Tuberculosis (TB) PDF

Less Common Extrapulmonary Forms TB may cause chorioretinitis, uveitis, panophthalmitis, and painful hypersensitivity-related phlyctenular conjunctivitis. Tuberculous otitis is rare and presents as hearing loss, otorrhea, and tympanic membrane perforation. In the nasopharynx, TB may simulate granulo...

Less Common Extrapulmonary Forms TB may cause chorioretinitis, uveitis, panophthalmitis, and painful hypersensitivity-related phlyctenular conjunctivitis. Tuberculous otitis is rare and presents as hearing loss, otorrhea, and tympanic membrane perforation. In the nasopharynx, TB may simulate granulomatosis with polyangiitis. Cutaneous manifestations of TB include primary infection due to direct inoculation, abscesses and chronic ulcers, scrofuloderma, lupus vulgaris (a smoldering disease with nodules, plaques, and fissures), miliary lesions, and erythema nodosum. Tuberculous mastitis results from retrograde lymphatic spread, often from the axillary lymph nodes. Adrenal TB is a manifestation of disseminated disease presenting rarely as adrenal insufficiency. Finally, congenital TB results from transplacental spread of tubercle bacilli to the fetus or from ingestion of contaminated amniotic fluid. This rare disease affects the liver, spleen, lymph nodes, and various other organs. 1367 Post-TB Complications TB may cause persisting pulmonary damage in patients whose infection has been considered cured on clinical grounds. Chronic impairment of lung functions, bronchiectasis, aspergillomas, and chronic pulmonary aspergillosis (Chap. 217) have been associated with TB. Chronic pulmonary aspergillosis may manifest as simple aspergilloma (fungal ball) or chronic cavitary aspergillosis. Early studies revealed that, especially in the presence of large residual cavities, Aspergillus fumigatus may colonize the lesion and produce symptoms such as respiratory impairment, hemoptysis, persistent fatigue, and weight loss, often resulting in the erroneous diagnosis of TB recurrence. The detection of Aspergillus precipitins (IgG) in the blood suggests chronic pulmonary aspergillosis, as do radiographic abnormalities such as thickening of the pleura and cavitary walls or the presence of a fungal ball inside the cavity. Treatment is difficult. Recent preliminary studies on the use of itraconazole for ≥6 months indicate improvement or stabilization of 60–75% of the radiologic and clinical manifestations. Surgical removal of lesions is risky except in simple aspergilloma. HIV-Associated TB (See also Chap. 202) TB is one of the most common diseases among HIV-infected persons worldwide. Responsible for up to 30% of all HIV-related mortality (208,000 deaths per year), TB is likely the main cause of death in this population. In certain urban settings in some African countries, the prevalence of HIV infection among TB patients reaches 70–80% (Fig. 178-11). A person with a positive TST who acquires HIV infection has a 3–13% annual risk of developing active TB, with the exact risk depending on the degree of immunosuppression when observation begins. Furthermore, a new TB infection acquired by an HIV-infected individual may evolve into active disease in a matter of weeks rather HIV prevalence in new and relapse TB cases, all ages (%) 0–4.9 5–9.9 10–19 20–49 ≥50 No data Not applicable FIGURE 178-11 Estimated HIV prevalence in new and relapse tuberculosis (TB) cases in 2018. (See disclaimer in Fig. 178-2. Reproduced with permission from Global Tuberculosis Report 2019. Geneva, World Health Organization; 2019.) CHAPTER 178 Tuberculosis Physical findings include hepatomegaly, splenomegaly, and lymphadenopathy. Eye examination may reveal choroidal tubercles, which are pathognomonic of miliary TB, in up to 30% of cases. Meningismus occurs in fewer than 10% of cases. A high index of suspicion is required for the diagnosis of miliary TB. Frequently, CXR (Fig. 178-5) reveals a miliary reticulonodular pattern (more easily seen on underpenetrated film), although no radiographic abnormality may be evident early in the course and among HIVinfected patients. Other radiologic findings include large infiltrates, interstitial infiltrates (especially in HIV-infected patients), and pleural effusion. Sputum-smear microscopy is negative in most cases. Various hematologic abnormalities may be seen, including anemia with leukopenia, lymphopenia, neutrophilic leukocytosis and leukemoid reactions, and polycythemia. Disseminated intravascular coagulation has been reported. Elevation of alkaline phosphatase levels and other abnormal values in liver function tests are detected in patients with severe hepatic involvement. TST results may be negative in up to half of cases, but reactivity may be restored during chemotherapy. Bronchoalveolar lavage and transbronchial biopsy are more likely to provide bacteriologic confirmation, and granulomas are evident in liver or bone-marrow biopsy specimens from many patients. If it goes unrecognized, miliary TB is lethal; with proper early treatment, however, it is amenable to cure. Glucocorticoid therapy has not proved beneficial. A rare presentation seen in the elderly, cryptic miliary TB has a chronic course characterized by mild intermittent fever, anemia, and—ultimately—meningeal involvement preceding death. An acute septicemic form, nonreactive miliary TB, occurs very rarely and is due to massive hematogenous dissemination of tubercle bacilli. Pancytopenia is common in this form of disease, which is rapidly fatal. At postmortem examination, multiple necrotic but nongranulomatous (“nonreactive”) lesions are detected. 1368 PART 5 Infectious Diseases than months or years. TB can appear at any stage of HIV infection, and its presentation varies with the stage. When cell-mediated immunity is only partially compromised, pulmonary TB presents in a typical manner (Figs. 178-6 and 178-7), with upper-lobe infiltrates and cavitation and without significant lymphadenopathy or pleural effusion. In late stages of HIV infection, when the CD4+ T-cell count is <200/μL, a primary TB–like pattern, with diffuse interstitial and subtle infiltrates, little or no cavitation, pleural effusion, and intrathoracic lymphadenopathy, is more common. However, these forms are becoming less common because of the expanded use of ART. Overall, sputum smears are less frequently positive among TB patients with HIV infection than among those without; thus the diagnosis of TB with traditional technology may be difficult, especially in view of the variety of HIV-related pulmonary conditions mimicking TB. Extrapulmonary TB is common among HIV-infected patients. In various series, extrapulmonary TB— alone or in association with pulmonary disease—has been documented in 40–60% of all cases in individuals co-infected with HIV. The most common forms are lymphatic, disseminated, pleural, and pericardial. Mycobacteremia and meningitis are also common, particularly in advanced HIV disease. The diagnosis of TB in HIV-infected patients may be complicated not only by the increased frequency of sputumsmear negativity (up to 40% in culture-proven pulmonary cases) but also by atypical radiographic findings, a lack of classic granuloma formation in the late stages, and a negative TST. The Xpert MTB/RIF assay is the preferred initial diagnostic option for pulmonary TB ensuring a sensitivity of 81% and a specificity of 98%, and therapy should be started on the basis of a positive result because treatment