Annals of Internal Medicine䊛 In the Clinic® Tuberculosis A lthough tuberculosis (TB) rates remain low in the United States, 10.4 million people were diagnosed and 1.4 million died of the disease worldwide in 2015. The past decade has seen major advances in prevention, diagnosis, and treatment. New diagnostics to detect latent TB infection (LTBI) and clinical disease have been developed, and new drugs, particularly for drug-resistant TB, have become increasingly available. Despite these advances, in 2014 TB surpassed HIV/AIDS as the deadliest infectious disease in the world (1), and it continues to be the leading killer of persons infected with HIV globally. The CME quiz is available at Annals.org. Complete the quiz to earn up to 1.5 CME credits. Physician Writer Karen R. Jacobson, MD, MPH doi:10.7326/AITC201702070 CME Objective: To review current evidence for screening and prevention, diagnosis, and treatment of tuberculosis. Funding Source: American College of Physicians. Acknowledgment: The author thanks Elizabeth J. Ragan for administrative and technical support on this manuscript and Dr. Patricio Escalante, writer of the earlier version. With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians. In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/guidelines/. Disclosures: Dr. Jacobson, ACP Contributing Author, has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum=M16-2138. © 2017 American College of Physicians Screening and Prevention Diagnosis Treatment Tool Kit Patient Information In the United States, 9421 TB cases (3 cases per 100 000 persons) were reported in 2014, a 69% decrease since a resurgence in 1992 (2). Sixty-six percent of these cases occurred in foreignborn persons, a rate of infection 13 times that of U.S.-born persons (2). Racial and ethnic groups are disproportionately affected—the highest rates of infection occur among Asians as well as native Hawaiians and other Pacific Islanders. Building on the momentum of new scientific discoveries, the World Health Organization (WHO) published the END TB Strategy in 2014, which aims to reduce TB incidence and deaths by 90% and 95%, respectively, by 2035 (3). Screening and Prevention 1. World Health Organization. Global Tuberculosis Report 2016. Geneva: World Health Organization; 2016. 2. Centers for Disease Control and Prevention. Fact Sheet: Trends in tuberculosis. 2014. Accessed at www.cdc.gov/tb /publications/factsheets /statistics/tbtrends.htm on 20 December 2016. 3. World Health Organization. The END TB Strategy: Global strategy and targets for tuberculosis prevention, care and control after 2015. Geneva: World Health Organization; 2014. Accessed at www .who.int/tb/strategy /End_TB_Strategy.pdf ?ua=1 on 20 December 2016. 4. Alvarez GG, Van Dyk DD, Davies N, Aaron SD, Cameron DW, Desjardins M, et al. The feasibility of the interferon gamma release assay and predictors of discordance with the tuberculin skin test for the diagnosis of latent tuberculosis infection in a remote aboriginal community. PLoS One. 2014;9: e111986. [PMID: 25386908] 5. Ribeiro-Rodrigues R, Kim S, Coelho da Silva FD, Uzelac A, Collins L, Palaci M, et al. Discordance of tuberculin skin test and interferon gamma release assay in recently exposed household contacts of pulmonary TB cases in Brazil. PLoS One. 2014;9: e96564. [PMID: 24819060] http://dx.doi .org/10.1371/journal.pone .0096564 on 20 December 2016. 6. European Centre for Disease Prevention and Control. Management of contacts of MDR TB and XDR TB patients. Stockholm: European Centre for Disease Prevention and Control; 2012. 姝 2017 American College of Physicians Who should be screened for latent TB infection? TB is caused by the acid-fast bacillus (AFB) Mycobacterium tuberculosis, which is transmitted through airborne respiratory droplets from the throat and lungs of persons with active respiratory disease. When M tuberculosis droplets are inhaled and delivered to the terminal airways, macrophages ingest the mycobacteria, which continue to multiply intracellularly and can potentially spread to other organs through the lymphatic system and bloodstream. Most TBinfected persons remain asymptomatic and enter the latency phase (LTBI). They have a 10% lifetime risk for progressing from latent to active TB; half of that risk is progression during the first 2 years after infection (“primary progression”). The goal of LTBI testing is to identify and treat persons at increased risk for TB. These persons include contacts of an individual with known infectious pulmonary TB, those at high risk for potential exposure, and those at high risk for rapid disease progression regardless of known TB contact (see the Box). Risk for primary progression in the first 2 years after infection is agedependent— children younger than 2 years have the highest risk. Thus, particular attention should be paid to LTBI screening ITC18 In the Clinic and treatment in young children (4, 5). If the results of the first test after exposure of close contacts of a known case patient with TB (persons from the same household sharing common habitation rooms, or those with prolonged and frequent exposure in such settings as workplaces, schools, prisons, hospitals, and some social settings) (6) are negative, the test should be repeated in 8 –12 weeks to confirm lack of conversion to positive results. What tests are used to screen for TB infection? The 2 tests used to detect TB are the Mantoux tuberculin skin test (TST) and interferon-␥–release assays (IGRAs). Neither test can distinguish between latent and active disease, and neither is appropriate as the sole investigation for active disease (Table 1). Both tests are based on cellmediated immunity and thus are more likely to yield false-negative results in persons with advanced immunosuppression. The TST has been used for more than 100 years. Purified protein derivative (PPD) is injected intradermally (usually into the inner surface of the forearm). The patient returns in 48 –72 hours, and the test is read by assessing the transverse diameter of induration (not erythema). Positive results indicate a delayed-type hyper- Annals of Internal Medicine 7 February 2017 sensitivity response mediated by T lymphocytes. To increase the specificity of the test, criteria for positivity are based on the patient's risk factors for M tuberculosis infection (Table 1). The largest threshold (≥15 mm induration) has the lowest sensitivity but the highest specificity and is therefore useful to evaluate patients in regions with high prevalence of nontuberculous mycobacterium rather than M tuberculosis, such as the United States. False-negative results are more common in patients with recent TB infection, age younger than 6 months, overwhelming active TB, recent vaccination with a live virus (e.g., measles), recent viral infection (e.g., measles or varicella), and anergy. False-positive results can be caused by a history of bacille Calmette-Guérin (BCG) vaccination or infection with nontuberculous mycobacterium. People who received the BCG vaccine should have their TST interpreted according to standard criteria, although recent BCG vaccination can be an indication for IGRA testing instead. For patients who received the BCG vaccine when they were younger than 1 year, no discernible effect on TST remains after 10 or more years (7). Patients with remote exposure to TB may initially have a negative TST result that can become positive several weeks later. This is called the “booster effect” and is considered a true-positive result. It is more common in elderly persons, although it may also occur more often in persons with a history of BCG or nontuberculous mycobacteria. For this reason, current guidelines recommend a 2-step initial TST for all health care workers, with the second test done on the opposite forearm 7–21 days after initial negative results (8). Two-step testing 7 February 2017 is not required when IGRA is used (9). The Centers for Disease Control and Prevention (CDC) now endorses IGRAs, including the QuantiFERON-TB Gold In-Tube (QFT) (Qiagen) and the T-SPOT.TB (Oxford Immunotec), in nearly all