Definition, Etiology, PathogenesisTop
Tuberculosis (TB) is an infectious disease caused by acid-fast bacilli belonging to the Mycobacterium tuberculosis complex, which includes Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium africanum. The pathogenesis of infection is as follows: mycobacteria are inhaled as droplet nuclei, which are phagocytized by macrophages, where intracellular multiplication of the bacilli occurs. Subsequently, destruction of the macrophages takes place and new cells become infected. Over the next 3 to 8 weeks, the bacilli may migrate to both pulmonary and extrapulmonary sites via lymphatic and/or hematogenous channels. At the same time, the patient develops a specific immune response mediated by CD4+ Th1 cells, which activates further macrophages (mediated by interferon [IFN] gamma and other mechanisms). This results in the formation of tuberculoid granulomas consisting of epithelioid and giant cells palisading around a central area of caseous necrosis at the sites of infection. Individuals are usually asymptomatic at this time but may demonstrate infection with a positive TB skin test (tuberculin skin test) (TST) and/or interferon gamma release assay (IGRA) blood test. Lesions may heal spontaneously through fibrosis.
The majority of infected individuals will remain disease-free and in a state of latent tuberculosis infection (LTBI) for their lifetime. Approximately 5% of newly infected hosts (often those with immune dysfunction) are unable to contain the infection and therefore proceed to early disease progression within the first 18 to 24 months (primary TB, or early disease progression). Young children and individuals with impaired cell-mediated immunity are most at risk. Disseminated and central nervous system (CNS) TB can occur in infants as early as a few months after the onset of infection. Primary TB may present with complicated lymphadenopathy, pleural disease, or caseating pneumonia. Approximately 5% of individuals with LTBI will develop postprimary or reactivation TB, which occurs 18 to 24 months or more after having acquired the infection. The source for this late disease progression is the repository of infected macrophages, which are capable of harboring viable mycobacteria across a lifetime. Pulmonary upper lobe fibrocavitary disease is the most common presentation of reactivation TB, although atypical pulmonary findings or extrapulmonary disease are present in up to 30% of cases.
High-risk groups: The global burden of TB can be reduced by identifying high-risk groups to be targeted for screening, preventative therapy, and early disease detection/treatment. A reduction in immune function is the proposed mechanism for the following risk factors: human immunodeficiency virus (HIV)-positive, transplantation, end-stage renal disease, tumor necrosis factor alpha inhibitor therapy, diabetes mellitus, immunosuppressive drugs (≥15 mg prednisone/d), body mass index (≤20 kg/m2), young age (<4 years). Other clinical risk factors include silicosis, malignancy (especially head and neck and hematologic), recent TB infection (≤2 years), fibronodular disease or granuloma (chest radiographs), heavy alcohol consumption (≥3 drinks/d), smoking (≥1 pack/d) (Table 1). Exposure categories relevant for risk assessment include contact with an index case of active TB and origin from a country with a high disease incidence. Demographic and socioeconomic determinants have an influence on the impact of the above risk factors for any given population.
Clinical Features and Natural History Top
Approximately 75% of active TB cases involve only the lungs. Extrapulmonary cases usually occur in a single remote site or may coexist with disease in the lungs. Multiple sites of involvement or dissemination often indicate a defect in host immunity. Clinical manifestations are highly varied. General signs and symptoms irrespective of the location of the lesions include fever, loss of appetite, weight loss, night sweats, and malaise. Blood tests are often normal but may reveal leukopenia or leukocytosis, anemia, elevated erythrocyte sedimentation rate, and very occasionally hyponatremia or hypercalcemia.
1. Symptoms: Chronic cough (initially nonproductive, subsequently associated with production of mucous or purulent sputum) and in some cases hemoptysis. Dyspnea develops in patients with advanced disease (such as caseating pneumonia or miliary TB), which may lead to respiratory insufficiency.
2. Signs: The physical examination in pulmonary TB is usually normal except for patients with advanced disease. Examination should include looking for indicators of extrapulmonary involvement, such as lymphadenopathy, pleural effusion, or ascites.
3. Selected types of pulmonary TB:
1) Miliary TB is caused by hematogenous dissemination of mycobacteria. The disease has a severe clinical course with high-grade fever and dyspnea. Small nodules reminiscent of millet seeds are visible on chest radiographs (although radiographs may be normal in the initial 2-3 days of dissemination). Patients often develop hepatomegaly, splenomegaly, as well as various abnormalities in bone marrow, the ocular fundus, and CNS.
2) Caseating pneumonia: The dominant clinical features are those of toxemia with hectic high-grade fever, severe dyspnea, and frequent occurrence of hemoptysis. Sputum smears reveal very high mycobacteria counts if the contents of the cavities discharge into airways, which directly communicate with outside air during coughing.
