Study Points

Tuberculosis: An Update

Course #54554 -

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  1. Evidence of tuberculosis (TB) has been found in archeological digs dating back

    HISTORICAL BACKGROUND

    Evidence of TB dating back 6,500 years has been found in archaeologic digs. There are signs of the organism in the remains of mummified Egyptians and mention of it in ancient Chinese and Sanskrit written records. Hippocrates made the first clinically detailed description between 460 and 375 B.C.E. He called the disease "phthisis." During the 16th to the 19th centuries, TB was epidemic in Europe, causing the death of as many as one in four persons.

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  2. What country was the last in the world without TB infection?

    HISTORICAL BACKGROUND

    Starting in Northern Europe more than 500 years ago, the disease spread steadily across the continent but did not move into Russia until the late 1800s. New Guinea, the last place left uninfected, developed TB for the first time in the 1940s.

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  3. Within the body, TB organisms

    PATHOGENESIS, TRANSMISSION, AND RISK FACTORS

    Inhaled droplet nuclei containing tuberculous bacilli accumulate in the alveoli of the middle or lower lobes of the lung. They replicate and gain access to regional lymphatic channels, mediastinal lymph nodes, and thence to the thoracic duct and bloodstream, by which they are disseminated throughout the body. In response, the immune system targets these scattered vascular foci of infection, first with macrophages that surround and engulf the organisms, then lymphocytes, and finally a characteristic, focal inflammatory reaction termed a granuloma. A healthy granulomatous reaction terminates active infection, usually before the person is symptomatic, though it does not eliminate all bacilli. In time, the granuloma becomes encapsulated, effectively sealing off any remaining viable organisms. Encapsulated granulomas are termed tubercles. With age, they usually calcify, and larger ones are visible later by chest x-ray and tissue scans. Most healthy persons remain asymptomatic throughout life, the only evidence of prior infection being the calcified granuloma or positive skin test.

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  4. The average time of exposure to someone with active TB until acquisition of infection is about

    PATHOGENESIS, TRANSMISSION, AND RISK FACTORS

    However, compared with other infectious diseases, TB is not easy to contract. The average time of exposure until acquired infection is about two months. There have been reports of infection occurring in much less time. In one well-reported incident, a passenger on an airline was very ill with TB and coughed throughout the entire flight. Later, it was learned that fellow passengers on the plane had become infected with TB [7]. This is a rare occurrence, but it serves as a reminder to those in the healthcare professions. Caring for patients with TB can be a health risk, and proper isolation techniques for prevention must be employed when working with known or suspected cases of active infection [7].

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  5. During the asymptomatic phase, the only evidence of infection with TB may be

    STAGES AND TYPES OF TUBERCULOSIS

    If the immune process works well and stops the proliferation of bacilli after the initial primary infection, healing occurs in the lungs, in the lymph nodes, and in the metastatic sites of infection. Depending upon the patient's age and presence of other infections, a latent period ensues. This period lasts a lifetime in 85% to 90% of those infected. During this asymptomatic phase, the only evidence of infection with M. tuberculosis may be skin-test reactivity to tuberculin [22]. Some patients will have fine, linear scarring in the lung or a focal calcification (Ghon lesion) visible usually in a middle or lower lobe, a sign of the struggle between M. tuberculosis and the cellular immune response.

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  6. Recurrence of TB occurs in what percentage of those with latent TB infection?

    STAGES AND TYPES OF TUBERCULOSIS

    It is estimated that 13 million persons in the United States are infected with the latent or asymptomatic form of TB [57]. Recurrence of the active disease occurs in 10% to 15% of infected patients, half of whom reactivate within the first two years after the primary infection. The cause for the reactivation is usually a breakdown in the patient's immune system rather than reinfection from newly inhaled bacteria. In the United States, the highest frequency of recurrent or reactivation TB is in middle-aged and older adults and immigrants [3].