clinical settings where TST is recommended (8, 10). One exception is children younger than 5 years, for whom some experts recommend both tests for increased specificity. IGRAs indicate sensitization to M tuberculosis by measuring the release of interferon-␥ in the blood by T cells as a response to M tuberculosis–associated antigen and do not require a second patient visit. The initially higher cost of IGRAs should be taken into account. These tests are considered to be as sensitive as but more specific than TSTs because persons who have other nontuberculous mycobacterium infections or have had BCG do not have positive results. IGRAs are preferred to TSTs in persons who received BCG as treatment for cancer or as a vaccine and in those who are less likely to return for a test reading in 48 –72 hours (11). Once a person has a positive TST or IGRA result, repeated testing has no clinical utility. Unless suspicion for error in interpretation or performance of the first test is high, a positive result should be considered a true positive. In a patient with a known positive TST result, repeated testing can result in a more severe, and at times necrotic, inflammatory response (12). Risk Factors for TB Infection or Progression to Disease After Infection Persons with HIV infection Patients with other immunocompromising conditions, including organ transplant recipients and others with illnesses that require immunosuppressive therapy (the equivalent of ≥15 mg of prednisone per day for ≥4 wk, which includes most persons receiving tumor necrosis factor-␣ antagonists) Persons recently in close contact with a person with active TB Persons with fibrotic changes on chest radiography consistent with old TB Recent (<5 y) arrivals from high-prevalence countries Mycobacteriology laboratory personnel Residents or employees in high-risk settings, such as prisons and jails, nursing homes and other long-term facilities for elderly persons, hospitals and other health care facilities, residential facilities for patients with AIDS, and homeless shelters Injection drug users, users of other drugs (e.g., crack cocaine), and tobacco smokers Persons with clinical conditions that put them at high risk for active disease (including diabetes mellitus; silicosis, intestinal bypass, gastrectomy, or other type of bariatric surgery; cancer of the head and neck; chronic malabsorption syndromes; end-stage renal disease; hematologic cancer; and body weight ≥10% below ideal level) Children aged ≤4 years exposed to adults with TB Two challenges for providers are how to interpret discordance between results on TST and IGRA and how to interpret reversions if a test is repeated. Historically, stable TST converters (i.e., those who do not revert with later testing) had significantly larger areas of induration than reverters at the Annals of Internal Medicine In the Clinic ITC19 姝 2017 American College of Physicians Table 1. Interpretation of Tuberculin Skin Test Results: Criteria for Tuberculin Positivity by Risk Group, According to Size of Induration, in Millimeters* ≥5 ≥10 ≥15 HIV-positive persons Recent contacts of persons with active TB Persons with fibrotic changes on chest X-ray consistent with old TB Patients who have had organ transplantation and other immunosuppressive conditions (receiving equivalent of ≥15 mg prednisone/d for >4 wk) Recent (<5 y) arrivals from high-prevalence TB countries Injection drug users Residents or employees of high-risk congregate settings, such as prisons and jails, nursing homes and other long-term facilities for elderly persons, health care facilities, residential facilities for AIDS patients, homeless shelters Persons with comorbid conditions that place them at high risk for TB (silicosis, diabetes mellitus, severe kidney disease, certain types of cancer, some intestinal conditions) Mycobacteriology laboratory personnel Children aged ≤4 y Persons with no risk factors for TB TB = tuberculosis. * Data from reference 2. time of TST conversion (13), making the larger threshold in most U.S.-based populations more likely to be true-positive. More concerning has been that rates of serial conversion from negative to positive IGRA results among health care workers in North America have been reported at nearly an order of magnitude higher than historical or concurrent TST conversion rates (14 – 16), accompanied by high rates (>60%) of reversion on subsequent testing. 7. Farhat M, Greenaway C, Pai M, Menzies D. Falsepositive tuberculin skin tests: what is the absolute effect of BCG and nontuberculous mycobacteria? Int J Tuberc Lung Dis. 2006;10:1192-204. [PMID: 17131776] 8. Centers for Disease Control and Prevention. Latent Tuberculosis Infection: A Guide for Primary Health Care Providers. 2014. Accessed at www.cdc.gov /tb/publications /ltbi/diagnosis.htm on 20 December 2016. 9. QIAGEN. Frequently Asked Questions: QuantiFERON® -TB Gold. 2013. Accessed at http://usa.quantiferon .com/irm/content/pdfs /FAQ_QFT_HCP-US_EN _1113_H_LR.pdf on 20 December 2016. 10. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Recomm Rep. 2010;59: 1-25. [PMID: 20577159] 姝 2017 American College of Physicians Hypotheses for IGRA variability in a single patient have included that initial conversion followed by reversion may reflect exposure that does not lead to persistent infection (17); operational reasons for variability in results on the QFT, including manufacturing and processing issues; analytic variability; and host immunologic changes over time (18). Recent studies have also found evidence of positive QFT results after TST in the prior 6 months, so such proximate dual testing should be particularly avoided (16, 17). For these reasons, providers should use the LTBI test that best fits their patient's needs and generally should use only one. ITC20 In the Clinic What can patients do to decrease the likelihood of infecting others? TB patients have been shown to infect up to 10 –15 other people over the course of a year. However, once a patient has received effective therapy for 2 weeks, risk for transmission is nearly, if not completely, eliminated (19 –21). Therefore, prompt identification of patients with active TB is critical to prevent transmission. Prevention of spread in hospitals includes respiratory isolation of patients with confirmed or suspected TB (22). Staff who come in contact with an infectious or suspected infectious patient should wear previously fitted particulate respirators (N95 masks). Patients suspected of having TB can be removed from isolation after 3 sputum smears, collected at least 8 hours apart, are confirmed to be negative and an alternative diagnosis has been made (22). Patients with confirmed TB can usually be removed from isolation once they begin adequate therapy; show a significant clinical response; and are negative for AFB on 3 sputum smears, also obtained at least 8 hours apart (22). Patients who are not too ill can be sent home after initiation of therapy, although they must be Annals of Internal Medicine 7 February 2017 isolated from outsiders. Healthy adults residing in the home have probably been exposed for weeks to months before diagnosis of the infected patient and are unlikely to benefit from isolation (23). However, if there are highrisk contacts in the household (i.e., children aged <5 years or immunocompromised persons), TB patients should reside elsewhere until they meet criteria for noninfection (22). The BCG vaccine is not used in the United States. However, knowledge of whether persons born in other countries received the vaccine, at what age, and whether they received a booster is particularly helpful when deciding which LTBI diagnostic test to use. An interactive Web site lists BCG vaccine practices in 180 countries (www.bcgatlas.org) (24). For patients with latent TB infection, what can be done to decrease the likelihood of developing active disease? Patients with evidence of LTBI (i.e., positive results on IGRA or TST), in whom active TB has been excluded, should be offered prophylaxis. Patients at greater risk for active disease should be particularly encouraged to take