1. Pleural TB typically presents with fever, nonproductive cough, dyspnea, and pleuritic pain. It is most commonly seen as a feature of primary TB but can also be a feature of TB reactivation, especially in the elderly. Pleural effusion is usually unilateral and is characterized by high cell counts (briefly showing neutrophilic predominance in the early stages but usually lymphocytic by the time fluid sampling takes place) as well as high protein and adenosine deaminase levels. Since the sensitivity of pleural fluid cultures is very low in primary TB and only ~30% in reactivation TB, open or closed pleural biopsy is often required for diagnosis.
2. Peripheral TB lymphadenitis affects predominantly children and young adults. Lymph nodes commonly involved include cervical (anterior and posterior) and supraclavicular lymph nodes, although disease in the axillary and inguinal sites may occur. Initially, the lymph nodes are enlarged, firm, and painless, with a normal appearance of the overlying skin. With time, gradual softening and formation of fistulas occurs. In ~50% of patients, TB lymphadenitis is accompanied by pulmonary lesions.
3. Genitourinary TB may present with sterile pyuria, gross hematuria, and mild symptoms of frequency, dysuria, and polyuria. Genitourinary TB in woman may manifest as pelvic pain and menstrual abnormalities and may lead to infertility. Men may develop prostatitis and epididymitis.
4. Bone and joint TB most frequently affects elderly patients. Tuberculous arthritis is usually a monoarthritis of the large joints presenting with arthralgia, edema, and limited mobility. Spinal or vertebral TB (Pott disease) presents with back pain and may lead to complications such as vertebral fractures and spinal cord compression.
5. CNS TB is a serious disease. Tuberculous meningitis most often occurs in children or in an immunocompromised host. The inflammatory process predominantly involves the base of the brain, damaging cranial nerves and leading to disturbances in cerebrospinal fluid circulation. Signs and symptoms include somnolence, headache, nausea, vomiting, and nuchal stiffness, often accompanied by paresis, pyramidal signs, and cerebellar signs. Altered mental status and seizures may also occur. Other types of CNS TB include tuberculoma, tuberculous abscess, cerebritis, and myelitis.
6. Abdominal TB can involve the intestines (often terminal ilium), peritoneum, and mesentery. Manifestations may include low-grade fever, weight loss, diarrhea, vomiting, abdominal pain, and ascites. Sometimes clinical features of appendicitis or intestinal obstruction are present.
7. Other types of extrapulmonary TB include ocular, pericardium, skin, breast, great vessels, and bone marrow TB. TB has the potential to cause disease in any organ.
Testing for active TB is indicated in anyone with clinical or radiographic indicators of TB. Every effort should be made to obtain a microbiological diagnosis. Acid-fast bacilli may be present on smear microscopy but could yield a false-positive result, especially in low-incidence regions with a high prevalence of nontuberculous mycobacterial infection/disease. Nucleic acid amplification test (NAAT) results are presumptive; thus, confirmation with culture is strongly recommended.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Note that study results demonstrate heterogeneity of commercial NAAT results. NAATs lack the diagnostic accuracy, particularly in the testing of sensitivity, to replace conventional tests for the diagnosis of TB. High Quality of Evidence (high confidence that we know true effects of the intervention). Ling DI, Flores LL, Riley LW, Pai M. Commercial nucleic-acid amplification tests for diagnosis of pulmonary tuberculosis in respiratory specimens: meta-analysis and meta-regression. PLoS One. 2008 Feb 6;3(2):e1536. doi: 10.1371/journal.pone.0001536. PubMed PMID: 18253484; PubMed Central PMCID: PMC2212137. Pai M, Minion J, Behr M, et al. Diagnosis of active tuberculosis and drug resistance. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:43-61. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf. Sputum collection can be obtained by spontaneous expectoration or induction using a hypertonic NaCl solution. Bronchoscopy is used to obtain bronchial washings if the sputum sample cannot be collected, previous samples are smear-negative, or other diagnoses, such as lung cancer, are suspected. Gastric aspirate can be used for pediatric patients not capable of producing sputum. Consider microbiological (smear and culture) and histologic examination of biopsy specimens obtained from a suspicious lesion.
