Tuberculosis: Active Disease

Definition, Etiology, PathogenesisTop

Tuberculosis (TB) is an airborne infectious disease caused by acid-fast bacilli (AFB) belonging to Mycobacterium tuberculosis complex. This complex includes M tuberculosis, M bovis, and M africanum.

Transmission from a patient with infectious TB occurs via the airborne route, through inhalation of infected droplet nuclei. In immunocompetent hosts alveolar macrophages ingest the M tuberculosis organisms and may (or may not) destroy them. If the innate macrophage response is inadequate to destroy the few bacteria transported in the droplet nucleus, they begin to replicate logarithmically, doubling every 24 hours until the macrophage explodes and releases countless progeny. The result is the attraction of new macrophages to the site where the cycle repeats itself. Additionally, the bacilli may then spread from the initial site of infection to other parts of the body via the lymphatic or circulatory systems, leading to extrapulmonary infection.

After 3 to 8 weeks the host 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. Additionally, as a result of a delayed-type hypersensitivity to the bacilli, individuals may demonstrate infection with a positive tuberculin skin test (TST) or interferon gamma release assay (IGRA). Initial infection and immune conversion are usually asymptomatic.

The majority of infected individuals 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). Primary TB may present with complicated lymph node disease (airway compression, caseating pneumonia, infiltration of adjacent structures), pleural disease (lymphocyte predominant exudative effusion), or peripheral lymphadenitis (usually in the neck). Approximately 5% of individuals with LTBI develop postprimary or reactivation TB, which occurs ≥24 months after acquiring 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 extrapulmonary disease is present in up to 30% of cases.

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 infection 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.

Pulmonary Tuberculosis

1. Symptoms: Cough lasting ≥2 to 3 weeks. The cough is initially dry, but after several weeks to months it becomes productive. Fever and night sweats are common, but they may be absent in the extremes of age. Additionally, the presence of hemoptysis, anorexia, weight loss, and pleuritic chest pain typically indicate more advanced disease.

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, and abdominal or bone and joint involvement, particularly in individuals with HIV infection.

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.

3. Radiography (see Diagnostic Tests, below).

Extrapulmonary Tuberculosis

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 exudative, unilateral, and characterized by high cell counts (briefly showing neutrophilic predominance in the early stages, but typically lymphocytes are predominant) as well as high protein, elevated lactate dehydrogenase (LDH) level, low glucose concentration, and a pH of <7.40 in most cases. Since pleural fluid AFB cultures are positive in <20% to 30% of individuals without HIV infection, a pleural biopsy for AFB smear and culture are often required to confirm the diagnosis.

2. Peripheral TB lymphadenitis commonly involves the cervical (anterior and posterior chain) 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 includes tuberculous meningitis, myelitis, tuberculomas, as well as tuberculous abscess and cerebritis. CNS TB is observed in up to 15% to 20% of miliary TB cases and in up to 50% of cases it is fatal. Tuberculous meningitis should be treated as a medical emergency. It is thought that the initial lesion is a tubercule in the superficial cortex or meninges that ruptures into the subarachnoid space. The clinical presentation involves fever, malaise, headache, and personality changes. This is followed by meningismus, confusion, and various cranial nerve palsies. Untreated TB meningitis can lead to seizures, coma, and death within weeks.

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.

DiagnosisTop

Testing for active TB is indicated in anyone with clinical or radiographic indicators of TB. Every effort should be made to obtain a microbiologic diagnosis. Tools for microbiologic testing include AFB smear, molecular tests (nucleic acid amplification test [NAAT]), and mycobacterial culture. Mycobacterial culture remains the gold standard, as it enables conventional drug susceptibility testing.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. For cases of pulmonary TB sputum collection can be obtained by spontaneous expectoration or induction using a hypertonic saline 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. All extrapulmonary biopsy samples should be sent for AFB smear microscopy, mycobacterial culture, and histologic examination.

Criteria for TB diagnosis without a microbiologic confirmation: Clinical judgment must be used when a suspect diagnosis of TB cannot be confirmed by a positive culture or molecular test result. 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 microbiologic 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 (FQNs) 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. 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 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.

Diagnostic Tests

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 reactivation TB, opacities are found predominantly in the apical and posterior segments of the upper lobes and the superior 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 aloneEvidence 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 microbiologic 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 (minimum 1 hour apart) 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.

3. NAAT 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 of >90% for M tuberculosis. Sensitivity in smear-negative specimens is only 50% to 70%. An automated, cartridge-based NAAT (CBNAAT) (Xpert MTB/RIF) can provide point-of-care testing to aid in the diagnosis of active TB and rifampin (INN rifampicin) resistance in a matter of hours. This has been shown to be a useful tool in developing countries with high TB prevalence and a lack of microbiologic laboratories.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.