prophylaxis, including those with HIV infection, close contacts of persons with active TB in the past 2 years (especially infants and children aged <5 years), those who have fibrotic changes on a chest radiograph consistent with old TB, those with medical conditions known to increase risk (e.g., diabetes mellitus; silicosis; organ transplantation; immunosuppressive therapy, such as the equivalent of >15 mg of prednisone per day for ≥1 month; and receipt of tumor necrosis factor-␣ antagonists), those who inject illicit drugs and other high-risk substance users, and residents and employees in high-risk congregate settings (e.g., correctional facilities, 7 February 2017 nursing homes, homeless shelters, and hospitals) (25, 26). Immunocompetent children younger than 5 years should be started on “window prophylaxis,” regardless of baseline TST/IGRA status, and this therapy should be stopped only if TST/IGRA results are negative 8–10 weeks after the last contact with a contagious case (27). The CDC endorses 4 LTBI treatment regimens: 9 or 6 months of isoniazid (INH), 3 months of INH plus rifapentine (RPT), or 4 months of rifampin (RIF) (Table 2). The newest, the “12-dose regimen,” is a combination of INH and RPT given weekly for 3 months; treatment completion was 82% among patients receiving the 12-dose regimen compared with 69% among those receiving 9 months of INH in the TB Trials Consortium Prevent TB study (P < 0.001) (28). Directly observed therapy (DOT) for this regimen is currently recommended because the impact of missed doses is unknown, but at least 1 CDC-sponsored study suggests that self-administration does not lead to inferior adherence in the United States (29). DOT also provides the opportunity to screen patients for adverse effects and to stop therapy if they occur. A meta-analysis reports that the weekly INH–RPT regimen had higher treatment completion and less hepatotoxicity but more frequent treatmentlimiting adverse events compared with 9 months of daily treatment with INH (30). The 12dose regimen is an option for otherwise-healthy persons aged 12 years or older. It is not recommended for children younger than 12 years, HIV-infected persons receiving antiretroviral medicines (due to drug interactions), pregnant women or women who expect to become pregnant during treatment, persons infected with drug-resistant strains (31), Annals of Internal Medicine In the Clinic ITC21 11. Ringshausen FC, Schablon A, Nienhaus A. Interferon-gamma release assays for the tuberculosis serial testing of health care workers: a systematic review. J Occup Med Toxicol. 2012;7:6. [PMID: 22537915] 12. Bunnet D, Kerleguer A, Kim P, Pean P, Phuong V, Heng N, et al. Necrotic tuberculin skin (Mantoux) test reaction: a case report and an estimation of frequency. Chest. 2015;148:e1-4. [PMID: 26149555] 13. Johnson DF, Malone LL, Zalwango S, Mukisa Oketcho J, Chervenak KA, Thiel B, et al; Tuberculosis Research Unit. Tuberculin skin test reversion following isoniazid preventive therapy reflects diversity of immune response to primary Mycobacterium tuberculosis infection. PLoS One. 2014;9: e96613. [PMID: 24796677] 14. Zwerling A, Benedetti A, Cojocariu M, McIntosh F, Pietrangelo F, Behr MA, et al. Repeat IGRA testing in Canadian health workers: conversions or unexplained variability? PLoS One. 2013;8:e54748. [PMID: 23382955] 15. Slater ML, Welland G, Pai M, Parsonnet J, Banaei N. Challenges with QuantiFERON-TB Gold assay for large-scale, routine screening of U.S. healthcare workers. Am J Respir Crit Care Med. 2013;188:1005-10. [PMID: 23978270] 16. Dorman SE, Belknap R, Graviss EA, Reves R, Schluger N, Weinfurter P, et al; Tuberculosis Epidemiologic Studies Consortium. Interferon-␥ release assays and tuberculin skin testing for diagnosis of latent tuberculosis infection in healthcare workers in the United States. Am J Respir Crit Care Med. 2014;189:77-87. [PMID: 24299555] 17. Andrews JR, Hatherill M, Mahomed H, Hanekom WA, Campo M, Hawn TR, et al. The dynamics of QuantiFERON-TB gold in-tube conversion and reversion in a cohort of South African adolescents. Am J Respir Crit Care Med. 2015;191: 584-91. [PMID: 25562578] 18. Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev. 2014;27:3-20. [PMID: 24396134] 姝 2017 American College of Physicians Table 2. Treatment Regimens for Latent TB* Drugs Duration Interval Comments INH 9 mo Daily Preferred treatment for: • Persons with HIV • Children aged 2–11 y • Pregnant women (with pyridoxine/vitamin B6 supplements)‡ Preferred treatment for pregnant women (with pyridoxine/vitamin B6 supplements)‡ Not indicated for HIV-infected persons, persons with fibrotic lesions on chest radiographs, or children Twice weekly§ INH 6 mo Daily INH + RPT 3 mo Twice weekly§ Once weekly§ RIF 4 mo Daily Rating (evidence)† Treatment for persons ≥12 y Not recommended for persons: • <2 y • Receiving antiretroviral treatment • Presumed to be infected with INH- or RIF-resistant Mycoplasma tuberculosis • Who are pregnant or expect to become pregnant Not recommended for persons: • Receiving medications that interact with rifamycins • Who wear contact lenses • Who are pregnant or expect to become pregnant HIV– HIV+ A2 A2 B2 B2 B1 C1 B2 A1 C1 A兩兩1 B2 B3 INH = isoniazid; RIF = rifampin; RPT = rifapentine; TB = tuberculosis. * Adapted from Centers for Disease Control and Prevention. Treatment Regimens for Latent TB Infection (LTBI) [Internet]. 2016. Available from www.cdc.gov/tb/topic/treatment/ltbi.htm. † A = preferred; B = acceptable alternative; C = offer if A or B are not available; 1 = randomized, clinical trial; 2 = data from clinical trials that were not randomized or were conducted in other populations; 3 = expert opinion. ‡ May be delayed until after delivery and cessation of breastfeeding except in cases of increased risk for placental infection or progression to active TB. § Using directly observed therapy. 兩兩 In otherwise-healthy HIV patients not receiving antiretroviral medication. 19. Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle. 1976;57:27599. [PMID: 827837] Accessed at http://dx.doi .org/10.1016/S0041 -3879(76)80006-2 on 20 December 2016. 20. Riley RL, Mills CC, O’Grady F, Sultan LU, Wittstadt F, Shivpuri DN. Infectiousness of air from a tuberculosis ward. Ultraviolet irradiation of infected air: comparative infectiousness of different patients. Am Rev Respir Dis. 1962;85:51125. [PMID: 14492300] 21. Dharmadhikari AS, Mphahlele M, Venter K, Stoltz A, Mathebula R, Masotla T, et al. Rapid impact of effective treatment on transmission of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2014;18: 1019-25. [PMID: 25189547] 22. Jensen PA, Lambert LA, Iademarco MF, Ridzon R. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep. 2005;54: 1-141. [PMID: 16382216] 姝 2017 American College of Physicians and those receiving medications that interact with rifamycins. In pregnant women, a 6- to 9-month course of INH may be delayed until after delivery and cessation of breastfeeding, except when risk for placental infection or progression to active TB is increased (i.e., immunocompromising conditions, such as HIV co-infection or recent M tuberculosis infection) (32). For those exceptions, treatment with INH plus pyridoxine/vitamin B6 (plus B6 to the newborn) should be initiated during pregnancy or breastfeeding with close monitoring for INH hepatotoxicity, which is more common in women during pregnancy. Treatment of LTBI in contacts of patients with drug-resistant TB is not well-studied. Current guidelines recommend considering an ITC22 In the Clinic alternative multidrug prophylaxis regimen if a person is at high risk for progression to active disease (i.e., HIV-positive) and the susceptibility of the infecting organism is known (33). Such patients should be referred to an experienced specialist. How can patients with active TB protect household members and other contacts from infection? Patients who are infected with or are suspected of being infected with TB must be educated to cover their mouth and nose when they cough or sneeze, not sleep in a room with other household members, and refrain from