Criteria for TB diagnosis without a microbiological confirmation: Clinical judgment must be used when a suspect diagnosis of TB cannot be confirmed by a positive culture. The risks of treating TB on speculation include exposure to potential drug toxicities, conversion to drug-resistant TB without the benefit of drug-susceptibility test results, and neglect of an unrecognized disease that has masked as TB. If negative results for all microbiological tests are yielded despite a rigorous investigative process and there is no improvement after a trial of therapy with a broad-spectrum antibiotic, initiation of a trial for treatment for TB may be considered. This should be done with great caution after all feasible investigative options have been exhausted. The exception would be any patient for whom a delay in diagnosis could lead to a poor outcome, such as CNS or disseminated TB. Fluoroquinolones should be avoided during the investigative workup, as this class of drug is active against M tuberculosis and may result in a temporary clinical improvement and reduced sensitivity on smear and culture testing. Specimens from patients with extrapulmonary TB usually contain few mycobacteria, and the diagnosis is often based on histologic findings. A TB expert, if available, should be consulted if the diagnosis is uncertain.
HIV-positive patients: In HIV-infected individuals, the clinical presentation is often atypical, especially when the CD4 count is <250 microL. An increased incidence of extrapulmonary disease and a higher risk of dissemination are to be anticipated. In HIV-positive patients with early TB, the lesions are typical. However, in the advanced disease they may involve the lower and middle zones of the lungs. Cavities are rarely observed. Smear-negative disease is a common finding in HIV infection. The sensitivity of cultures increases with the number of evaluations performed, particularly if the examined material is induced sputum or lavage fluid obtained during bronchoscopy. In addition to sputum cultures, it may be necessary to perform blood cultures and biopsies of lymph nodes and bone marrow.
1. Chest radiography: In patients with primary TB, opacities are typically present in the middle and lower areas of the lungs and are accompanied by hilar and paratracheal lymphadenopathy. In patients with postprimary (reactivation) TB, opacities are found predominantly in the apical and posterior segments of the upper lobes and the upper segments of the lower lobes. In patients with advanced disease, cavities are often visible as radiolucent areas surrounded by an opaque rim. In some cases, infiltrates appear as solitary pulmonary nodules, which result from the encapsulation of caseous masses (tuberculomas). In immunocompromised patients, radiologic features may be atypical. Chest imaging is not specific for the diagnosis of TB and should not be used for this purpose alone;Evidence 2Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). Note that chest radiography has substantial limitations in the diagnosis of pulmonary TB disease. The low specificity could lead to overdiagnosis, resulting in overtreatment and the encumbrance of placing an unmanageable burden on resource-poor countries. High Quality of Evidence (high confidence that we know true effects of the intervention). Menzies D, Khan K. Diagnosis of tuberculosis infection and disease. In: Long R, ed. Canadian Tuberculosis Standards (6th edition). Canada: Canadian Lung Association, 2007;53-91. Pai M, Minion J, Behr M, et al. Diagnosis of active tuberculosis and drug resistance. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:43-61. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf. Kumar N, Bhargava SK, Agrawal CS, George K, Karki P, Baral D. Chest radiographs and their reliability in the diagnosis of tuberculosis. JNMA J Nepal Med Assoc. 2005 Oct-Dec;44(160):138-42. PubMed PMID: 16751817. therefore, the diagnosis should be confirmed by microbiological testing.
2. Sputum smear microscopy: Tuberculous bacilli are identified with specific staining (Ziehl-Neelsen) using a bright light or florescence microscopy. Multiple samples are obtained to increase the diagnostic yield. Recent evidence supports that collection of 2 samples obtained on the same day has the same sensitivity (64%) and specificity (98%) compared with standard collection over multiple days. Collection of a total of 3 specimens (same day with 1 hour apart or multiple days) is recommended in Canada and other low-incidence settings where smear-negative TB is the most common presentation.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Note that a switch from the conventional 3 specimens/multiple days to 2 specimens/same day sputum collection for active TB case-finding may be useful in high-incidence countries or in settings where patients are likely to default from the diagnostic pathway. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness of populations and imprecision. Pai M, Minion J, Behr M, et al. Diagnosis of active tuberculosis and drug resistance. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:43-61. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf. World Health Organization. Same-day diagnosis of tuberculosis by microscopy. Policy statement. http://apps.who.int/iris/bitstream/10665/44603/1/9789241501606_eng.pdf. Published 2011. Accessed January 13, 2017. Specificity may be reduced in countries with a low incidence of TB and a high prevalence of nontuberculous mycobacterium.
3. Mycobacterial culture and phenotypic drug-sensitivity testing: Mycobacterial culture is the current gold-standard method for the detection of active TB disease with the highest sensitivity. Various solid or liquid culture medias exist and yield results in 2 to 8 weeks. The sensitivity of 3 sputum cultures is >90%. Drug-susceptibility test results are usually available within 1 week. They should be routinely performed in all first positive culture isolates obtained from each new case.