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  7. The usual cause for secondary or reactivation TB is a breakdown of the patient's

    STAGES AND TYPES OF TUBERCULOSIS

    It is estimated that 13 million persons in the United States are infected with the latent or asymptomatic form of TB [57]. Recurrence of the active disease occurs in 10% to 15% of infected patients, half of whom reactivate within the first two years after the primary infection. The cause for the reactivation is usually a breakdown in the patient's immune system rather than reinfection from newly inhaled bacteria. In the United States, the highest frequency of recurrent or reactivation TB is in middle-aged and older adults and immigrants [3].

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  8. The most common early symptoms of pulmonary TB are

    PULMONARY TUBERCULOSIS

    The early symptoms of active pulmonary TB are often so subtle as to be missed at first by most patients. Because of this, they will frequently have difficulty pinpointing exactly when their illness began. Some patients without obvious symptoms are diagnosed solely by a routine chest x-ray. For those who do have symptoms, the most common manifestations are gradual onset and progression of fever, malaise, cough, anorexia, and weight loss. The fever is one that is not so high as to be noticed or to be disquieting. When the fever breaks during the early morning hours, it is often associated with "night sweats." Weight loss may result from the infectious process itself, or it can be a sign that malnutrition and depletion of immune reserves preceded, and to some extent caused, the infection.

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  9. Groups considered high risk for contracting TB who should be screened include HIV- infected persons, injecting drug users, and

    PULMONARY TUBERCULOSIS

    HIGH-RISK GROUPS TO SCREEN FOR TUBERCULOSIS

    Persons with HIV infection
    Close contacts of persons with active, infectious TB
    Persons with conditions that weaken their immunity, thereby putting them at greater risk for contracting the disease (includes chronic renal failure, diabetes, prolonged steroid use, immunosuppressive therapy, malnutrition, gastrectomy)
    Injecting drug users
    Residents and employees of long-term care facilities, prisons, mental institutions, homeless shelters, or other group homes
    Emergency medical personnel
    Firefighters
    Persons spending time in countries with a high prevalence of TB
    Foreign-born persons originating from countries with a high prevalence of TB
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  10. Foreign-born persons originating from countries with high TB prevalence should be

    PULMONARY TUBERCULOSIS

    HIGH-RISK GROUPS TO SCREEN FOR TUBERCULOSIS

    Persons with HIV infection
    Close contacts of persons with active, infectious TB
    Persons with conditions that weaken their immunity, thereby putting them at greater risk for contracting the disease (includes chronic renal failure, diabetes, prolonged steroid use, immunosuppressive therapy, malnutrition, gastrectomy)
    Injecting drug users
    Residents and employees of long-term care facilities, prisons, mental institutions, homeless shelters, or other group homes
    Emergency medical personnel
    Firefighters
    Persons spending time in countries with a high prevalence of TB
    Foreign-born persons originating from countries with a high prevalence of TB
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  11. A negative reaction to a tuberculin skin test

    PULMONARY TUBERCULOSIS

    TUBERCULIN SKIN TEST

    When applying a skin test using the Mantoux technique, the injection should be made with a single-use, disposable tuberculin syringe. Draw up 0.1 mL of PPD, containing 5 tuberculin units (TU). The skin should be cleansed, as with any injection, and the skin stretched taut.
    Using a 26- or 27-gauge needle, the tuberculin syringe should be held close to the skin so the needle hub touches it as the needle is inserted into the skin, with the bevel up. This decreases the needle angle at the skin surface and helps to ensure the fluid is injected just beneath the surface of the skin into the dermis to form a wheal, taking care not to inject subcutaneously.
    The site of the injection should be circled with a pen and the location documented on the patient's medical record (in case the pen circle should wash off).
    Examine the site of the Mantoux intradermal injection within 48 to 72 hours of injection. Always use sufficient lighting to examine the area. Use a pen to outline the diameter of induration (firm-to-hard zone of elevation or swelling). The area of erythema (redness) is not measured, and erythema without induration is of no significance. Use a standard centimeter rule or a clear plastic ruler that has been marked with circles of various diameters. Place the ruler over the outlined induration to measure its diameter. The presence and degree of induration is an indicator of prior TB infection and, to some extent, the probability of current active TB.
    A reaction of <5 mm is negative. Reactions 10 mm are "positive." An intermediate reaction of 5–10 mm is suspicious for prior infection in high-risk persons.
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  12. When teaching a patient to produce a sputum specimen, instruct him or her to