delays may be fatal. A negative Xpert MTB/RIF result, however, does not exclude a diagnosis of TB. Culture remains the gold standard. Recent assessment of a test based on the detection of mycobacterial lipoarabinomannan antigen in urine has shown favorable results in assisting with the detection of TB in HIV-positive people (see “Additional Diagnostic Procedures,” below). The immune reconstitution inflammatory syndrome (IRIS) or TB immune reconstitution disease consists of exacerbations in systemic manifestations (lymphadenopathy, fever) or respiratory signs (worsening of pulmonary infiltrations, pleural effusion) as well as laboratory or radiographic manifestations of TB. This syndrome has been associated with the administration of ART and occurs in ~10% of HIV-infected TB patients. Usually developing 1–3 months after initiation of ART, IRIS is more common among patients with advanced immunosuppression and extrapulmonary TB. “Unmasking IRIS” may develop after the initiation of ART in patients with undiagnosed subclinical TB. The earlier ART is started and the lower the baseline CD4+ T-cell count, the greater the risk of IRIS. Death due to IRIS is relatively infrequent and occurs mainly among patients who have a high preexisting mortality risk. The presumed pathogenesis of IRIS consists of an immune response that is elicited by antigens released as bacilli are killed during effective chemotherapy and that is temporally associated with improving immune function. There is no diagnostic test for IRIS, and its confirmation relies heavily upon case definitions incorporating clinical and laboratory data; a variety of case definitions have been suggested. The first priority in the management of a possible case of IRIS is to ensure that the clinical syndrome does not represent a failure of TB treatment or the development of another infection. Mild paradoxical reactions can be managed with symptom-based treatment and do not worsen outcomes of treatment for TB. However, IRIS can result in serious neurologic complications or death in patients with CNS TB. Therefore, ART should not be initiated during the first 8 weeks of TB treatment in patients with TB meningitis. Glucocorticoids have been used for severe paradoxical reactions; prednisolone given for 4 weeks at a low dosage (1.5 mg/kg per day for 2 weeks and half that dose for the remaining 2 weeks) has reduced the need for hospitalization and therapeutic procedures and has hastened alleviation of symptoms, as reflected by Karnofsky performance scores, quality-of-life assessments, radiographic response, and C-reactive protein levels. The effectiveness of glucocorticoids in alleviating the symptoms of IRIS is probably linked to suppression of proinflammatory cytokine concentrations as these medications reduce serum concentrations of IL-6, IL-10, IL-12p40, TNF-α, IFN-γ, and IFN-γ-inducible protein 10. Recommendations for the prevention and treatment of TB in HIVinfected individuals are provided below. DIAGNOSIS The key to the early diagnosis of TB is a high index of suspicion. Diagnosis is not difficult in persons belonging to high-risk populations who present with typical symptoms and a classic chest radiograph showing upper-lobe infiltrates with cavities (Fig. 178-6). On the other hand, the diagnosis can easily be missed in an elderly nursing-home resident or a teenager with a focal infiltrate. Often, the diagnosis is first entertained when the chest radiograph of a patient being evaluated for respiratory symptoms is abnormal. If the patient has no complicating medical conditions that cause immunosuppression, the chest radiograph may show typical upper-lobe infiltrates with cavitation (Fig. 178-6). The longer the delay between the onset of symptoms and the diagnosis, the more likely is the finding of cavitary disease. In contrast, immunosuppressed patients, including those with HIV co-infection, may have “atypical” findings on CXR—e.g., lower-zone infiltrates without cavity formation— or interstitial disease only. The several approaches to the diagnosis of TB require, above all, a well-organized microbiology laboratory network with an appropriate distribution of tasks at different levels of the health care system. Besides clinical assessment and radiography, screening and referral are the principal tasks at the peripheral and community levels. Diagnosis at a secondary level (e.g., a traditional district hospital in a high-incidence setting) can be accomplished nowadays through real-time automated nucleic acid amplification technology (e.g., the Xpert MTB/RIF assay, which also allows detection of drug resistance) or through traditional AFB microscopy, where new tools have not yet been introduced. At a tertiary level, additional technology is necessary, including molecular tests, rapid culture, and DST. ■ NUCLEIC ACID AMPLIFICATION TECHNOLOGY Several test systems based on amplification of mycobacterial nucleic acid have become available in the past few years and are now the preferred first-line diagnostic tests. These tests are progressively replacing smear microscopy, as they ensure rapid confirmation of all types of TB. One system that permits rapid diagnosis of TB with high specificity and sensitivity (approaching that of liquid culture) is the fully automated, real-time nucleic acid amplification technology known as the Xpert MTB/RIF assay. Xpert MTB/RIF can simultaneously detect TB and rifampin resistance in <2 h and has minimal biosafety and training requirements. Therefore, it can be housed in nonconventional laboratory settings as long as a stable and uninterrupted power supply can be assured. The WHO recommends its use worldwide as the firstline diagnostic test in all adults and children with signs or symptoms of active TB. Given the test’s high sensitivity, the WHO also recommends its use as the initial diagnostic test for people living with HIV in whom TB is suspected. In the diagnosis of pulmonary TB, this test has an overall sensitivity of 85% reaching 98% among AFB-positive cases and ~70% among AFB-negative specimens; its specificity is 98%. When compared to phenotypic drug susceptibility testing for simultaneous detection of rifampin resistance, Xpert MTB/RIF has an overall sensitivity of 96% and a specificity of 98%. The newer Xpert MTB/RIF Ultra assay (Ultra), which uses the same GeneXpert diagnostic platform, has an overall sensitivity of 90% including “trace calls” (i.e., the “noise” produced by detection of DNA from nonviable bacilli) as positive with the greatest increases among smear-negative, culture-positive cases (+17%) and among HIV-infected persons (+12%). If “trace calls” are excluded, sensitivity decreases to 86%. Because of this greater sensitivity and the capacity to also detect nonviable bacilli, the new Ultra cartridge has 2% lower specificity than the original test. However, excluding “trace calls,” specificity increases to 98%. Among people with HIV co-infection, Ultra sensitivity is 88% and specificity 95%. Sensitivity and specificity for detection of rifampin resistance by Ultra are 94% and 99%, respectively, similar to those by the Xpert MTB/RIF assay. In the diagnosis of extrapulmonary TB, Xpert MTB/RIF and Ultra should be the initial test applied to CSF from patients in whom TB ■ AFB MICROSCOPY In many low- and middle-income settings, a presumptive diagnosis is still commonly based on the finding of AFB on microscopic examination of a diagnostic specimen, such as a