4. NAAT: Amplification of nucleic acids is a rapid method to assist with the diagnosis of TB and detection of drug resistance. Commercial government-approved assays, if available, are the most reliable. These tests are routinely used on smear-positive specimens and yield sensitivity and specificity >90%. Sensitivity in smear-negative specimens is only 50% to 70%, and thus NAAT testing is reserved for smear-negative cases that have a high pretest probability of active TB. In extrapulmonary specimens, sensitivity is lower. An automated, cartridge-based NAAT (Xpert MTB/RIF) can provide point-of-care testing to aid in the diagnosis of active TB and rifampin (INN rifampicin) resistance and has been shown to be a useful tool in developing countries with high TB prevalence. Data to support the accuracy for detection of TB disease and rifampin resistance in low-burden countries is lacking. It is therefore a conditional recommendation in Canada for all results generated by the Xpert MTB/RIF assay to be confirmed with government-approved commercial assays.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Note that since Canada is a low multidrug-resistant TB prevalence setting, false-positive results for rifampin resistance using Xpert MTB/RIF may be of concern. Therefore, there is a conditional recommendation for at least one respiratory sample to be tested with a Health Canada–approved nucleic acid amplification test for all new smear-positive cases. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness to different settings. Steingart KR, Sohn H, Schiller I, et al. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009593. doi: 10.1002/14651858.CD009593.pub2. Review. Update in: Cochrane Database Syst Rev. 2014;(1):CD009593. PubMed PMID: 23440842; PubMed Central PMCID: PMC4470352.
1. General principles of treatment:
1) Early identification and treatment of active TB is aimed at rapid killing of TB bacilli to effect rapid clinical improvement and to prevent transmission to others.
2) Treatment should be guided by the results of drug-sensitivity testing to effect cure and to prevent the emergence of drug resistance.
3) Good adherence to drug therapy and full completion of drug regimens are important for prevention of treatment failure and disease relapse.
4) A treatment regimen should always include at least 3 drugs during the first 2 months (initial intensive phase) and at least 2 drugs for another 4 to 7 months (continuation phase) that are effective against the mycobacteria isolated from the patient.
5) Never add only one new drug to an ineffective regimen.
6) Close supervision and monitoring is best accomplished with directly observed therapy (DOT), which is recommended (if available) for individuals at risk of nonadherence or in those cases when treatment failure would have major implications for the individual or public health sector (drug resistance, disease relapse, pediatric disease, substance abuse, suspect nonadherence, mental health illness, homelessness).Evidence 5Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Note that despite low quality of evidence, it is recommended that all jurisdictions across Canada should have the capacity to provide directly observed therapy, which should be applied at a minimum to the patient groups at risk for treatment failure or relapse. Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to population indirectness, heterogeneity, and imprecision. Karumbi J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database Syst Rev. 2015 May 29;(5):CD003343. doi: 10.1002/14651858.CD003343.pub4. Review. PubMed PMID: 26022367; PubMed Central PMCID: PMC4460720. World Health Organization. Treatment of tuberculosis: guidelines. http://www.who.int/tb/publications/tb_treatmentguidelines/en/. Published 2010. Accessed January 13, 2017. Menzies D, Elwood K. Treatment of Tuberculosis Disease. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:97-123. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf.
7) Some patients may be considered for intermittent, thrice-weekly therapy, which is only recommended if administered by DOT and usually after having completed the first 2 months of daily therapy.Evidence 6Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Note that intermittent dosing schedules have the potential to improve adherence in the community and are recommended for a subgroup of patients during the continuation phase. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision (small number of events in tested groups). Mwandumba HC, Squire SB. Fully intermittent dosing with drugs for treating tuberculosis in adults. Cochrane Database Syst Rev. 2001;(4):CD000970. Review. PubMed PMID: 11687088. Menzies D, Elwood K. Treatment of Tuberculosis Disease. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:97-123. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf. Intermittent therapy is not recommended for patients with multidrug-resistant TB (MDR-TB) or for persons with HIV infection.
8) Reporting suspect or confirmed TB cases to public health authorities is a requirement in many countries and is strongly recommended in others.
2. Anti-TB drugs: The drug regimens for TB therapy, as stated in this section, are consistent with Canadian and World Health Organization (WHO) guidelines. Flexibility in selection of drug choices and schedules is often required and related to drug intolerance or limited resources. All drug regimens must adhere to the general principles of treatment of active TB. If modifications in drug choices or schedules are required, referral to an expert in the management of TB is recommended.
1) First-line (first-choice) agents include isoniazid (INH), rifampin (RMP), pyrazinamide (PZA), and ethambutol (EMB). Drugs and dosage: Table 2.
2) Second-line (alternative) agents include fluoroquinolones (FQNs), amikacin, streptomycin, ethionamide, capreomycin, cycloserine, para-aminosalicylic acid, kanamycin, and clarithromycin.