    PULMONARY TUBERCULOSIS

    The optimal time to collect a specimen is early morning, after the patient has had nothing by mouth for about eight hours. The mouth should be rinsed with water to reduce contamination of the sample with the normal flora of the mouth, but the teeth should not be brushed prior to the collection.

    Patients are provided a sterile container with a screw-top lid. They should avoid putting the rim of the jar inside their lips, but rather hold it below their bottom lip. Specimens should not be saliva or nasopharyngeal secretions, but should come from the lungs after a deep cough. A sample of 5–10 cc (1–2 teaspoons) of sputum is adequate. Patients should be instructed to notify the practitioner as soon as the sample has been obtained so it can be sent to the laboratory promptly.

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  13. Nucleic acid amplification tests (NAATs) for the diagnosis of TB

    PULMONARY TUBERCULOSIS

    There are two U.S. Food and Drug Administration (FDA) approved, commercially available nucleic acid amplification tests (NAATs) for use in confirming M. tuberculosis in procured specimens [71]. The Xpert MTB/RIF Assay, which is able to detect the presence of M. tuberculosis organisms as well as resistance to rifampin, is an automated, cartridge-based system (GeneXpert platform) that requires a sputum sample [55]. Results are available within two hours. The second approved probe is the amplified M. tuberculosis direct (Hologic Amplified MTD) test, which uses transcription-mediated amplification in order to identify and magnify the RNA target. Results are generally available within three to four hours. This test is approved for the detection of tuberculosis in both smear-positive and smear-negative cultures [26]. Non-FDA approved NAATs (often called "in-house" tests) may be used to diagnose TB and to test for drug-resistant TB [46,58]. The Xpert MTB/RIF Ultra and the Xpert MTB/XDR tests are two examples, the latter of which is a drug susceptibility test that can identify resistance to isoniazid, fluoroquinolones, second-line injectable drugs (e.g., amikacin, capreomycin, kanamycin), and ethionamide [72].

    These tests are able to differentiate the DNA of different species of M. tuberculosis, also called DNA fingerprinting or genotyping. Because most strains of bacteria share patterns, it has been difficult to follow the person-to-person transmission of certain strains. Using genotyping, researchers have shown that each strain has a distinct DNA fingerprint and that all samples sharing the same DNA fingerprint were isolated from people who live together. This will help track the path of transmission and aid public health researchers to pinpoint patterns of infection, which in turn helps to plan prevention programs that target the areas of heightened infection rates.

    A task force supported by the CDC and pulmonary/infectious disease subspecialty societies recommends that a NAAT should be performed on at least one respiratory specimen from each patient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established and for whom the test result would alter case management or TB control activities [46].

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  14. The most common site for extrapulmonary TB is the

    EXTRAPULMONARY TUBERCULOSIS

    The kidney is the most common site for extrapulmonary TB. From there, the bacilli spread to the bladder and, in men, to the prostate, seminal vesicles, and epididymis. Often, the first sign of the infection is an enlarging scrotal mass. Pyelography will then often reveal a cavitary lesion of the renal parenchyma and irregularities of the ureters. Diagnosis is easily confirmed by urine smear and culture.