having home visitors until they are noninfectious. What are the physician's public health responsibilities after diagnosing active TB? All 50 states require health care providers to notify the TB pro- Annals of Internal Medicine 7 February 2017 gram in their respective departments of health within 24 hours in cases of suspected or confirmed active TB (34); requirements for further reporting vary by state. Within 24 hours, a state's TB program is responsible for notifying the local board of health of the patient's residence, to set up processes to screen potential contacts, and take steps to avoid further transmission. Providers must report treatment progress as well as patients who are nonadherent, leave medical facilities against medical advice, or continue to place others at risk. Screening and Prevention... Clinicians should screen close contacts of a person with active pulmonary TB or those who are at high risk for infection or progression to disease once infected. Clinicians should prevent infection by identifying and treating persons with active pulmonary TB. Patients with evidence of infection but not disease should be offered LTBI therapy. Patients suspected of having TB should be placed on airborne isolation, and staff who provide care should wear particulate respirators. Clinicians should notify public health authorities about patients with suspected active TB. CLINICAL BOTTOM LINE Diagnosis What are the signs and symptoms of active TB? Table 3 shows some of the main findings from the history and physical examination that are associated with active TB. Pulmonary disease is overwhelmingly the most common presentation (>80%) (35). Persons with compromised immune systems (e.g., HIV co-infected patients) may present with few classic symptoms and are more likely to present with extrapulmonary TB. What are the signs and symptoms of active TB among HIV co-infected patients? Signs and symptoms vary by degree of immunodeficiency. Patients with CD4 counts greater than 350 per cubic millimeter are more likely to present with classic constitutional symptoms; those with CD4 counts less than 200 per cubic millimeter are more likely to have atypical and asymptomatic presentation and extrapulmonary disease (36, 37). For this reason, the index of sus- 7 February 2017 picion for active TB should be high in patients with HIV who have been exposed to TB. Active microbiological screening for TB, regardless of whether symptoms are present, is important because disease can be missed when screening is based on signs and symptoms alone. Up to 25% of patients screened before starting antiretroviral drugs in South Africa were found to have microbiologically confirmed TB (38, 39). How is active TB diagnosed? In resource-rich settings, patients with symptoms, signs, or radiographic findings suggestive of active TB should receive 3 serial sputum microscopy and mycobacterial cultures collected at least 8 hours apart, in addition to chest radiography. Sputum induction should be done if patients cannot expectorate spontaneously. If there are signs of extrapulmonary disease, samples from those areas, such as lymph nodes or the pleural space, should also be evaluated. Histopathologic evidence of caseating Annals of Internal Medicine In the Clinic ITC23 23. Kamat SR, Dawson JJ, Devadatta S, Fox W, Janardhanam B, Radhakrishna S, et al. A controlled study of the influence of segregation of tuberculous patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in South India. Bull World Health Organ. 1966;34:517-32. [PMID: 5296379] 24. Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M. The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med. 2011;8: e1001012. [PMID: 21445325] 25. Centers for Disease Control and Prevention. Deciding When to Treat Latent TB Infection. 2016. Accessed at www .cdc.gov/tb/topic /treatment/decideltbi .htm on 20 December 2016. 26. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst Rev. 2000:CD001363. [PMID: 10796642] 27. Loeffler AM. Pediatric Tuberculosis: An Online Presentation. 2010. Accessed at www .currytbcenter.ucsf.edu /products/pediatric -tuberculosis-online -presentation?productID =ONL-10 on 20 December 2016. 28. Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, BlivenSizemore E, et al; TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365:2155-66. [PMID: 22150035] www .ncbi.nlm.nih.gov /pubmed/22150035 on 20 December 2016. 29. Belknap R, Borisov A, Holland D, Feng P-J, Millet J-P, Martinson N, et al. Adherence to OnceWeekly SelfAdministered INH and Rifapentine for Latent TB: iAdhere. In: Conference on Retroviruses and Opportunistic Infections. Seattle; 2017. Accessed at www.croiconference .org/sessions/adherence -once-weekly-self -administered-inh-and -rifapentine-latent-tb -iadhere on 20 December 2016. 姝 2017 American College of Physicians Table 3. Findings From the History and Physical Examination in Patients With Active TB History Notes TB exposure, infection, disease, or treatment Patients with recent exposure to TB are more likely to develop disease; however, known exposure is not necessary to have TB. Clinicians may contact their local health department to learn whether a patient has received TB treatment in the past and what regimen was used HIV infection or other medical conditions, or demographic factors that may increase the risk for, or change the presentation of, TB HIV-infected patients with latent TB infection have >20-fold risk for progression to active TB than patients without HIV. Signs and symptoms of other concurrent medical conditions may mask signs and symptoms of TB Fever Less likely to be present in elderly persons. Absence of fever does not rule out TB. Patients may report feeling feverish without having fever Malaise Night sweats A classic symptom of TB but may only be present in disease of long duration Weight loss More common in advanced, extrapulmonary, or disseminated disease Gynecologic symptoms Pelvic pain, menstrual irregularities, and infertility are the most common Physical Examination Systemic signs Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy, and splenomegaly can be present Throat examination Hoarseness Lymph node examination May be palpable with pulmonary, disseminated disease, or scrofula Pulmonary examination Generally not helpful but may include rales, signs of consolidation, or findings consistent with (often unilateral) pleural effusion (including pleuritic pain) Pericardial disease Tachycardia, increased venous pressure, hepatomegaly, pulsus paradoxus, and friction rub Abdominal examination Ascites, “doughy” abdomen, or abdominal mass. Hepatosplenomegaly in disseminated disease Genitourinary examination Recurrent urinary tract infection with no organisms on culture. In men, beaded vas deferens on palpation, draining scrotal sinus, epididymitis or induration of prostrate or seminal vesicles Musculoskeletal examination Joint swelling, gibbus deformity, or localized pain Neurologic examination Abnormal behavior, headache, seizure TB = tuberculosis. 30. Sharma SK, Sharma A, Kadhiravan T, Tharyan P. Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB. Cochrane Database Syst Rev. 2013:CD007545. [PMID: 23828580] 31. Castro KG. New Regimen Makes Treating Latent Tuberculosis Infection Easier. Medscape. 2012. 32. Sackoff JE, Pfeiffer MR, Driver CR, Streett LS, Munsiff SS, DeHovitz JA. Tuberculosis prevention for non-US-born pregnant women. Am J Obstet Gynecol. 