3. Adjunctive use of glucocorticoids coupled with effective anti-TB therapy is recommended for HIV noninfected patients with TB meningitisEvidence 7Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD002244. doi: 10.1002/14651858.CD002244.pub3. Review. Update in: Cochrane Database Syst Rev. 2016;4:CD002244. PubMed PMID: 18254003. (IV dexamethasone 0.4 mg/kg daily for 2 weeks with the dose tapered over the next 8 weeks). Use of glucocorticoids for treatment of TB pericarditis is suggested but is of less certain efficacyEvidence 8Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Mayosi BM, Ntsekhe M, Volmink JA, Commerford PJ. Interventions for treating tuberculous pericarditis. Cochrane Database Syst Rev. 2002;(4):CD000526. Review. PubMed PMID: 12519546. (prednisone 1 mg/kg daily for 4 weeks with the dose tapered over the next 8 weeks). Replacement steroids may be used for TB-induced adrenal insufficiency, which can be associated with disseminated TB. Since evidence for use of steroids in other clinical scenarios is not robust, clinical judgment is reserved for the following: severe TB pleuritis and peritonitis with pleural effusion, life-threatening airway obstruction; lymph node TB with signs of compression of the adjacent organs; severe hypersensitivity reactions to anti-TB drugs that cannot be replaced with other agents; immune reconstitution inflammatory syndrome in patients with HIV infection.
4. Patients with new-onset TB:
1) Standard treatment for the initial intensive phase (first 2 months) for drug-sensitive (or expected drug-sensitive) TB includes combined use of INH, RMP, PZA, and EMB for 2 months. EMB can be discontinued as soon as drug-susceptibility tests indicate pansensitivity.
2) Standard treatment for the continuation phase (after the first 2 months and until treatment completion) for drug-sensitive TB includes combined use of INH and RMP for 4 more months for a total of 6 months of therapy. In patients with risk factors for relapse, the continuation phase should be prolonged to 7 months to provide a total of 9 months of therapy.Evidence 9Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Treatment periods of 6 months or more result in higher success rates. Without strong evidence to demonstrate equivalent efficacy for shorter courses, a 6- to 9-month treatment duration is recommended. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Gelband H. Regimens of less than six months for treating tuberculosis. Cochrane Database Syst Rev. 2000;(2):CD001362. Review. PubMed PMID: 10796641. Jo KW, Yoo JW, Hong Y, et al. Risk factors for 1-year relapse of pulmonary tuberculosis treated with a 6-month daily regimen. Respir Med. 2014 Apr;108(4):654-9. doi: 10.1016/j.rmed.2014.01.010. PubMed PMID: 24518046. Risk factors for relapse include extensive disease and/or cavities on chest radiographs in the first 2 months of therapy, culture-positive after 2 months of therapy, or radiographic evidence for cavitation at treatment completion.
5. Monitoring adverse effects of anti-TB drugs: Monitoring for adverse effects of TB medications is important in order to detect adverse events, such as liver toxicity (INH, RMP, PZA), hypersensitivity reaction (RMP), optic neuritis (EMB), and neuropathy (INH) (Table 3). Serious reactions should prompt stopping all potentially offending drugs with immediate initiation of 2 alternate TB medications. The evidence for standard baseline and follow-up monitoring schedules is weak. Most clinicians measure serum levels of liver enzymes, bilirubin, urea/blood urea nitrogen, creatinine, uric acid, and perform a complete blood count when starting TB medications, and will schedule follow-up visits with liver enzyme measurements at least monthly thereafter. Hepatotoxic drugs must be discontinued in all patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥5 × upper limit of normal (ULN) and in patients with ALT and/or AST levels ≥3 × ULN who have gastrointestinal manifestations (jaundice, nausea, loss of appetite, abdominal distention, or abdominal pain). Advise patients to refrain from drinking alcohol while on INH, RMP, or PZA to reduce the risk of hepatic injury. When drug schedules must be altered due to adverse effects, consultation with a TB expert is advised to ensure that revised treatment schedules offer the best chance of treatment success with a minimal risk of further adverse reactions. If EMB is required beyond the first few weeks of drug therapy while awaiting drug susceptibility results, refer the patient for periodic ophthalmologic examinations.
6. Monitoring the clinical response to treatment: Methods to monitor response to therapy are based on expert opinion, and practices vary between institutions and countries. Microbiological testing of sputum is useful to assess the risk of transmitting infection to others and for early detection of treatment failure. Canadian experts suggest patients who are smear-positive at diagnosis should have sputum smears sent weekly until found to be negative. Thereafter, sputum cultures should be obtained at the end of the second month and near the end of drug therapy. If treatment failure is suspected, 2 sputum samples for smear and culture should be obtained and repeat drug-susceptibility testing should be requested on specimens that remain culture-positive. Clinical assessment should occur monthly with chest radiographs at 2 and 6 months.
