARS-CoV-2 nasopharyngeal swab test one to three days before the trip, repeat the viral test three to five days after travel and self-quarantine for seven days after travel (or 10 days if testing is omitted). Returning travelers from any destination are encouraged to observe standard precautions, monitor health, and follow state, territorial, tribal, and local recommendations or requirements after travel [13].

As of May 2022, the CDC recommends that persons who are up to date with COVID-19 vaccination can travel with low risk to themselves and others [13]. Up-to-date COVID-19 vaccination status is defined as having received the initial primary series and an interval-appropriate booster dose. Such persons can travel safely within the United States without the need for pre-travel testing or post-travel self-quarantine if they continue to take COVID-19 precautions while traveling.

Recommended Criteria to Guide Evaluation of Patients Under Investigation for COVID-19

CDC guidance specifies who should be tested for COVID-19 and encourages clinicians to use clinical judgment in determining whether a patient with signs and symptoms compatible with COVID-19 should be tested [14]. Symptoms to be considered include fever, chills, cough, sore throat, muscle aches, shortness of breath, new loss of taste or smell, and vomiting or diarrhea. As noted, SARS-CoV-2 can cause asymptomatic, pre-symptomatic, and minimally symptomatic infection, leading to virus shedding that may result in transmission to others who are particularly vulnerable to severe disease and death. Special attention should be paid to older adults and to patients with underlying conditions or immunosuppressed states. Even mild signs and symptoms of COVID-19 should be evaluated among potentially exposed healthcare personnel because of their extensive contact with vulnerable patients in healthcare settings.

The CDC has established priorities for COVID-19 diagnostic testing [14]. High priority for testing applies to hospitalized patients with compatible clinical features, healthcare facility workers and those who work in congregate living settings with symptoms, and residents in long-term care facilities (including prisons and shelters) with symptoms. Priority designation for testing applies to any person in the community with symptoms of potential COVID-19. In addition, persons without symptoms may be prioritized by health departments or clinicians for reasons such as public health monitoring, sentinel surveillance, or screening purposes.

Clinicians should work with their local and state health departments to coordinate testing through public health laboratories or work with commercial or clinical laboratories using SARS-CoV-2 diagnostic tests granted an Emergency Use Authorization by the FDA. Patients should be evaluated and discussed with public health departments on a case-by-case basis if their clinical presentation or exposure history is equivocal.

Other considerations that may guide testing include epidemiologic factors (e.g., close contact with an individual who in the past 14 days has tested positive for SARS-CoV-2) and the occurrence of local transmission or a cluster of COVID-19 within a specific community setting (e.g., nursing home, manufacturing facility) [14]. Close contact is defined as one of the following:

- Being within approximately 6 feet (2 meters), or within the room or care area, of a novel coronavirus case for a prolonged period of time while not wearing recommended personal protective equipment or PPE (e.g., gowns, gloves, certified disposable N95 respirator, eye protection); close contact can include caring for, living with, visiting, or sharing a healthcare waiting area or room with a novel coronavirus case.

- Having direct contact with infectious secretions of a novel coronavirus case (e.g., being coughed on) while not wearing recommended personal protective equipment.

Any patient with fever and severe acute lower respiratory illness (e.g., pneumonia, ARDS) requiring hospitalization and without alternative explanatory diagnosis (e.g., influenza) should be evaluated for COVID-19, even if no source of exposure has been identified [14].

A symptomatic patient should be provided a surgical mask and placed on respiratory isolation, preferably in an airborne isolation negative pressure room. Caregivers should observe enhanced precautions (i.e., wear gloves, gown, eye protection device [other than prescription eye glasses], and N95 respirator). For information on the management of patients with COVID-19, see https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html.

Diagnostic Testing

The CDC recommends that healthcare providers should immediately notify both infection control personnel at their healthcare facility and their local or state health department in the event of a newly diagnosed or suspected case of COVID-19.

Confirmation of COVID-19 is performed using the RT-PCR assay for SARS-CoV-2 on respiratory specimens (which can include nasopharyngeal or oropharyngeal aspirates or washes, nasopharyngeal or oropharyngeal swabs, bronchoalveolar lavage, tracheal aspirates, or sputum) and serum. The FDA has worked to expedite the availability of tests through emergency authorization of commercial laboratories that have developed SARS-CoV-2 testing capability. Information on specimen collection, handling, and storage is available at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html. After initial confirmation of COVID-19, additional testing of clinical specimens can help inform clinical management, including discharge planning. Additional guidance for collection, handling, and testing of clinical specimens is available at the CDC website [12].

Infection with both SARS-CoV-2 and with other respiratory viruses has been reported, and detection of another respiratory pathogen does not rule out COVID-19 [15].

Interim Clinical Guidance for Management of Patients with Confirmed COVID-19

Interim clinical guidance and additional resources for clinicians caring for patients with COVID-19 is provided and updated at the CDC and NIH websites, selected aspects of which are reproduced in this section [15].