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  15. Miliary tuberculosis refers to an infection affecting the

    EXTRAPULMONARY TUBERCULOSIS

    Under conditions of poor immune function or trauma, previously quiescent TB foci may destabilize, releasing viable bacilli into the bloodstream. Unchecked, this leads to a sustained, active systemic infection with small metastatic lesions throughout the body. Although not immediately evident on chest x-ray, eventually the films will show multitudes of small nodules spread throughout both lungs, having the appearance of millet seeds. Prominent symptoms include chronic fever, night sweats, weakness, malaise, weight loss, and dyspnea. Bone marrow and liver biopsies are often taken to complete the diagnosis.

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  16. Two first-line drugs used in the treatment of drug-susceptible TB include

    TREATMENT

    TREATMENT OF DRUG-SUSCEPTIBLE TUBERCULOSIS IN ADULTS

    DrugDaily Dose (Adult)Adverse/Toxic Reactions
    First-Line Drugs
    Isoniazid5 mg/kg PO/IM (up to 300 mg)Hepatotoxicity, hepatitis, peripheral neuropathy, hypersensitivity, flu-like symptoms
    Rifampin10 mg/kg PO/IV (up to 600 mg)Orange discoloration of urine and other secretions, nausea, vomiting, hepatitis, hepatotoxicity, fever, purpura
    Rifabutin5 mg/kg PO (up to 300 mg)Rash, GI disturbance, neutropenia Not approved by FDA for treatment of TB
    Rifapentine10–20 mg/kgRed-orange stain on body fluids, hyperuricemia, abnormal liver function tests
    Ethambutol800 mg PO (40–55 kg), 1,200 mg PO (56–75 kg), or 1,600 mg PO (76–90 kg)Optic neuritis, decreased visual acuity, color blindness, skin rash
    Pyrazinamide1,000 mg PO (40–55 kg), 1,500 mg PO (56–75 kg), or 2,000 mg PO (76–90 kg)Hepatotoxicity, hyperuricemia, skin rash, arthralgias, GI irritation
    Second-Line Drugs
    Streptomycin15 mg/kg IM/IVOtotoxicity, nephrotoxicity, hypokalemia
    Ethionamide15–20 mg/kg PO (usually 250–500 mg once or twice daily)GI disturbance, hepatotoxicity, depression, drowsiness, hypothyroidism, metallic taste
    Para-aminosalicylic acid8–12 g PO (typically 4,000 mg in two to three divided doses)GI disturbance, sodium load, hepatotoxicity
    Amikacin/kanamycin15 mg/kg IM/IV (up to 1 g) or 15 mg/kg dose three times per week for decreased renal functionAuditory and renal toxicity, hypokalemia, vestibular toxicity Not approved by FDA for treatment of TB
    Cycloserine
    10–15 mg/kg PO (usually 250–500
    mg once or twice daily)
    Psychosis, personality changes, rash, impaired coordination, convulsions, depression
    Capreomycin15 mg/kg IM/IVAuditory and renal toxicity, vestibular toxicity, hypokalemia
    Moxifloxacin400 mg daily PO/IV
    Nausea, diarrhea
    Not approved by FDA for treatment of TB
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  17. Chemoprophylaxis is recommended for all of the following groups of people with a positive tuberculin test of 6 mm, EXCEPT:

    CHEMOPROPHYLAXIS FOR TUBERCULOSIS

    Preventive therapy is recommended for the all persons, regardless of age, with a positive TB blood test (IGRA) [57]. Persons in the following risk groups should be given high priority for preventive therapy if their reaction to the tuberculin skin test result is 5 mm or greater [57]:

    • Persons with HIV infection

    • Close contacts of a TB case

    • Patients who have had organ transplants and other immunosuppressed patients (receiving the equivalent of ≥15 mg/day of prednisone for at least one month)

    • Persons with fibrotic changes on chest radiograph consistent with old TB disease

    Persons in the following risk groups should be given priority for preventive therapy if their reaction to the tuberculin test is 10 mm or greater [57]:

    • Recent arrivals to the United States (within the last five years) from high-prevalence countries