smear of expectorated sputum or of tissue (e.g., a lymph node biopsy). Although inexpensive, AFB microscopy has relatively low sensitivity (40–60%) in cultureconfirmed cases of pulmonary TB. The traditional method—light microscopy of specimens stained with Ziehl-Neelsen basic fuchsin dyes—is satisfactory, although time consuming and operator dependent. Most modern laboratories processing large numbers of diagnostic specimens use auramine–rhodamine staining and fluorescence microscopy; this approach is more sensitive than the Ziehl-Neelsen method. However, it is expensive because it requires high-cost mercury vapor light sources and a darkroom. Less expensive light-emitting diode (LED) fluorescence microscopes are now recommended by the WHO as the microscopy tool of choice. They are as sensitive as—or more sensitive than—traditional fluorescence microscopes. As a result, conventional light and fluorescence microscopes are being replaced with this more recent technology, especially in developing countries. For patients with signs or symptoms of pulmonary TB, it has been recommended that one or two sputum specimens, preferably collected early in the morning, should be submitted to the laboratory for AFB smear and mycobacterial culture. If tissue is obtained, it is critical that the portion of the specimen intended for culture not be put in preservation fluid such as formaldehyde. The use of AFB microscopy in examining urine or gastric lavage fluid is limited by the low numbers of organisms, which can cause false-negative results, or the presence of commensal mycobacteria, which can cause false-positive results. ■ MYCOBACTERIAL CULTURE Definitive diagnosis depends on the isolation and identification of M. tuberculosis from a clinical specimen. Commercial liquid-culture systems such as the Mycobacterial Growth Indicator Tube (MGIT) system (Becton Dickinson; Franklin Lakes, NJ) are recommended by the WHO as the reference standard for culture. The MGIT system uses a fluorescent compound sensitive to the presence of oxygen dissolved in the liquid medium. The appearance of fluorescence, detected by fluorometric technology, indicates active growth of mycobacteria. MGIT cultures usually become positive after a period ranging from 10 days to 2–3 weeks; the tubes are read weekly until the eighth week of incubation before the result is declared to be negative. Specimens may also be inoculated onto egg- or agar-based medium (e.g., Löwenstein-Jensen or Middlebrook 7H10 or 7H11) and incubated at 37°C (under 5% CO2 for Middlebrook medium). Because most species of mycobacteria, including M. tuberculosis, grow slowly, 4–8 weeks may be required before growth is detected on these conventional culture media. Although M. tuberculosis may be identified presumptively on the basis of growth time and colony pigmentation and morphology, a variety of biochemical tests have traditionally been used to speciate mycobacterial isolates. In modern, well-equipped laboratories, commercial liquid culture for isolation and species identification by molecular methods or highpressure liquid chromatography of mycolic acids has replaced isolation on solid media and identification by biochemical tests. A low-cost, rapid immunochromatographic lateral-flow assay based on detection of MTP64 antigen may also be used for species identification of the M. tuberculosis complex in culture isolates. These new methods, which are increasingly used in limited-resource settings, have decreased the time required for bacteriologic confirmation of TB to 2–3 weeks. ■ DRUG SUSCEPTIBILITY TESTING Universal DST is considered by the WHO as the current standard of care for all TB patients and should consist of DST to at least rifampin for all initial isolates of M. tuberculosis, as rifampin resistance is an excellent proxy for MDR-TB diagnosis. Susceptibility testing is particularly important if one or more risk factors for drug resistance are identified or if the patient either fails to respond to initial therapy or has a relapse after the completion of treatment (see “Treatment Failure and Relapse,” below). In addition, expanded and rapid susceptibility testing for isoniazid and key second-line anti-TB drugs (especially the fluoroquinolones and the injectable drugs) is mandatory when RR-TB is found in order to guide selection of the appropriate treatment regimens. Susceptibility testing may be conducted directly by molecular techniques (with the clinical specimen) or indirectly (with mycobacterial cultures) on solid or liquid medium. Results are obtained rapidly by direct susceptibility testing on liquid medium, with an average reporting time of 3 weeks. With indirect testing on solid medium, results may not be available for ≥8 weeks. Highly reliable genotypic methods for the rapid identification of genetic mutations in gene regions known to be associated with resistance to rifampin (such as those in rpoB) and isoniazid (such as those in katG and inhA) have been developed and are being widely implemented for screening of patients at increased risk of drug-resistant TB. Apart from the Xpert MTB/RIF, Xpert MTB/RIF Ultra, and Truenat MTB-Rif Dx assays, which, as mentioned above, effectively detect rifampin resistance, the most widely used tests are molecular line probe assays (LPAs). LPAs are a family of DNA strip-based tests capable of detecting bacterial DNA and identifying drug resistance-associated mutations. After extraction of DNA from M. tuberculosis isolates or from clinical specimens, the resistance gene regions are amplified by polymerase chain reaction (PCR), and labeled and probe-hybridized PCR products are detected by colorimetric development. This assay reveals the presence of M. tuberculosis as well as mutations in target resistance-gene regions. Given the rapidity and accuracy of commercially available LPAs, the WHO recommends that they (rather than phenotypic culture-based tests) may be used to detect resistance to isoniazid and rifampin when 1369 CHAPTER 178 Tuberculosis meningitis is suspected as well as a replacement test (preferable to conventional microscopy, culture, and histopathology) for selected nonrespiratory specimens—those obtained by gastric lavage, fineneedle aspiration, or pleural or other biopsies. Sensitivity varies according to specimen type being the lowest in pleural fluid (50% with Xpert MTB/RIF and 71% with Ultra) and the highest in synovial fluid (97%) and lymph node biopsy (100% with Ultra). “Trace calls” in specimens from persons with extrapulmonary TB, as well as for HIVinfected patients and children, should be considered true positives, given the high risk of severe morbidity and premature death, while among other cases they warrant additional tests to confirm the diagnosis of TB and prevent overtreatment. Among patients with a recent history of TB, “trace calls” may represent false positivity due to DNA from dead bacilli under degradation. Truenat MTB and MTC Plus are two newly introduced rapid molecular tests with a sensitivity of 83% and 89%, respectively, if compared to bacteriological culture, and with specificity of 98% and 99%, respectively. Truenat MTB-Rif Dx detects rifampin resistance with a sensitivity of 93% and a specificity of 95%. These rapid tests, developed in India by MolBio Diagnostics Pvt Ltd Goa, have accuracy comparable to that of Xpert MTB/RIF and Ultra. Being portable and battery-operated, they can be used in the most peripheral care settings. New