2006;194: 451-6. [PMID: 16458645] 33. Management of persons exposed to multidrugresistant tuberculosis. MMWR Recomm Rep. 1992;41:61-71. [PMID: 1640921] 姝 2017 American College of Physicians granulomas is suggestive of active TB but is not diagnostic; similarly, AFB positivity alone does not confirm diagnosis. The gold standard for TB diagnosis is a positive mycobacterial culture from liquid medium. Negative results on AFB smears occur in half of patients with active pulmonary TB and in an even higher percentage of HIV co-infected persons; therefore, mycobacterial cultures should be routinely done, even in patients with negative smears. In persons suspected of having disseminated TB or who are highly immunosuppressed (i.e., advanced AIDS), blood culture and collection of first-void urine for mycobacterial analysis can be done. ITC24 In the Clinic Bronchoscopy with either bronchoalveolar lavage or biopsy should be used for diagnosis in patients who are suspected of having active disease but have negative sputum samples (40). Symptoms similar to those of TB, such as weight loss, fever, and cough, can be caused by nontuberculous mycobacteria, aspiration pneumonia, lung abscesses, Wegener granulomatosis, actinomycosis, and cancer. Thus, TB infection should be confirmed on culture whenever possible. Clinicians should be aware of other diseases that may resemble TB on pathologic examination, including nontuberculous mycobacteria, syphilis, brucellosis, sarcoidosis, or such fungal diseases as histoplasmosis or coccidiomycosis (41). Annals of Internal Medicine 7 February 2017 A major operational challenge in diagnosing TB is the lag time until results from solid media (i.e., Löwenstein–Jensen medium) are available. Liquid medium (e.g., Mycobacteria Growth Indicator Tube) has a shorter median time to positivity for both smearpositive (7 vs. 14 days) and smear-negative (14 vs. 25 days) disease (42). The CDC has endorsed the additional use of nucleic acid amplification (NAA) testing on sputum specimens when TB is suspected (43). This test can provide results in 24 – 48 hours and has a greater positive predictive value for true M tuberculosis (>95%) compared with AFB smear-positive specimens in settings where nontuberculous mycobacterium are common. NAA can also rapidly confirm the presence of M tuberculosis in 50%– 80% of AFB smearnegative, culture-positive specimens. Compared with culture, results are available weeks earlier for 80%–90% of patients with suspected pulmonary TB among those in whom it is ultimately confirmed by culture (44). Thus, although NAA should not replace culture, it can facilitate earlier decision making regarding whether to initiate treatment for TB. The Xpert MTB/RIF assay is an NAA test that uses a disposable cartridge in the GeneXpert Instrument System, and results are available within 2 hours. This assay has been reported to have specificity of 99% and sensitivity of 98% in smear-positive and specificity of 99% and sensitivity of 67% in smear-negative sputum specimens (45). Xpert MTB/RIF testing has been widely implemented in resourcelimited settings with high TB prevalence (46). In a large U.S. study, diagnostic performance of this test was similar to that in high–TB burden settings, supporting its use for initial evalua- 7 February 2017 tion of suspected TB in conjunction with other tests (47). Two negative Xpert MTB/RIF tests may in the future replace the current standard of 3 sputum smears to rule out infectious TB, permitting removal of respiratory precautions. A result indicating RIF susceptibility can also reassure providers that the patient is unlikely to have multidrug resistance (MDR). How should drug susceptibility testing be done, and in which patients? If active TB is confirmed, susceptibility testing for first-line drugs should be done, ideally on the initial, pretreatment isolate. Drug-resistant TB was previously believed to be caused by acquired resistance in initially drugsusceptible disease due to poorquality drugs, poor adherence, or a weak drug combination. However, a globally increasing proportion of drug-resistant cases is now occurring due to person-to-person transmission. Thus, the ability to predict who has drug-resistant disease has weakened, making baseline resistance testing even more important. Culture remains the standard for drug susceptibility testing and should be done at a reference laboratory. If available, Xpert MTB/RIF can detect RIF resistance, allowing for more rapid triage of samples for additional testing. If RIF resistance is detected, drug susceptibility testing for both first-line and secondline drugs should be done (see the CDC TB Web site for details) and the treatment regimen should be adjusted accordingly. Drug-resistant TB refers to M tuberculosis with resistance to any of the TB drugs. An important distinction is MDR TB, which is defined as resistance to INH and RIF. Patients with this type of Annals of Internal Medicine In the Clinic ITC25 34. Centers for Disease Control and Prevention. Menu of Suggested Provisions For State Tuberculosis Prevention and Control Laws. 2010. Accessed at www.cdc.gov /tb/programs/laws/menu /caseid.htm on 20 December 2016. 35. Sandgren A, Hollo V, van der Werf MJ. Extrapulmonary tuberculosis in the European Union and European Economic Area, 2002 to 2011. Euro Surveill. 2013;18. [PMID: 23557943] 36. Schutz C, Meintjes G, Almajid F, Wilkinson RJ, Pozniak A. Clinical management of tuberculosis and HIV-1 co-infection. Eur Respir J. 2010;36: 1460-81. [PMID: 20947678] 37. Mendelson M. Diagnosing tuberculosis in HIVinfected patients: challenges and future prospects. Br Med Bull. 2007;81-82:149-65. [PMID: 17470475] 38. Lawn SD, Edwards DJ, Kranzer K, Vogt M, Bekker LG, Wood R. Urine lipoarabinomannan assay for tuberculosis screening before antiretroviral therapy diagnostic yield and association with immune reconstitution disease. AIDS. 2009; 23:1875-80. [PMID: 20108382] 39. Kranzer K, Houben RM, Glynn JR, Bekker LG, Wood R, Lawn SD. Yield of HIV-associated tuberculosis during intensified case finding in resourcelimited settings: a systematic review and metaanalysis. Lancet Infect Dis. 2010;10:93-102. [PMID: 20113978] 40. Malekmohammad M, Marjani M, Tabarsi P, Baghaei P, Sadr Z, Naghan PA, et al. Diagnostic yield of postbronchoscopy sputum smear in pulmonary tuberculosis. Scand J Infect Dis. 2012;44:36973. [PMID: 22497518] www.ncbi.nlm.nih.gov /pubmed/22497518 on 20 December 2016. 41. Zumla A, James DG. Granulomatous infections: etiology and classification. Clin Infect Dis. 1996;23:146-58. [PMID: 8816144] 42. Chihota VN, Grant AD, Fielding K, Ndibongo B, van Zyl A, Muirhead D, et al. Liquid vs. solid culture for tuberculosis: performance and cost in a resource-constrained setting. Int J Tuberc Lung Dis. 2010;14:1024-31. [PMID: 20626948] 姝 2017 American College of Physicians 43. Update: nucleic acid amplification tests for tuberculosis. MMWR Morb Mortal Wkly Rep. 2000;49:593-4. Accessed at https://stacks .cdc.gov/view/cdc/27233 on 20 December 2016. 44. Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep. 2009;58:7-10. [PMID: 19145221] 45. Steingart K, Schiller I, Horne D, Boehme CC, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2014;(1): CD009593. www.ncbi .nlm.nih.gov/pubmed /19145221 on 20 December 2016. 46. World Health Organization. Policy statement: automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system. Geneva: World Health Organization; 2011. Accessed at http://apps .who.int/iris/bitstream /10665/44586/1 /9789241501545_eng .pdf on 20 December 2016. 