7. Patients with a history of prior anti-TB treatment: Active TB in a patient who received prior therapy usually implies treatment failure, disease relapse, or in rare instances new reinfection (patients who are HIV-positive, immunocompromised). Consultation with a TB expert is advised. Drug-resistant TB should be suspected in patients who have previously been treated for active TB and therefore an expanded, empiric initial treatment regimen may be indicated (INH, RMP, PZA, EMB, and FQN). Rapid drug-susceptibility testing (subject to available resources) is recommended, so that drug resistance can either be excluded or promptly identified in order to provide appropriate and timely therapy. If drug resistance is ruled out, a standard 9-month course of drug therapy under DOT is recommended.
8. Treatment of drug-resistant TB: Drug-resistant mycobacterial strains may be resistant to only one drug or to multiple drugs. MDR-TB is resistance to at least INH and RMP. Pre-extensively drug-resistant TB (pre-XDR-TB) is resistance to INH and RMP plus either a FQN or one of the 3 injectable second-line drugs (amikacin, kanamycin, or capreomycin). Extensively drug-resistant TB (XDR-TB) is resistance to at least INH and RMP plus a FQN and one of the 3 injectable second-line drugs. There are recommended regimens for the management of drug-resistant TB; however, an individualized therapeutic approach based on drug-susceptibility test results, extent of disease, response to therapy, and drug tolerance is required. All treatment should be given by DOT. MDR-TB should be treated by a specialized health-care team with expertise in the management of drug-resistant tuberculosis.
1) INH-resistant TB: RMP + EMB + PZA daily for 6 to 9 months. A daily or thrice-weekly schedule after the first 2 months. In patients with extensive pulmonary lesions, add a FQN for the entire treatment and stop PZA after 2 months.
2) RMP-resistant TB: INH + EMB + a third-generation (levofloxacin) or fourth-generation (moxifloxacin) FQN daily for 12 to 18 months with PZA for the first 2 months. A daily or thrice-weekly schedule after the first 2 months. In patients with extensive pulmonary lesions, add a parenteral drug for the first 2 to 3 months.
3) MDR-TB: Assess drug sensitivity for all first-line and second-line drugs as a guide for individualized therapy. Use ≥4 anti-TB drugs of probable effectiveness. Start selection using first-line drugs followed by second-line drugs with initial inclusion of PZA. In each case, use a third- or fourth-generation FQN plus a parenteral drug, with drug choices being made on the basis of sensitivity tests. In case of resistance to FQN, consider including linezolid and clofazimine. Treatment should last ≥20 months, with the intensive phase (including use of parenteral drug) lasting ≥8 months.
4) XDR-TB: The principles are similar to the treatment of MDR-TB. Consider the use of bedaquiline or high-dose INH. Another parenteral drug may be added (one with susceptibility to the TB strain, or one that has not been used before if the strain is resistant to all drugs from this group).
9. Treatment of TB in pregnant and breastfeeding women: INH, RMP, and EMB are considered safe in pregnancy. Therefore, use all 3 for initial treatments. Patients treated with INH should receive pyridoxine. PZA in pregnancy is recommended by the WHO, although there is some controversy regarding its safety. The use of PZA for pregnant women in Canada is restricted to those with extensive disease or intolerance to other first-line drugs. Breastfeeding is not contraindicated. Most second-line agents are not considered safe in pregnancy, which is related to toxic or teratogenic effects on the fetus, especially in the case of aminoglycosides (ototoxicity), FQN (bone growth), and ethionamide (teratogenic effects and increased risk of maternal nausea and vomiting). Sputum smear-positive mothers should be isolated from newborns until the smear results become negative. The infant must be urgently assessed to exclude active TB with a clinical examination, chest radiographs, cultures (which may include lumbar puncture), and abdominal ultrasound. A course of preventive treatment with INH is initiated for the infant if there is no evidence of active TB. Some countries recommend that the infant receive the BCG vaccine once the treatment has been completed.
10. Patients with renal failure: Use INH and RMP at standard doses (these are excreted predominantly with bile). Use EMB at a dose of 15 mg/kg and PZA at a dose of 25 mg/kg, both at a reduced frequency of 3 times a week (if undergoing hemodialysis, administer after dialysis).
11. Patients with liver failure: INH, RMP, and PZA may cause drug-induced hepatotoxicity.
1) Acute liver failure: Consider a brief delay in starting anti-TB treatment until liver function has been stabilized. If treatment is deemed necessary, use FQN + EMB + parenteral (amikacin) for 2 months and then FQN + EMB for a total of 18 months. If liver function has stabilized, RMP may be introduced with careful monitoring of liver parameters.