high-throughput automated platforms for TB diagnosis and drugresistant variants are becoming available (Abbott RealTime MTB and RIF/INH, FluoroType MTBDR, BD Max MDR-TB). These platforms are suitable for centralized laboratories and have the advantage of processing a large number of samples in a reasonable time. Sensitivity is higher than 91% and specificity ranges from 97 to 100%. Head-to-head studies with Xpert MTB/RIF have shown comparable performance. Another available molecular test for detection of M. tuberculosis is based on the loop-mediated isothermal amplification (LAMP) temperature-independent technology that amplifies DNA, is relatively simple to use, and is interpreted through a visual display. The TB-LAMP assay (LoopampTM M. tuberculosis complex detection kit; Eiken Chemical Company, Japan) requires minimal laboratory infrastructure and has few biosafety requirements. It may be used as a replacement for sputum-smear microscopy for the diagnosis of adult pulmonary TB and as a follow-up test to smear microscopy for the further investigation of smear-negative specimens from adults with suspected pulmonary TB. The TB-LAMP assay should not replace rapid molecular tests that detect both TB and rifampin resistance, and its usefulness in HIV-infected people in whom TB is suspected remains unclear. 1370 PART 5 Infectious Diseases patients have sputum smear–positive specimens or a cultured isolate of M. tuberculosis. These recommendations do not eliminate the need for conventional culture-based testing to identify resistance to other drugs and to monitor emergence of additional drug resistance. A similar approach has been developed for second-line anti-TB drugs, such as the fluoroquinolones and the injectable drugs kanamycin, amikacin, and capreomycin. Therefore, second-line LPAs (instead of phenotypic culture-based DST) are now recommended by the WHO as the initial test for rapid detection of resistance to the fluoroquinolones or the second-line injectable drugs in isolates from patients with confirmed RR-TB or MDR-TB. As with first-line LPAs, these recommendations do not eliminate the need for conventional phenotypic, culture-based testing to identify resistance to other drugs and to monitor for the emergence of additional resistance. Detection of pyrazinamide resistance is important among persons with MDR/RR-TB. The WHO has recently recommended the use of a LPA with reverse hybridization-based technology in culture isolates rather than phenotypic culture-based DST. Finally, a few noncommercial, inexpensive culture and susceptibility testing methods (e.g., microscopically observed drug susceptibility, nitrate reductase, and colorimetric redox indicator assays) have been used in resource-limited settings. Their use is restricted to national reference laboratories with proven proficiency and adequate external quality control as an interim solution while genotypic or automated liquid-culture technology is introduced. Whole genome sequencing (WGS) of M. tuberculosis provides comprehensive information on mutations conferring resistance and is a promising alternative to existing phenotypic and molecular DST methods. Recent studies have confirmed the potential for WGS to identify genetic polymorphisms that reliably predict drug susceptibility phenotype within a clinically relevant timeframe and a comparable cost range. The clinical use of WGS, however, has been hampered by the requirement for a culture sample before DNA processing. Recently, amplification and sequencing of relevant genomic targets directly from sputum samples have been successfully tested and targeted newgeneration sequencing (tNGS) is now a possible option. Evidence is accumulating supporting the clinical application of NGS-based diagnostic systems for TB to replace traditional diagnostic tests in the future. ■ RADIOGRAPHIC PROCEDURES CXR is a rapid imaging technique that has historically been used as a primary tool to detect pulmonary TB. CXR has high sensitivity but poor specificity. Although TB may often present with typical patterns strongly suggesting the disease, some abnormalities seen in TB are also present in several other lung conditions. The initial suspicion of pulmonary TB is often based on abnormal CXR findings in a patient undergoing triage for respiratory symptoms. The presence of lesions suggestive of TB should prompt bacteriologic investigations in all cases, without exception. Although the “classic” picture is that of upper-lobe disease with infiltrates and cavities (Fig. 178-6), virtually any radiographic pattern—from a normal film or a solitary pulmonary nodule to diffuse alveolar infiltrates in a patient with adult respiratory distress syndrome—may be seen. In the era of HIV/AIDS, no radiographic pattern can be considered pathognomonic, but CXR can assist in diagnosing TB or ruling it out before initiation of any preventive treatment. CXR is also helpful as a screening test used preceding rapid molecular assays to improve their predictive value. Digital CXR technology, which allows display of images in a digital format on a computer screen instead of on x-ray film, offers several advantages: the procedure time is reduced, the running costs are lower, the imaging is of superior quality, and telemedicine assistance is available, including computer-aided detection (CAD) and interpretation of findings using software programs that analyze digital imaging for abnormalities compatible with TB. However, the limited evidence available suggests that while sensitivity may be high, specificity is variable. A recent systematic review of CAD studies concluded that the diagnostic accuracy of this technology is still limited and that generalizability to low-prevalence settings is still uncertain. CT (Fig. 178-7) may be useful in interpreting questionable findings on plain CXR and in diagnosing some forms of extrapulmonary TB (e.g., intrabdominal disease, Pott’s disease; Fig. 178-10). A recent study has shown the potential of positron emission tomography combined with CT for detection of subclinical disease that may be progressing toward full-blown TB in HIV-infected people. MRI is useful in the diagnosis of bone lesions and intracranial TB. ■ ADDITIONAL DIAGNOSTIC PROCEDURES Other diagnostic tests may be used when pulmonary TB is suspected. Sputum induction by ultrasonic nebulization of hypertonic saline may be useful for patients who cannot produce a sputum specimen spontaneously. Frequently, patients with radiographic abnormalities that are consistent with other diagnoses (e.g., bronchogenic carcinoma) undergo fiberoptic bronchoscopy with bronchial brushings and endobronchial or transbronchial biopsy of the lesion. Bronchoalveolar lavage of a lung segment containing an abnormality may also be performed. In all cases, it is essential that specimens be submitted for molecular testing with the Xpert MTB/RIF assay, mycobacterial culture, and AFB smear. For the diagnosis of primary pulmonary TB in children, who often do not expectorate sputum, induced sputum specimens and specimens from early-morning gastric lavage may yield positive results in the Xpert MTB/RIF assay or on culture. Invasive diagnostic procedures are indicated for patients with suspected extrapulmonary TB. In addition to testing of specimens from involved sites (e.g., CSF for tuberculous meningitis, pleural fluid and biopsy samples for pleural disease), biopsy and culture of bone marrow and liver tissue have a