47. Luetkemeyer AF, Firnhaber C, Kendall MA, Wu X, Mazurek GH, Benator DA, et al; AIDS Clinical Trials Group A5295 and Tuberculosis Trials Consortium Study 34 Teams. Evaluation of Xpert MTB/ RIF versus AFB smear and culture to identify pulmonary tuberculosis in patients with suspected tuberculosis from low and higher prevalence settings. Clin Infect Dis. 2016;62:1081-8. [PMID: 26839383] 48. Migliori GB, Lange C, Girardi E, Centis R, Besozzi G, Kliiman K, et al; SMIRA/TBNET Study Group. Extensively drugresistant tuberculosis is worse than multidrugresistant tuberculosis: different methodology and settings, same results [Letter]. Clin Infect Dis. 2008;46:958-9. [PMID: 18288911] drug resistance require a change to a second-line regimen and have significantly worse outcomes than those with drug-susceptible TB (1). Patients with MDR TB and resistance to 2 of the second-line drugs, a fluoroquinolone and an injectable aminoglycoside (e.g., amikacin, capreomycin, or kanamycin), are considered to have extensively drug-resistant (XDR) TB and have extremely poor treatment outcomes, partially due to the few good drugs left to treat them (48). When should clinicians refer patients with suspected active TB to an expert? Providers who rarely care for patients with TB should consult an expert if the patient has a negative AFB smear and culture results but pulmonary TB is still suspected clinically, if the patient has drugresistant TB, or if the patient has been treated previously for TB. Delayed or inappropriate treatment may lead to prolonged transmission of disease and development of drug resistance. Diagnosis... Patients should be tested for TB if they have prolonged cough, hemoptysis, chest pain, or systemic symptoms. Clinical suspicion should be higher in patients who are HIV-positive, even if they have few symptoms and a clear chest radiograph. Patients with negative microbiologic testing but for whom clinical suspicion is still high should receive empirical treatment with assessment for clinical response after 2 months. Patients should be referred to a TB expert if the primary physician has little experience with TB, the presentation is not straightforward, drug resistance is present, or the patient does not respond to therapy. CLINICAL BOTTOM LINE Treatment 姝 2017 American College of Physicians What is the standard drug treatment for active TB in cases of drug-susceptible M tuberculosis infection? The most recent professional guidelines for treating drugsusceptible TB were published in June 2016 (49). The preferred regimen for treating adults with TB that is known or believed to be drug-susceptible consists of an intensive phase of 4 drugs (INH, RIF, ethambutol [EMB], and pyrazinamide [PZA]) for 2 months, followed by a continuation phase consisting of 2 drugs (INH plus RIF), usually for 4 months. If the M tuberculosis isolate is found to be susceptible to INH and RIF, EMB can be stopped early in the intensive phase. Pyridoxine (vitamin B6) ITC26 In the Clinic should be given with INH to all persons at risk for neuropathy (i.e., pregnant women; breastfeeding infants; HIV-infected persons; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; and persons of advanced age). If given correctly and taken completely, this regimen has a 95% cure rate (50). The preferred schedule is daily dosing during both the intensive and continuation phases with DOT 5 days per week (49). If daily DOT is difficult, intermittent dosing can be done as an alternative in HIV-negative, pulmonary TB cases caused by drugsusceptible organisms without cavitation, but this should be reviewed with a TB specialist. Annals of Internal Medicine 7 February 2017 What is the best way to monitor the results of treatment and to detect adverse effects during active TB therapy? Table 4 shows recommended baseline, follow-up, and end-oftreatment evaluations for patients treated with first-line TB medications (49). The baseline visit should assess AFB smear and TB culture status as well as drug susceptibility of the infecting isolate with rapid molecular diagnostic and traditional susceptibility testing. A chest radiograph should be done to assess the extent of cavitation. Blood should be drawn to assess general health, including liver and kidney function. Weight should be recorded, and baseline symptoms should be assessed. Patients should be screened for HIV, hepatitis B and C viruses, alcoholism, and diabe- tes—these are common comorbidities among TB patients and are associated with variable treatment outcomes. Sputum specimens should be collected at treatment months 1 and 2 to assess response and, beyond that point, if treatment failure or delayed conversion is suspected. If a patient is culturepositive at treatment month 3, drug-susceptibility testing should be repeated to assess for acquired drug resistance. Medication adverse effects are common. In a prospective cohort study of Chinese patients receiving standard first-line treatment, 15% had a documented adverse drug reaction that led to interruption or discontinuation of therapy; of these, 7.7% resulted in hospitalization, disability, or death (51). The most serious ad- Table 4. Recommended Baseline, Follow-up, and End-of-Treatment Evaluations for Patients Treated With First-Line TB Medications* Test Month of Treatment Completed Baseline 1 2 3 4 Microbiology Sputum smears and culture Drug susceptibility testing • • • • ° ° ° Imaging Chest radiograph or other imaging • • Clinical Assessment Weight Symptom and adherence review Vision assessment • • • • • • • • • • • • • • • • • • • • • ° ° ° ° ° ° Laboratory Testing AST, ALT, bilirubin, alkaline phosphate Platelet count Creatinine HIV serology Hepatitis B and C screen Diabetes screen • • • • ° ° ° ° ° ° ° ° 5 6 7 8 End of treatment ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° 49. Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drugsusceptible tuberculosis. Clin Infect Dis. 2016;63: e147-95. [PMID: 27516382] 50. Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. N Engl J Med. 2013;368:745-55. [PMID: 23425167] www .ncbi.nlm.nih.gov /pubmed/23425167 on 20 December 2016. ° ° ° ALT = alanine aminotransferase; AST = aspartate aminotransferase; TB = tuberculosis. * Adapted from reference 49. • = recommended diagnostics or procedures; ° = optional or contingent diagnostics or procedures. 7 February 2017 Annals of Internal Medicine In the Clinic ITC27 姝 2017 American College of Physicians 51. Lv X, Tang S, Xia Y, Wang X, Yuan Y, Hu D, et al. Adverse reactions due to directly observed treatment strategy therapy in Chinese tuberculosis patients: a prospective study. PLoS One. 2013; 8:e65037. [PMID: 23750225] 52. Saukkonen JJ, Powell K, Jereb JA. Monitoring for tuberculosis drug hepatotoxicity: moving from opinion to evidence [Editorial]. Am J Respir Crit Care Med. 2012; 185:598-9. [PMID: 22422902] 53. Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, et al; Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet. 2002;360: 528-34. [PMID: 12241657] 54. Jo KW, Yoo JW, Hong Y, Lee JS, Lee SD, Kim WS, et al. Risk factors for 1-year relapse of pulmonary tuberculosis treated with a 6-month daily regimen. Respir Med. 2014;108:654-9. [PMID: 24518046] 55. Horne DJ, Royce SE, Gooze L, Narita M, Hopewell PC, Nahid P, et al. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect Dis. 2010;10: 387-94. [PMID: 20510279] 56. Chang KC, Leung CC, Yew WW, Ho SC, Tam CM. A nested casecontrol study on treatment-related risk factors for early relapse of tuberculosis. Am J Respir Crit Care Med. 2004;170:1124-30. [PMID: 15374844] 57. Availability of an assay for detecting Mycobacterium tuberculosis, including rifampin-resistant strains, and considerations for its use—United States, 2013. MMWR Morb Mortal Wkly Rep. 2013;62:821-7. [PMID: 24141407] Accessed at www.ncbi.nlm.nih.gov /pubmed/24141407 on 20 December 2016. 58. Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J; British Infection Society. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect. 2009;59:167-87. [PMID: 19643501] 姝 2017 American College of Physicians verse effect is often hepatotoxicity, which occurred in 3%–13% of patients in a review of retrospective studies (52). Patients are encouraged to abstain from alcohol and avoid acetaminophencontaining products while receiving TB treatment. Persons who have evidence of hepatotoxicity at baseline, develop symptoms of hepatotoxicity, chronically consume alcohol, have viral hepatitis or a history of liver disease, or are HIV co-infected should have liver function tests regularly throughout treatment. Patients on an EMB-containing regimen should have their vision assessed at baseline and on a monthly basis thereafter with a visual acuity test (e.g., Snellen test) and a color discrimination test (e.g., Ishihara test). When and why should the standard treatment regimen be modified? During treatment, a sputum specimen for AFB and mycobacterial culture should be obtained monthly until results are negative for 2 consecutive months. Positive culture results after 2 months of therapy have been shown to predict relapse after therapy completion, although sensitivity is low (53–55). Cavitation on initial chest radiograph has also been shown to predict relapse (53, 56). In patients treated for 6 months, a positive culture at 2 months and