As noted, the clinical presentation of COVID-19 can range from asymptomatic to critically ill, and older patients and those with comorbidities are considered at greater risk for more severe disease. Among patients who developed severe disease, the median time to dyspnea was 5 to 8 days, the median time to ARDS was 8 to 12 days, and the median time to ICU admission was 10 to 12 days. Clinicians should be aware of the potential for some patients to rapidly deteriorate one week after illness onset. Among all hospitalized patients, 26% to 32% of patients were admitted to the ICU [15]. Only 3% to 17% of all patients with COVID-19 develop ARDS, but this increases to 20% to 42% for hospitalized patients and 67% to 85% for patients admitted to the ICU. Mortality among patients admitted to the ICU ranges from 39% to 72%, depending on the study [15]. The median length of hospitalization among survivors was 10 to 13 days.

Clinical management entails prompt implementation of recommended infection prevention and control measures and supportive management of complications, including advanced organ support if indicated [15]. Healthcare personnel should care for patients in an airborne infection isolation room. Isolation Precautions should be used when caring for the patient. For more detailed recommendations, see the CDC's Interim Infection Prevention and Control Recommendations for Patients with Suspected or Confirmed Coronavirus Disease 2019 (COVID-19) in Healthcare Settings at https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html. The NIH and the Infectious Diseases Society of America provide updated COVID-19 management guidelines, including specific recommendations for the use of remdesivir and dexamethasone in hospitalized patients [10,57].

Management of COVID-19 in the Ambulatory Care Setting

Patients with a mild clinical presentation may not initially require hospitalization [15]. However, clinical signs and symptoms may worsen with progression to lower respiratory tract disease in the second week of illness; all patients should be monitored closely. As noted, possible risk factors for progressing to severe illness may include, but are not limited to, older age, obesity (body mass index >35), and underlying chronic comorbidities (e.g., lung disease, cancer, heart failure, cerebrovascular disease, renal disease, liver disease, diabetes, immunocompromising conditions, pregnancy).

Approximately 80% of patients with symptomatic SARS-CoV-2 infection have mild COVID-19 (having no viral pneumonia or hypoxemia) and do not require medical intervention or hospitalization [57]. Such patients can be managed in the ambulatory setting. Patients with moderate COVID-19 (having signs of viral pneumonia but without hypoxemia) or severe COVID-19 (those having dyspnea, hypoxemia, or lung infiltrates) require in-person evaluation and ongoing observation for progression of pulmonary disease. It is important to identify those patients at risk for progression to severe disease and therefore candidates for early therapeutic intervention.

Several therapeutic options are now available for nonhospitalized patients with mild COVID-19 who are at risk for disease progression, including anti-SARS-CoV-2 monoclonal antibody, parenteral remdesivir, and oral anti-SARS-CoV-2 agents. Factors to consider in selecting the best treatment option for a given patient are clinical efficacy and availability of the treatment option, feasibility of parenteral administration (for remdesivir or monoclonal antibody), potential drug-drug interactions (particularly those associated with use of nirmatrelvir-ritonavir), and the local prevalence of SARS-CoV-2 VOCs [57]. As of May 2022, Omicron is the predominant SARS-CoV-2 variant and sotrovimab is the only monoclonal antibody product with acceptable activity against this variant. Administration of remdesivir requires three consecutive days of intravenous infusion. Selection of nirmatrelvir-ritonavir necessitates reviewing the patient’s concurrent medications and supplements to evaluate potential drug-drug interaction. Molnupiravir, which has a lower efficacy than the other treatment options, should only be used when other options are not available [57].

The CDC advises that the decision to monitor a patient in the inpatient or outpatient setting should be made on a case-by-case basis. Important considerations are the patient's clinical status, reliability of clinical monitoring, and need and options for home isolation to reduce risk of secondary transmission. For more information, see the CDC's Criteria to Guide Evaluation of Patients Under Investigation (PUI) for COVID-19 at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-criteria.html.

The CDC recommends that for most patients with confirmed SARS-CoV-2 infection the decision to discontinue transmission-based precautions should be made using a symptom-based strategy [88]. In general, patients with mild-to-moderate COVID-19 who are not immunocompromised may discontinue isolation once five to seven days have passed since onset of illness, respiratory symptoms have improved, and at least 24 hours have passed since resolution of fever (without the use of fever-reducing medications). For patients who were asymptomatic throughout their infection, precautions may be discontinued when at least five days have passed since the date of their first positive viral diagnostic test. Symptomatic and asymptomatic persons should continue to wear a well-fitted mask (for five additional days) when around others at home and in public. Additional considerations apply to patients who have sustained severe or critical illness and to those who are significantly immunocompromised [88].

9. OTHER AVAILABLE RESOURCES

CDC Information for Healthcare Professionals about Coronavirus (COVID-19)

https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html

CDC Information for Healthcare Professionals about COVID-19 Vaccination

https://www.cdc.gov/vaccines/covid-19/index.html

CDC Coronavirus Disease 2019 (COVID-19) Resources for Health Departments

https://www.cdc.gov/coronavirus/2019-ncov/php/index.html

World Health Organization Coronavirus Disease 2019 (COVID-19) Pandemic

https://www.who.int/emergencies/diseases/novel-coronavirus-2019

Johns Hopkins University and Medicine Coronavirus Resource Center

https://coronavirus.jhu.edu

NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines

https://www.covid19treatmentguidelines.nih.gov

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management

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