good diagnostic yield in disseminated (miliary) TB, particularly in HIV-infected patients, who also have a high frequency of positive blood cultures. Xpert MTB/RIF should always be the initial diagnostic test in patients where TB meningitis is suspected; any positive results should prompt immediate treatment initiation, while negative results should be followed up by additional testing. In some cases, the results of culture or Xpert MTB/RIF are negative but a clinical diagnosis of TB is supported by consistent epidemiologic evidence (e.g., a history of close contact with an infectious patient) and a compatible clinical and radiographic response to treatment. In the United States and other industrialized countries with low rates of TB, some patients with limited abnormalities on CXR and sputum positive for AFB are infected with nontuberculous mycobacteria, most commonly organisms of the M. avium complex or M. kansasii (Chap. 180). Factors favoring the diagnosis of nontuberculous mycobacterial disease over TB include an absence of risk factors for TB and the presence of underlying chronic pulmonary disease. Patients with HIV-associated TB pose several diagnostic problems (see “HIV-Associated TB,” above). HIV-infected patients with sputum culture–positive, AFB-positive TB may present with a normal chest radiograph. The Xpert MTB/RIF assay is the preferred rapid diagnostic test in this population of patients because of its simplicity and increased sensitivity (~60–70% among AFB-negative, culturepositive cases and 97–98% among AFB-positive cases). With the advent of ART, the occurrence of disseminated M. avium complex disease that can be confused with TB has become much less common. A test based on the detection of mycobacterial lipoarabinomannan antigen in urine has emerged as a potentially useful point-of-care test for TB in HIVinfected persons with low CD4+ T-cell counts. The lateral-flow urine lipoarabinomannan assay can be performed manually and read by eye. After a systematic review of the evidence, the WHO recommends that this assay be used to assist in the diagnosis of TB in HIV-positive adults who have signs and symptoms of TB and a CD4+ T-cell count of ≤100 cells/μL or in HIV-positive patients who are seriously ill regardless of CD4+ T-cell count or with an unknown CD4+ count. The WHO recommends that this test not be used, pending information on recent promising technological test advances, for TB diagnosis or as a screening test for TB in any other patient categories. One limitation of the available lipoarabinomannan point-of-care test, AlereLAM (Alere Determine TB LAM Ag), is the low sensitivity (45%). A novel assay, FujiLAM (SILVAMP TB LAM) has recently shown a sensitivity of 70%. ■ SEROLOGIC AND OTHER DIAGNOSTIC TESTS FOR ACTIVE TB Several serologic tests based on detection of antibodies to a variety of mycobacterial antigens have been carefully assessed by the WHO and found not to be useful as diagnostic aids because of their low sensitivity and specificity and their poor reproducibility. In 2011, after a rigorous evaluation of these tests, the WHO issued a “negative” recommendation in order to prevent their abuse in the private sector of many resource-limited countries. Various methods aimed at detection of mycobacterial antigens in diagnostic specimens are being investigated but are limited at present by low sensitivity. Determinations of adenosine deaminase and IFN-γ levels in pleural fluid may be useful adjunctive tests in the diagnosis of pleural TB; their utility in the diagnosis of other forms of extrapulmonary TB (e.g., pericardial, peritoneal, and meningeal) is less clear. ■ BIOMARKERS In view of the limitations of current diagnostics, research on TB biomarkers and multiple marker biosignatures that could be used as a point-of-care test for disease or triage is a high priority and has been crystallized in well-defined target product profiles by the WHO. Recent systematic reviews revealed that promising host biomarkers under study, such as antibodies, cytokines, chemokines, and RNA signatures, by far exceed pathogen biomarkers that can be obtained from urine or blood. However, currently, candidate biomarkers require additional studies to fully assess their performance. Tuberculin Skin Testing In 1891, Robert Koch discovered that components of M. tuberculosis in a concentrated liquid-culture medium, subsequently named “old tuberculin,” were capable of eliciting a skin reaction when injected subcutaneously into patients with TB. In 1932, Seibert and Munday purified this product by ammonium sulfate precipitation to produce an active protein fraction known as tuberculin purified protein derivative (PPD). In 1941, PPD-S, developed by Seibert and Glenn, was chosen as the international standard. Later, the WHO and UNICEF sponsored large-scale production of a master batch of PPD (RT23) and made it available for general use. The greatest limitation of PPD is its lack of mycobacterial species specificity, a property due to the large number of proteins in this product that are highly conserved in the various species. In addition, subjectivity of the skin-reaction interpretation that is dependent on the operator, deterioration of the product, and batch-to-batch variations limit the usefulness of PPD. The skin test with tuberculin PPD (TST) is most widely used in screening for TB infection. It probably measures the response to antigenic stimulation by T cells that reside in the skin rather than the response of recirculating memory T cells. The test is of limited value in the diagnosis of active TB because of its relatively low sensitivity and specificity and its inability to discriminate between TB infection and active disease. False-negative reactions are common in immunosuppressed patients and in those with overwhelming TB. False-positive reactions may be caused by infections with nontuberculous mycobacteria (Chap. 180) and by BCG vaccination. A repeated TST can produce larger reaction sizes due to either boosting or true conversion. The “boosting phenomenon” is a spurious TST conversion resulting from boosting of reactivity on a subsequent TST 1–5 weeks after the initial test. Distinguishing boosting from true conversion is difficult yet important and can be based on clinical and epidemiologic considerations. For instance, true conversions are likely after BCG vaccination in a previously TST-negative person or in a close contact of an infectious patient. IFN-γ Release Assays Two in vitro assays that measure T-cell release of IFN-γ in response to stimulation with the highly TB-specific RD1-encoded antigens ESAT-6 and CFP-10 were introduced in the early 2000s and are commercially available. The T-SPOT.TB test (Oxford Immunotec; Oxford, United Kingdom) is an enzyme-linked immunospot assay, and the QuantiFERON-TB Gold test (Qiagen GmbH; Hilden, Germany) is a whole-blood enzyme-linked immunosorbent TREATMENT Tuberculosis The two main aims of TB treatment are (1) to prevent morbidity and death by curing TB while preventing recurrences and emergence of drug resistance, and (2) to interrupt transmission by rendering patients noninfectious to others. Chemotherapy for TB became possible with the discovery of streptomycin in 1943. Randomized clinical trials clearly indicated that the administration of streptomycin to patients with chronic TB reduced mortality rates and led to cure in the majority of cases. However, monotherapy with streptomycin 1371 