cavitation were associated with a relapse rate of almost 20% within 1 year of treatment completion compared with 2% in patients with neither factor (54). Expert opinion based on these findings recommends extending the continuation phase for an additional 3 months (i.e., a continuation phase of 7 months leading to a total of 9 months' treatment) (49). Because of the complexity, length, and adverse effects of treatment, complete adherence ITC28 In the Clinic is challenging. Breaks earlier in treatment and of longer duration can have more serious effects and may warrant restarting the treatment “clock” (49). Specifically, if treatment is interrupted for 2 weeks or more during the intensive phase, the patient should restart this phase from the beginning. If treatment is interrupted for less than 2 weeks in the intensive phase, continuation of therapy until all doses are completed is acceptable as long as this occurs within 3 months. For the continuation phase, if a patient takes more than 80% of all doses and AFB smear results were initially negative, further therapy may not be necessary. If the AFB was positive, the patient should take all doses until completed. If more than 80% of all doses have been missed but during less than 2 consecutive months, the patient can continue therapy until completion. If more than 2 consecutive months were missed, the patient should repeat a full course of therapy from the beginning (intensive and continuation phases) (57). How should patients with extrapulmonary TB be treated? The principles for treating pulmonary TB apply to extrapulmonary disease. Increasing evidence suggests that 6 –9 months of INH- and RIF-containing regimens are effective for TB treatment in most extrapulmonary disease sites, although the robustness of the data for extrapulmonary disease is not as great as for pulmonary TB (49). The clear exception is TB meningitis, for which the ideal treatment regimen is not known but most experts recommend 2 months of the 4-drug regimen and then 10 months of INH plus RIF (58). A mortality benefit has also been shown with the addition of corticosteroids (dexamethasone or Annals of Internal Medicine 7 February 2017 prednisolone) to this regimen, tapered over 6 – 8 weeks (59, 60). No large randomized, controlled trials or systematic reviews found differences in mortality, cardiac tamponade, or constrictive pericarditis among patients with TB pericarditis who did or did not receive steroids (49, 61). Regardless, experts recommend that addition of steroids be considered in patients at highest risk for inflammatory complications (i.e., presence of large pericardial effusions, high levels of inflammatory cells or markers in pericardial fluid, or early signs of pericardial constriction). For monitoring treatment response, bacteriologic evaluation is often limited by difficulty in obtaining follow-up specimens. Sputum specimens should be obtained when concurrent pulmonary TB is present; otherwise, response to therapy is often judged on clinical and radiographic findings. What is the approach to treatment of active TB and HIV co-infection? Because patients with HIV infection often have more rapid progression to TB and higher mortality related to delayed treatment initiation, TB medication should be started as soon after diagnosis as possible (62). The recommended regimen for drugsusceptible TB is the same for co-infected patients and HIVuninfected patients. For HIVinfected patients receiving antiretroviral therapy (ART) (which should be all patients), the standard 6-month daily regimen for drug-susceptible TB is recommended (49). In rare cases where an HIV-infected person does not receive ART during TB treatment, the continuation phase can be extended for an additional 3 months (i.e., a total of 9 months' treatment). As with HIV- 7 February 2017 uninfected patients, regimens should be extended for the reasons outlined above. HIVinfected patients should not receive intermittent dosing regimens, regardless of whether they are receiving ART, because these regimens have been associated with higher rates of relapse and acquired drug resistance in coinfected persons (53, 63). Management of patients coinfected with HIV and TB is complicated by the timing of ART initiation, potential drug interactions between HIV and TB medications, and paradoxical reactions (i.e., immune reconstitution inflammatory syndrome [IRIS] [see below]). Research now strongly supports early initiation of ART for patients with TB. A systematic review found that the overall reduction in mortality with ART initiation during TB treatment was 24% (relative risk [RR], 0.76 [95% CI, 0.57–1.01]) (49). Overall risk for HIV disease progression was reduced by 34% by early or immediate ART (RR, 1.88 [CI, 1.31– 2.69]). Based on this review, patients with a CD4 count less than 0.050 × 109 cells/L should be started on ART within 2 weeks after initiation of TB therapy, and those with a CD4 count of 0.050 × 109 cells/L or greater should be started between 8 and 12 weeks after initiation. The important exception is HIV-infected patients with TB meningitis, in whom ART should not be initiated during the first 8 weeks of anti-TB therapy at any CD4 count to avoid increased morbidity from IRIS. The major concern with regard to drug interactions in co-infected patients is that between RIF, a potent inducer of multiple drugmetabolizing enzymes and drug transporters, and ART. Although RIF has been shown to decrease Annals of Internal Medicine In the Clinic ITC29 59. Critchley JA, Young F, Orton L, Garner P. Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and metaanalysis. Lancet Infect Dis. 2013;13:223-37. [PMID: 23369413] 60. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TTO, Nguyen TCT, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004 Oct 21;351(17):1741–51. [PMID: 15496623] Accessed at www.ncbi.nlm .nih.gov/pubmed /15496623 on 20 December 2016. 61. Mayosi B, Ntsekhe M, Smieja M. Immunotherapy for tuberculous pericarditis. N Engl J Med. 2014;371:2532-3. [PMID: 25539114] 62. Holtz TH, Kabera G, Mthiyane T, Zingoni T, Nadesan S, Ross D, et al. Use of a WHO-recommended algorithm to reduce mortality in seriously ill patients with HIV infection and smear-negative pulmonary tuberculosis in South Africa: an observational cohort study. Lancet Infect Dis. 2011; 11:533-40. [PMID: 21514234] 63. Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet. 1999 May 29; 353:1843-7. [PMID: 10359410] 姝 2017 American College of Physicians drug levels of efavirenz, efavirenz-based ART with RIFcontaining TB treatment is the most well-characterized regimen with the best-documented outcomes for patients and low discontinuation rates; as such, it remains the preferred drug combination (64). Alternative regimens that include protease inhibitor– based ART paired with a rifabutin-containing TB regimen and nevirapine-based ART paired with a RIF-containing TB regimen have also been endorsed if a patient cannot take efavirenz. If possible, co-infected patients should be managed by providers with experience treating the 2 diseases due to the complexity of the treatment regimens. 64. Tuberculosis (TB): Managing drug interactions in the treatment of HIVrelated tuberculosis. 2013. Accessed at www .cdc.gov/tb/publications /guidelines/tb_hiv_drugs/table1a.htm on 21 December 2016. 65. Török ME, Yen NT, Chau TT, Mai NT, Phu NH, Mai PP, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)— associated tuberculous meningitis. Clin Infect Dis. 2011;52:1374-83. [PMID: 21596680] 66. Horsburgh CR, Barry CE, Lange C. Treatment of tuberculosis. N Engl J Med. 2015 Nov 26;373: 2149-60. [PMID: 26605929] 67. World Health Organization. WHO treatment guidelines for drugresistant tuberculosis— 2016 update. Geneva: World Health Organization; 2016. 