2) Chronic liver failure: Adjust treatment to the severity of liver failure and number of other coadministered hepatotoxic drugs.
12. Unconscious patients: In patients in whom enteral nutrition is administered via a gastrostomy or nasogastric tube, crushed oral anti-TB drugs can be given 2 to 3 hours before or after meals. Other options include intramuscular INH, intravenous RMP (when available), intravenous amikacin/intramuscular streptomycin, and intravenous FQN.
13. Patients after organ or bone marrow transplantation: Caution is necessary because of the possible interactions of rifamycins (RMP, rifabutin, rifapentine) with calcineurin inhibitors (cyclosporine [INN ciclosporin] and tacrolimus; doses of these agents should be increased 3- to 5-fold with concomitant monitoring of their blood levels) and with glucocorticoids (steroid dose may need to be increased by 50%).
14. HIV-positive patients: Treatment of TB in HIV-infected patients should be guided by a physician with expertise in the management of both diseases or in close collaboration with a physician expert in HIV care. A standard regime should be used, but with close attention of drug interactions between TB and antiretroviral treatment (ART). In the case of slow clinical or microbiological improvement, extend treatment to 9 months, or by at least an additional 4 months after obtaining sterile sputum culture results. In patients not receiving ART, the diagnosis of TB is an indication for starting such therapy. Initiate anti-TB treatment first and then add ART (efavirenz combined with 2 nucleoside reverse-transcriptase inhibitors after 2-8 weeks), depending on CD4 counts. Do not use RMP in patients treated with protease inhibitors, as it decreases blood levels of these drugs (substitute rifabutin to replace RMP after a 2-week washout period). Administration of ART in HIV-positive patients with TB may lead to immune reconstitution inflammatory syndrome, which may require treatment with glucocorticoids.
15. In patients treated with anti-TNF agents who develop TB in the course of therapy, anti-TNF treatment should be discontinued. It may be resumed no earlier than after one month of appropriate anti-TB treatment and confirmation of susceptibility of the mycobacteria to the drugs used.
Pneumothorax, bronchopleural fistula, pleural empyema, pleural fibrosis (fibrothorax), pulmonary hemorrhage, and amyloidosis.
1. Rapid diagnosis and implementation of treatment for active TB.
2. Airborne precautions should be used for patients with suspect or confirmed respiratory TB who are admitted to hospital or assessed in ambulatory facilities.
3. Partnership with public health services who implement and set standards for TB surveillance, screening, isolation practices, and DOT.
4. Targeted screening and preventative therapy for LTBI: see Tuberculosis: Latent Tuberculosis Infection.
5. Vaccination against TB (BCG): BCG is a live attenuated vaccine derived from Mycobacterium bovis. Policies and practices vary widely across the world. In the majority of countries, BCG vaccination is recommended either at birth or before 1 year of age. There is much debate about the efficacy of BCG in preventing development of TB infection, although most experts agree that the vaccine may prevent dissemination of the TB bacilli. In Canada, BCG is currently only recommended for infants in certain high-risk communities and also to be considered for travelling infants planning an extended stay in a country with a high incidence of TB.
Risk factor Estimated risk for TB relative to people with no known risk factors Reference number High risk AIDS 110-170 5 HIV infection 50-110 6, 7 Transplantation (related to immune-suppressant therapy) 20-74 8-12 Silicosis 30 13, 14 Chronic renal failure requiring hemodialysis 7-50 15-18, 46, 47 Carcinoma of head and neck 11.6 19 Recent TB infection (2 years) 15 20, 21 Abnormal chest radiographs: fibronodular disease 6-19 22-24 Moderate risk Tumor necrosis factor alpha inhibitors 1.5-5.8 25, 26, 43 Diabetes mellitus (all types) 2-3.6 27-29 Treatment with glucocorticoids (>15 mg/d prednisone) 4.9 30 Young age when infected (0-4 years) 2.2-5 31 Slightly increased risk Heavy alcohol consumption (>3 drinks/d) 3-4 32, 33 Underweight (<90% ideal body weight; for most people, this is a body mass index <20) 2-3 34 Cigarette smoker (1 pack/d) 1.8-3.5 35-38 Abnormal chest radiographs: granuloma 24, 39 Low risk Person with positive TST, no known risk factors, normal chest radiographs (“low-risk reactor”) 40 Very low risk Person with positive 2-step TST (booster), no other known risk factors, and normal chest radiographs 0.5 Extrapolated from 40 and 1 Source: ©All Rights Reserved. Canadian Tuberculosis Standards, 7th Edition. The Public Health Agency of Canada, The Lung Association, and the Canadian Thoracic Society, 2014. Adapted and