CHAPTER 178 Tuberculosis ■ DIAGNOSIS OF M. TUBERCULOSIS INFECTION Two tests currently exist for identification of individuals with TB infection: the TST and IGRA, both of which measure host immunological response to TB antigens. These tests have limitations, especially in settings or populations with high TB and/or HIV prevalence. assay for measurement of IFN-γ. The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay, which facilitates blood collection and initial incubation, also contains another specific antigen, TB7.7. These tests mainly measure the response of recirculating memory CD4+ T cells— normally part of a reservoir in the spleen, bone marrow, and lymph nodes—to persisting bacilli-producing antigenic signals. However, CD8+ cells can also release IFN-γ in vitro in response to stimulation with TB antigens, and they seem to do so especially in the early phase of infection and in the phase of reactivation. Therefore, a new version of the QFT-GIT assay, called QuantiFERON-TB Gold Plus (QFTPlus), has been developed that operates through two antigen tubes: TB1, containing long peptides from ESAT-6 and CFP-10 and inducing a CD4+ T-cell response, and TB2 that also contains shorter peptides stimulating CD8+ cells. The QFT-Plus may have an increased sensitivity, compared to QFT-GID, but this conclusion needs confirmation. In settings or population groups with low TB and HIV burdens, IGRAs have previously been reported to be more specific than the TST as a result of less cross-reactivity with BCG vaccination and sensitization by nontuberculous mycobacteria; i.e., RD1 antigens are not encoded in the genome of either BCG strains or most nontuberculous mycobacteria. Recent studies suggest that IGRAs may not perform well in serial testing (e.g., among health care workers) and that interpretation of results depends on cutoff values used to define positivity. Potential advantages of IGRAs include logistical convenience, the need for fewer patient visits to complete testing, and the avoidance of somewhat subjective measurements (e.g., skin induration). However, IGRAs require that blood be drawn and then delivered to the laboratory in a timely fashion. IGRAs also require that testing be performed by specially trained technicians in a laboratory setting. These requirements pose challenges similar to those faced with the TST, including coldchain requirements and batch-to-batch variations. Because of higher specificity and greater availability of resources, IGRAs have usually replaced the TST for TB infection diagnosis in low-incidence, highincome settings. However, in high-incidence TB and HIV settings and population groups, evidence about the performance and usefulness of IGRAs is still limited, and cost considerations may currently limit wider use. A number of national guidelines on the use of IGRAs for TB infection testing have been issued. In the United States, an IGRA is preferred to the TST for most persons over the age of 5 years who are being screened for TB infection. However, for individuals at high risk of progression to active TB (e.g., HIV-infected persons), either test— or, to optimize sensitivity, both tests—may be used. Because of the paucity of data on the use of IGRAs in children, the TST is preferred for TB infection testing of children aged <5 years. In Canada and some European countries, a two-step approach for those with positive TSTs—i.e., an initial TST followed by an IGRA—is often recommended. However, a TST may boost an IGRA response if the interval between the two tests exceeds 3 days. In conclusion, both the TST and IGRA, although useful as diagnostic aids, are imperfect tests for TB infection: while they can identify infected persons, they have low predictive value in identifying individuals with the highest risk of progression toward disease, cannot differentiate between active TB and TB infection, cannot distinguish new infections from reinfections, and display reduced sensitivity in immunocompromised patients. was soon associated with the development of resistance to this drug and the resulting failure of treatment. With the introduction into clinical practice of para-aminosalicylic acid (PAS) and isoniazid, it became axiomatic in the early 1950s that cure of TB required the concomitant administration of at least two agents to which the organism was susceptible. Furthermore, early clinical trials demonstrated that a long period of treatment—i.e., 12–24 months—was required to prevent recurrence. The introduction of rifampin in the early 1970s heralded the era of effective short-course chemotherapy, with a treatment duration of <12 months. The discovery that pyrazinamide, which was first used in the 1950s, augmented the potency of isoniazid/rifampin regimens led to the use of a 6-month course of this triple-drug regimen as standard therapy. Streptomycin was added as the fourth drug mainly to prevent the emergence of drug resistance. These four drugs (with streptomycin replaced by ethambutol) still form the basis of the optimal treatment regimen for rifampin-susceptible TB. The emergence of drug-resistant TB in the 1990s prompted attempts to standardize the approach to treatment of this condition mainly on the basis of expert opinion. This event has also stimulated research on and development of new anti-TB agents in the past 15 years. In 2013 and 2014, respectively, bedaquiline and delamanid—the first two drugs specifically developed for TB during nearly half a century—received conditional approval by the US Food and Drug Administration (FDA) and other drugregulatory authorities; approval was based on the results of phase 2b clinical trials in which the drugs were added to the 18- to 24-month WHO-recommended regimen for MDR-TB. Bedaquiline and delamanid are now being used increasingly for treatment of MDR-TB under specific conditions. In 2019, another new drug, pretomanid, was approved by the FDA as part of a new combination regimen with bedaquiline and linezolid for patients with MDR-TB caused by a strain with additional resistance to a fluoroquinolone or a second-line injectable drug, or were intolerant of therapy, or in whom treatment had failed. DRUGS Four major drugs are considered first-line agents for the treatment of TB: isoniazid, rifampin, pyrazinamide, and ethambutol. Table 178-2 presents currently recommended dosages in adults and children. Some studies have suggested increased effectiveness when isoniazid, rifampin, and pyrazinamide are given at higher dosage; thus if these findings are confirmed, dosages may be revised in the future. These drugs are well absorbed after oral administration, with peak serum levels at 2–4 h and nearly complete elimination within 24 h. Isoniazid and rifampin, two key anti-TB drugs, are recommended on the basis of their bactericidal activity (i.e., their ability to rapidly reduce the number of viable organisms and render patients noninfectious). All four agents are recommended in light of their sterilizing activity (i.e., their ability to sterilize the affected tissues, measured in terms of the ability to prevent relapses) and the lowered risk that drug-resistant mutant bacilli will be selected when the drugs are used in combination. Two additional rifamycins, 1372 PART 5 Infectious Diseases TABLE 178-2 Recommended Dosagea for Initial Treatment of Tuberculosis in Adults and Children DAILY DOSE DRUG Isoniazid Rifampin Pyrazinamide Ethambutolb ADULT 5 mg/kg, max 300 mg 10 mg/kg, max 600 