姝 2017 American College of Physicians Co-infected patients are at risk for paradoxical worsening of TB symptoms and lesions after beginning TB therapy and ART. This reaction is a consequence of reconstitution of the immune response brought on by ART and is referred to as IRIS. IRIS in patients with TB is reported more commonly in those with CD4 counts less than 0.050 × 109 cells/L. Before it can be diagnosed, other reasons for the worsening signs and symptoms need to be excluded, especially treatment failure due to drug resistance or other opportunistic diseases. Patients who start ART within 2 weeks of TB therapy have higher IRIS rates than those who start between 8 and 12 weeks; hence, the recommendation to delay ART in patients with higher CD4 counts. In patients with a CD4 cell count less than 50 per cubic millimeter, starting ART within 2 weeks after TB treatment initiation is recommended. Most IRIS can be managed symptomatically by adding anti-inflammatory agents, such as ibuprofen or corticosteroids (49). The exception is central nervous system TB, including TB meningitis: Patients in ITC30 In the Clinic whom ART was initiated within 2 weeks of TB therapy had increased rates of adverse events and higher mortality (65). What are the indications for DOT for active TB? Adherence to TB treatment is challenging but critical for both improved patient outcomes and to avoid disease transmission; therefore, DOT (in which ingestion of each dose is witnessed) has been widely endorsed. DOT remains the standard of practice in most U.S. and European TB programs (49) and is discussed in detail elsewhere (49). When should patients be treated for drug-resistant TB, and what is the basic approach? Patients infected with M tuberculosis that is resistant only to INH (i.e., INH-monoresistant TB) can receive the 3 other first-line drugs (RIF, EMB, and PZA) for the full 6 months of treatment, or a fluoroquinolone (levofloxacin or moxifloxacin) could be added to the 3-drug regimen (66). Patients with MDR TB (i.e., documented resistance to both INH and RIF), or RIF-resistant TB need a greater adjustment. The WHO has recommended, on the basis of a large retrospective meta-analysis, that patients with MDR TB receive 5 drugs to which their isolate is susceptible in the induction phase, which should last 6 to 8 months (67). This regimen ideally should include a fluoroquinolone and an injectable aminoglycoside (amikacin, kanamycin, or capreomycin). Patients should then enter a continuation phase with 4 of those drugs (with removal of the injectable) for an additional 12–18 months, resulting in a total of 18 –24 months of treatment. Ideally, these regimens should be tailored to the susceptibility profile of the specific patient's infection. Annals of Internal Medicine 7 February 2017 In May 2016, the WHO endorsed the “shorter” MDR TB regimen, previously known as the “Bangladesh regimen.” It consists of 7 drugs given for 9 –12 months, with cure rates of 85%– 89% and few relapses in specific settings. Clinical trials in additional settings are under way, but the WHO encourages use of this reg- imen in MDR TB patients who have no evidence of resistance to any of the 7 drugs, have no history of exposure to second-line TB medications for more than a month or intolerance to any of the medications and low risk for toxicity, are not pregnant, and do not have extrapulmonary disease (68). 68. World Health Organization. The Shorter MDR-TB Regimen. Geneva: World Health Organization; 2016. Accessed at www .who.int/tb/Short_MDR _regimen_factsheet.pdf on 20 December 2016. Treatment... Active TB should be treated with a regimen and for a length of time tailored to patient characteristics and organism susceptibility. Patients with complications or adverse drug effects that cannot be managed at home should be hospitalized, but patients should not be hospitalized solely for isolation. Patients should be monitored at least monthly for clinical response and adverse drug effects. Sputum of patients whose initial cultures are positive should be cultured monthly until negative. DOT should be considered, especially for patients who do not respond to therapy, have HIV infection, are receiving intermittent drug regimens, or have drug-resistant TB. Patients who have HIV coinfection, are drug-resistant, are failing therapy, or have extrapulmonary disease ideally should be managed in consultation with experts. CLINICAL BOTTOM LINE In the Clinic Tool Kit Tuberculosis https://medlineplus.gov/tuberculosis.html Information on tuberculosis from the National Institutes of Health MedlinePlus. www.mayoclinic.org/diseases-conditions/tuberculosis /home/ovc-20188556 Information on tuberculosis from the Mayo Clinic that is useful to both patients and medical professionals. www.cdc.gov/tb/publications/pamphlets/TBgtfctsEng.pdf Patient handout on tuberculosis from the Centers for Disease Control and Prevention. www.cdc.gov/tb/esp/publications/pamphlets/TBgtfctsSpan.PDF Patient handout in Spanish from the Centers for Disease Control and Prevention. Guidelines www.cdc.gov/tb/publications/guidelines/default.htm Access guidelines on a variety of specific topics related to tuberculosis. www.who.int/publications/guidelines/tuberculosis/en World Health Organization guidelines on tuberculosis. Other Information www.who.int/tb/en The World Health Organization provides information about global efforts to eliminate tuberculosis and related programs. 7 February 2017 Annals of Internal Medicine ITC31 IntheClinic Patient Information 姝 2017 American College of Physicians WHAT YOU SHOULD KNOW ABOUT TUBERCULOSIS In the Clinic Annals of Internal Medicine What Is Tuberculosis? Tuberculosis (TB) is a disease caused by bacteria that attack the lungs. There are 2 kinds of TB: • Active TB makes a person feel sick and can spread to others by coughing, sneezing, or speaking. • Latent TB does not make you feel sick and does not spread to others. People with latent TB are infected with the bacteria but do not have the disease. Some people with latent TB may progress to active TB later on. People who are older, have HIV infection or other immunosuppression, have poor nutrition, or other health problems are at greater risk. What Are the Warning Signs? Latent TB has no symptoms. How Is It Diagnosed? There are 2 types of tests for TB infection: a skin test and a blood test. These tests can check for both latent and active TB but cannot tell you which type you have. If either test is positive, your doctor will test your sputum and order a chest X-ray. This will help him or her know whether you have active TB that can spread to other people. People should be tested for TB infection if they: • Have had close contact with someone who has active TB • Have certain chronic illnesses, such as HIV • Have come to the United States in the past 5 years from a country where TB is common • Work with bacteria in laboratories • Are health care workers • Live or work in facilities where many people congregate, such as jails, nursing homes, and homeless shelters • Are smokers or drug users How Is It Treated? • Active TB can be treated and usually cured by taking medicines for 6 or more months. • Latent TB can be treated with medicine taken for 3 to 9 months. This medicine will help prevent you from getting active TB. • If TB is not treated, it can be deadly. What Is Drug-Resistant TB? • Drug-resistant TB happens when the medicines usually used to treat TB do not work. The bacteria causing the disease is “resistant” to the medicines. • This type of TB is rare in the United States but is becoming more common in other parts of the world. • It is usually treated with more and stronger medicines for a long period. Questions for My Doctor • If I have latent TB, is it safe for me to be around other people? • How did I get TB? • Will I develop active TB? • Do I need treatment? • What treatment is best for me? • How long do I have to stay on treatment? • What medicines are safe to take with TB medicines? • How long will it take to be cured? • Can I leave my house and go to work? For More Information MedlinePlus https://medlineplus.gov/tuberculosis.html Centers for Disease Control and Prevention www.cdc.gov/tb/faqs Patient Information Symptoms of active TB in the lungs include the following: • A long-lasting cough • Chest pain • Coughing up blood or mucus • Weight loss • Feeling weak or tired • Fever and chills • Night sweats