    • Persons who inject illicit drugs

    • Residents and employees of high-risk congregate settings

    • Mycobacteriology laboratory personnel

    • Children younger than 4 years of age, or children and adolescents exposed to adults in high-risk categories

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  18. Bacille Calmette-Guérin (BCG) vaccine

    CHEMOPROPHYLAXIS FOR TUBERCULOSIS

    Although not recommended or routinely used in the United States, many other countries, particularly developing countries with limited financial resources, have used the BCG vaccine to control TB [20]. The WHO estimates that more than 1 billion people have received BCG, making it one of the most widely used vaccines in the world. Studies have shown BCG to have variable efficacy against all TB strains. Analysis of these studies is difficult due to the fact that several different strains of the vaccine are used worldwide. There are serious concerns about its use in immunocompromised patients [20].

    Generally, the vaccine is given to infants and children who have (1) a negative tuberculin skin test; (2) are at high risk of continuing exposure to persons with infectious TB; (3) cannot be placed on long-term preventive therapy; or (4) are continually exposed to persons with INH- or rifampin-resistant disease. As BCG is a live, attenuated vaccine, administration will cause a person to convert from a negative TB skin test to a positive one, requiring any subsequent skin testing to be confirmed by blood test.

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  19. Prophylactic treatment for children of patients infected with TB is

    CHILDREN AND TB

    Prophylactic treatment for children of patients with TB is highly recommended. The treatment regimens most effective for children are limited, compared with those used for adult patients with TB. However, the once-weekly, three-month regimen of isoniazid-rifapentine is now approved for use in children 2 to 17 years of age, thereby permitting a relatively brief and more manageable course of antituberculous prophylaxis [65]. Nine-month treatment with INH alone has proved to be successful in most children and is also recommended [52]. Children taking INH do not seem to develop the transient elevation of liver enzymes seen in adults, so liver function does not have to be monitored unless the patient has a history of other liver disease. When INH is not tolerated, the American Academy of Pediatrics recommends six months of daily rifabutin at a dosage of 10–20 mg/kg [52]. As noted, ethambutol is usually avoided in children younger than 7 years of age because it is difficult to properly monitor visual acuity and color perception in children that young. It is rare for children to develop drug-induced hepatitis, so monthly follow-ups do not include liver function studies, as in adults. Good indicators of improvement are increased appetite, weight gain, and lower evening temperatures.

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  20. It is important for the healthcare professional to explain to the patient with TB and his/her caregiver

    CARE OF THE PATIENT WITH TB

    It is important for healthcare professionals to give both the patient and the caregiver explicit verbal and written instructions outlining which medications should be taken and how often. Some even make a poster with sample tablets glued to it, so the patient has a constant visual reminder of what needs to be taken. These instructions should also include the name and telephone number of a physician or nurse to call if questions arise.

    Patients' health literacy is typically low, and an inability to follow a prescription is the foremost problem associated with poor health literacy [19]. Patients whose primary language is not English, racial/ethnic minorities, and patients older than 60 years of age have the lowest health literacy, which is unfortunate given that most cases of TB occur in these populations [19,23,54]. Many patients report that the clinician did not provide information in words they could understand, and some individuals feel shame about their lack of understanding and fail to ask for clarification due to embarrassment. Non-English-proficient patients require a professional translator (i.e., not a family member) to be present at each visit. It is vital that the patient understand the importance of precisely following the drug regimen.

    Patients and caregivers should be taught the signs and symptoms of drug toxicity and side effects, such as those with rifampin, which causes feces, saliva, tears, and urine to be a red-orange color. It is important to strongly reinforce that they must not stop taking the medications without permission.

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  • Participation Instructions
    • Review the course material online or in print.
    • Complete the course evaluation.
    • Review your Transcript to view and print your Certificate of Completion. Your date of completion will be the date (Pacific Time) the course was electronically submitted for credit, with no exceptions. Partial credit is not available.