mg 25 mg/kg, max 2 g 15 mg/kg PEDIATRIC 10 (7–15) mg/kg, max 300 mg 15 (10–20) mg/kg, max 600 mg 35 (30–40) mg/kg 20 (15–25) mg/kg The duration of treatment with individual drugs varies by regimen, as detailed in Table 178-3. bIn certain settings, streptomycin (15 mg/kg daily, with a maximal dose of 1 g; or 25–30 mg/kg thrice weekly, with a maximal dose of 1.5 g) can replace ethambutol in the initial phase of treatment. However, streptomycin generally is no longer considered a first-line drug. Source: Based on recommendations of the American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention and the World Health Organization. a rifapentine and rifabutin, are also available; however, their level of cross-resistance with rifampin is high. For a detailed discussion of the drugs used for the treatment of TB, see Chap. 181. Because of a lower degree of effectiveness and tolerability, several classes of second-line drugs are generally used only for the treatment of patients with drug-resistant TB. These agents have previously been classified in various manners to facilitate a standardized approach to their use. In the latest WHO guidance on the treatment of MDR-TB, they are now grouped in three ranked categories for the purpose of designing more individualized regimens of 18–20 months’ duration. Group A drugs include three classes of oral agents: the fluoroquinolones levofloxacin and moxifloxacin; the oxazolidinone linezolid; and the recently introduced diarylquinoline bedaquiline, which was granted accelerated approval by the FDA in late 2012. Group B drugs include two other oral agents: clofazimine and cycloserine (or its analogue terizidone). Group C drugs include the nitroimidazole delamanid; imipenemcilastatin or meropenem; the injectable aminoglycosides amikacin and streptomycin (the latter formerly a first-line agent, now rarely used for drug-resistant TB because resistance levels worldwide are high and it is more toxic than the other drugs in the same class); ethionamide or prothionamide; and PAS. In addition, the firstline anti-TB drugs ethambutol and pyrazinamide (both included in Group C) as well as high-dose isoniazid (only for the shorter regimen; see below) are used for MDR-TB treatment. Information about drugs used in the treatment of drug-resistant TB (including dosages) can be found in the following WHO Handbook: http://apps.who.int/ iris/bitstream/10665/130918/1/9789241548809_eng.pdf. Recent information from the phase 3 clinical trial of delamanid (a drug granted accelerated approval by the European Medicines Agency [EMA] in late 2013) added to an optimized longer WHO background regimen shows that treatment success is not different from that obtained with the addition of placebo. The future role of delamanid as a replacement drug in MDR-TB treatment remains to be assessed. The new classification scheme excludes the second-line injectable aminoglycoside kanamycin and the polypeptide capreomycin. Amithiozone, which has been associated with severe and at times fatal skin reactions— including Stevens-Johnson syndrome—among HIV-infected patients, is no longer recommended. Finally, amoxicillin–clavulanic acid is recommended only as an adjunct to carbapenems. REGIMENS Standard regimens are divided into an intensive (bactericidal) phase and a continuation (sterilizing) phase. During the intensive phase, the majority of tubercle bacilli are killed, symptoms resolve, and usually the patient becomes noninfectious. The continuation phase is required to eliminate persisting mycobacteria and prevent relapse. The treatment regimen of choice for virtually all forms of drugsusceptible TB in adults consists of a 2-month initial (intensive) phase of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a 4-month continuation phase of isoniazid and rifampin (Table 178-3). This regimen can cure TB in >90% of patients. In children, most forms of TB in the absence of HIV infection or suspected isoniazid resistance can be safely treated without ethambutol in the intensive phase. Treatment should be given daily throughout the course. Systematic reviews have demonstrated that the use of an intermittent thrice-weekly regimen in the intensive phase is associated with increased risk of treatment failure, relapse, and acquisition of drug resistance. Furthermore, a thrice-weekly regimen in the continuation phase only has also been associated with increased rates of failure and relapse, while a twice-weekly regimen in the continuation phase increased the risk of acquisition of drug resistance as well as rates of failure and relapse. Therefore, the WHO now recommends that TB treatment in all cases be administered daily. The 2016 guidelines by the ATS, the CDC, and the IDSA, while recommending daily administration of drugs, include a provision for use of intermittent thrice-weekly supervised regimens among patients who are not infected with HIV and are at low risk of relapse (i.e., have pulmonary TB caused by drug-susceptible 1373 TABLE 178-3 Recommended Antituberculosis Treatment Regimens INITIAL PHASE INDICATION New smear- or culture-positive cases New culture-negative cases Pregnancy Relapses and treatment defaultf Failuresf Resistance (or intolerance) to H Resistance (or intolerance) to R MDR-TB (resistance to at least H + R) XDR-TB Intolerance to Z DURATION, MONTHS 2 2 2 Throughout (6) 2 CONTINUATION PHASE DRUGS DURATION, MONTHS 4 HRZEa,b HRZEa 4 HREe 7 Tailored according to rapid drug susceptibility testing Tailored according to rapid drug susceptibility testing RZEQ Same as for MDR-TB; see below See Tables 178-4 and 178-5 See Table 178-4 HRE 7 DRUGS HRa,c HRa,d HR HR All drugs should be given daily. bA 4-month regimen of 8 weeks of once-daily rifapentine, isoniazid, pyrazinamide and moxifloxacin followed by 9 weeks of once-daily rifapentine, isoniazid, and moxifloxacin is a possible alternative. cA clinical trial showed that HIV-negative patients with noncavitary pulmonary tuberculosis who have negative sputum AFB smears after the initial phase of treatment can be given once-weekly rifapentine/isoniazid in the continuation phase. However, this regimen is rarely used. dThe American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America suggest that a 2-month continuation phase could be used in HIV-seronegative patients with sputum smear–negative and culture-negative TB. eThe 6-month regimen with pyrazinamide can probably be used safely during pregnancy and is recommended by the WHO and the International Union Against Tuberculosis and Lung Disease. If pyrazinamide is not included in the initial treatment regimen, the minimal duration of therapy is 9 months. fThe availability of rapid molecular methods to identify drug resistance allows initiation of a proper regimen at the start of treatment. Abbreviations: E, ethambutol; H, isoniazid; MDR-TB, multidrug-resistant tuberculosis; Q, a quinolone antibiotic; R, rifampin; WHO, World Health Organization; XDR-TB, extensively drug-resistant tuberculosis; Z, pyrazinamide. a drugs and use of these alternative regimens are uncommon. To prevent isoniazid-related neuropathy, pyridoxine (10–25 mg/d) should be added to the regimen given to persons at high risk of vitamin B6 deficiency (e.g., alcoholics; malnourished persons; pregnant and lactating women; and patients with conditions such as chronic renal failure, diabetes, and HIV infection, which are also associated with neuropathy). Finally, to facilitate absorption