reproduced with permission from the Minister of Health, 2016. AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; TB, tuberculosis; TST, tuberculin skin test. Daily 3 times a week By weight Maximum (mg) By weight Maximum (mg) First-line drugs Isoniazid 5 mg/kg 300 10 mg/kg 600 Rifampin (INN rifampicin) 10 mg/kg 600 10 mg/kg 600 Pyrazinamide 20-25 mg/kg 2000 30-40 mg/kg 4000 Ethambutol 15-20 mg/kg1 1600 25-40 mg/kg 2400 Second-line drugs Fluoroquinolones2: moxifloxacin 400 4 Fluoroquinolones2: levofloxacin 750-1000 4 Injectables: amikacin3 15 mg/kg as a single dose5 4 1 Optimal dosing is unclear. It is clear that eye toxicity is dose dependent, and its risk is higher at 25 mg/kg than at 15 mg/kg. 2 Gatifloxacin is not recommended in Canada because of dysglycemia problems. This drug has been used in recent trials and is still used in some countries. 3 Of the injectables, amikacin is preferred for use in Canada because of the ready availability of the drug, familiarity with its use by clinicians, nurses, and pharmacists, and the ability to measure serum drug concentration in many facilities. Streptomycin is not available in Canada but may be preferred in some low- and middle-income countries, as rates of toxicity are similar and costs may be lower. 4 There are inadequate data from randomized trials on the use of fluoroquinolones or injectables as part of intermittent regimens. If these drugs are needed because of intolerance or resistance to first-line drugs, daily therapy is suggested. 5 Initial dosage if renal function is normal. Dosing should be adjusted based on peak and trough serum levels in consultation with a pharmacist. Source: ©All Rights Reserved. Canadian Tuberculosis Standards, 7th Edition. The Public Health Agency of Canada, The Lung Association, and the Canadian Thoracic Society, 2014. Adapted and reproduced with permission from the Minister of Health, 2016. INN, International Nonproprietary Name.
Estimated risk for TB relative to people with no known risk factors
Transplantation (related to immune-suppressant therapy)
Chronic renal failure requiring hemodialysis
15-18, 46, 47
Carcinoma of head and neck
Recent TB infection (2 years)
Abnormal chest radiographs: fibronodular disease
Tumor necrosis factor alpha inhibitors
25, 26, 43
Diabetes mellitus (all types)
Treatment with glucocorticoids (>15 mg/d prednisone)
Young age when infected (0-4 years)
Slightly increased risk
Heavy alcohol consumption (>3 drinks/d)
Underweight (<90% ideal body weight; for most people, this is a body mass index <20)
Cigarette smoker (1 pack/d)
Abnormal chest radiographs: granuloma
Person with positive TST, no known risk factors, normal chest radiographs (“low-risk reactor”)
Very low risk
Person with positive 2-step TST (booster), no other known risk factors, and normal chest radiographs
Extrapolated from 40 and 1
Source: ©All Rights Reserved. Canadian Tuberculosis Standards, 7th Edition. The Public Health Agency of Canada, The Lung Association, and the Canadian Thoracic Society, 2014. Adapted and reproduced with permission from the Minister of Health, 2016.
AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; TB, tuberculosis; TST, tuberculin skin test.
3 times a week
Rifampin (INN rifampicin)
15 mg/kg as a single dose5
1 Optimal dosing is unclear. It is clear that eye toxicity is dose dependent, and its risk is higher at 25 mg/kg than at 15 mg/kg.
2 Gatifloxacin is not recommended in Canada because of dysglycemia problems. This drug has been used in recent trials and is still used in some countries.
3 Of the injectables, amikacin is preferred for use in Canada because of the ready availability of the drug, familiarity with its use by clinicians, nurses, and pharmacists, and the ability to measure serum drug concentration in many facilities. Streptomycin is not available in Canada but may be preferred in some low- and middle-income countries, as rates of toxicity are similar and costs may be lower.
4 There are inadequate data from randomized trials on the use of fluoroquinolones or injectables as part of intermittent regimens. If these drugs are needed because of intolerance or resistance to first-line drugs, daily therapy is suggested.
5 Initial dosage if renal function is normal. Dosing should be adjusted based on peak and trough serum levels in consultation with a pharmacist.
INN, International Nonproprietary Name.
Common adverse events
Uncommon but important adverse events
Rank for probability of hepatitis1
Rank for probability of rash
Rash, hepatitis, neuropathy
CNS toxicity, anemia
Rifampin (INN rifampicin)
Drug interactions, rash
Hepatitis, influenza-like illness, neutropenia, thrombocytopenia
Hepatitis, rash, arthralgia
Tendonitis, tendon rupture, QT interval prolongation
1 1, most likely; 4, least likely.
CNS, central nervous system; INN, International Nonproprietary Name.