of rifampin, the drug should be taken on an empty stomach and without meals. PATIENT CARE AND SUPPORT Poor adherence to treatment is one of the most important impediments to cure. Moreover, the tubercle bacilli harbored by patients who do not fully adhere to the prescribed regimen are likely to become resistant to the drugs to which they are irregularly exposed. Both patient- and provider-related factors may affect adherence. Patient-related factors include a lack of belief that the illness is worth the cost of adherence; the existence of concomitant medical conditions (notably alcohol or substance abuse); lack of social support; fear of the stigma and discrimination associated with TB; and poverty, with attendant joblessness and homelessness. Provider-related factors that may prevent adherence include lack of support, education, and encouragement of patients and inconvenient clinical services. A variety of interventions to increase the chances of completion of the months-long treatment course are available. First, a package of social support interventions that are complementary and not mutually exclusive, consisting of educational, psychological, and material goods and services, may enable people with TB to address hurdles to treatment adherence. Health education and counseling on the disease’s seriousness and solutions and on the importance of treatment adherence until cure should be provided to all patients at the start of and throughout the course of TB therapy. Psychological support (i.e., counseling sessions or peer-group support) can be particularly relevant in the context of the stigma and discrimination often affecting people with TB and their families. Material support (e.g., food or financial support in forms such as meals, food baskets, food supplements, food vouchers, transport subsidies, living allowances, housing incentives, or financial bonuses) reduces indirect costs incurred by patients or their attendants in accessing health services and mitigates the consequences of income loss related to the disease. Second, it is paramount that health services be arranged to meet the needs and reasonable expectations of patients. Components of optimal health services include a suitable geographic location, a schedule responsive to patients’ needs, functional channels of communication between patients and their health care providers (e.g., CHAPTER 178 Tuberculosis organisms that, at the start of treatment, is noncavitary and/or sputum smear–negative). The same guidelines suggest that a 4-month regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol may be adequate for treatment of HIV-negative adults with sputum smear–negative and culture-negative pulmonary TB (i.e., paucibacillary TB). A continuation phase of once-weekly rifapentine and isoniazid is effective in HIV-seronegative patients without cavitation on CXR. In general, however, this regimen should be used with great caution. Patients with cavitary pulmonary TB and delayed sputumculture conversion (i.e., those who remain culture-positive at 2 months) should be retested immediately for drug-resistant TB, and a change of regimen should be considered. A full course of 6 months with four-drug therapy should be performed not including interruptions of >4 weeks. In some developing countries where the ability to ensure adherence to treatment is limited, a continuationphase regimen of daily isoniazid and ethambutol for 6 months has been used in the past. This regimen is clearly associated with a higher rate of relapse, treatment failure, and death, especially among HIV-infected patients, and is no longer recommended by the WHO. Several studies attempting to reduce treatment duration to 4 months by using fluoroquinolones (with moxifloxacin replacing ethambutol or isoniazid, or gatifloxacin replacing ethambutol) were conducted over the last decade. The main finding was that shorter (4-month) fluoroquinolone-containing regimens are associated with significantly higher rates of relapse at 18 months than the standard 6-month rifampin-containing regimen. In addition, the studies showed no reduction in adverse events with the fluoroquinolone-containing regimen and no difference in all-cause and TB-related mortality rates. Therefore, shortening of the treatment duration to 4 months through the use of fluoroquinolones has not been recommended. However, the recent Tuberculosis Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (Study 31/A5349) showed that a 4-month daily regimen that included isoniazid, pyrazinamide, rifapentine at a daily dose of 1200 mg and moxifloxacin at a daily dose of 400 mg was noninferior to the standard 6-month regimen and had a similar adverse event profile. In early 2021, this option was therefore considered by the WHO as a possible alternative to the old standard provided that rigorous antibacterial stewardship is ensured especially to prevent fluoroquinolone resistance and that rifapentine becomes more widely available. Alternative regimens for patients who exhibit drug intolerance or adverse reactions are listed in Table 178-3. However, severe side effects prompting discontinuation of any of the first-line 1374 PART 5 Infectious Diseases a telephone short-messaging system, audio/video call capability, home or workplace visits), and a staff willing and competent to care for people with TB, to address their concerns, and to base the care they provide on sound ethical standards. Third, it is crucial to offer the patient a suitable option for treatment administration that minimizes the chance of nonadherence. Such options traditionally include unsupervised, self-administered therapy; in-person directly observed therapy (DOT); and nondaily DOT (e.g., supervision not for every dose but weekly or a few times per week) at a location mutually agreed on by patient and health care provider, with supervisory responsibility delegated to a qualified person. Direct supervision of adherence is crucial in view of the lack of tools to accurately predict adherence to selfadministered treatment and of the public health importance of TB. The WHO, along with the ATS, the CDC, and the IDSA, states that ideally all patients should have their therapy directly supervised, especially during the initial phase, with proper social support based on a patient-centered approach as described above. In several countries, personnel to supervise therapy are usually available through TB control programs of local public health departments, often involving members of the community who are accepted by the patient and who have been properly trained and educated by health workers to undertake the supervisory role. Direct supervision with social support has been shown to significantly increase the proportion of patients completing treatment in all settings and to lessen the chances of treatment failure, relapse, and default. In general, community- or home-based DOT is recommended over health facility–based DOT or unsupervised treatment; DOT administered by trained lay providers or health care workers is recommended over DOT administered by family members. Recently, comparison of video-observed therapy (VOT) with in-person DOT has shown similar outcomes. In a multicenter, analyst-blinded, randomized controlled superiority trial of VOT through daily remote observation using a smartphone app versus DOT done 3−5 times weekly at home, community, or clinic settings, VOT was superior to DOT in ensuring scheduled observa