4. Mycobacterial culture and phenotypic drug-sensitivity testing: Mycobacterial culture is the current gold-standard method for the detection of active TB disease with a sensitivity and specificity of 80% and 98%, respectively. Various solid or liquid culture medias exist and yield results in 2 to 8 weeks. Drug-susceptibility testing should be routinely performed in all first positive culture isolates obtained from each new case.

5. TST or IGRA are not the tests to be used in the assessment of active TB.

TreatmentTop

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 prevent complications and 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 ≥3 drugs during the first 2 months (intensive phase) and then (continuation phase) ≥2 drugs 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 thrice-weekly therapy in the continuation phase. This is only recommended if administered by DOT and 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 resistant TB (multidrug-resistant TB and extensively drug-resistant TB [MDR-TB/XDR-TB]), persons with HIV coinfection, and those with high bacillary load (cavitary disease) or smear-positive disease initially.

8) Reporting suspect or confirmed active TB cases to public health authorities is a requirement in many countries and is strongly recommended in others.

2. Drugs used in active TB treatment: 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 agents include isoniazid (INH), rifampin (RMP), pyrazinamide (PZA), and ethambutol (EMB). Drugs and dosage: Table 1.

2) Second-line agents include 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 may reduce death in HIV-negative patients but is of less certain efficacy in HIV-positive patientsEvidence 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 active TB:

1) Standard treatment for the 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 additional months for a total duration of therapy of 6 months. 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, cavities on chest imaging in the first 2 months of therapy, positive mycobacterial cultures after 2 months of therapy, or radiographic evidence of cavitation after 6 months of therapy.

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 peripheral neuropathy (INH) (Table 2). 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 (BUN), creatinine, uric acid, and perform a complete blood count (CBC) 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, a baseline visual acuity and color vision assessments are recommended with periodic repeat examinations thereafter to assess for optic neuritis.

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. Microbiologic 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 imaging suggested at 2 and 6 months after treatment initiation.

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.

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). 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, pre-XDR-TB, and XDR-TB should be treated by a specialized health-care team with expertise in the management of drug-resistant tuberculosis.

1) INH-monoresistant TB: RMP + EMB + PZA daily for 6 to 9 months. In the continuation phase, a daily or thrice-weekly schedule may be used. In patients with extensive pulmonary lesions, add an FQN for the entire treatment and stop PZA after 2 months.

2) RMP-monoresistant TB: INH + EMB + PZA + a third or fourth-generation FQN (levofloxacin or moxifloxacin) daily for 2 months. This is followed by INH + EMB + FQN daily or thrice weekly for additional 10 to 16 months. In patients with extensive pulmonary lesions consider adding an injectable agent at least for the first 2 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. The duration of MDR-TB treatment is on average 20 to 24 months.Evidence 10Weak 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 as per the guideline GRADE indicators. World Health Organization. Treatment of tuberculosis: guidelines. http://www.who.int/tb/publications/tb_treatmentguidelines/en/. Published 2010. Of note, the WHO recommends a shorter duration of treatment in specific circumstances. This differs, however, from various other international guidelines.

Although randomized trials to study the benefit of adjunctive therapy with vitamin D for the treatment of active TB have provided conflicting results, a recent meta-analysis indicated vitamin D accelerated the time to sputum conversion in a subgroup of patients with MDR pulmonary TB.Evidence 11Weak 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 indirectness and imprecision. Jolliffe DA, Ganmaa D, Wejse C, et al. Adjunctive vitamin D in tuberculosis treatment: meta-analysis of individual participant data. Eur Respir J. 2019 Mar 7;53(3). pii: 1802003. doi: 10.1183/13993003.02003-2018. Print 2019 Mar. PubMed PMID: 30728208.

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 active TB during pregnancy and breastfeeding: INH, RMP, and EMB are considered safe in pregnancy. Therefore, all these 3 drugs should be used for initial treatment. Patients treated with INH should receive pyridoxine (vitamin B6). 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. Most second-line agents, however, are not considered safe during pregnancy. This is due to inadequate data indicating safety or a known risk of teratogenicity.

Breastfeeding is not contraindicated during TB treatment. Mothers breastfeeding while on TB treatment should receive pyridoxine supplements. At most, 3% of the maternal dose is excreted into breast milk. That amount ingested by a newborn does not produce toxic effects.

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 severe liver disease: INH, RMP, and PZA may cause drug-induced hepatotoxicity. All 3 should be avoided if possible. Given the potency and effectiveness of RMP, it may be considered in people with extensive pulmonary or extrapulmonary disease. A suggested regimen is FQN + EMB + parenteral (amikacin) for 2 months followed by FQN + EMB for a total of 18 months. If liver function has stabilized, RMP may be introduced with careful monitoring of liver parameters.

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 transplant: 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 microbiologic 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 after 2 to 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.

ComplicationsTop

Pneumothorax, bronchopleural fistula, pleural empyema, pleural fibrosis (fibrothorax), pulmonary hemorrhage, and amyloidosis.

PreventionTop

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.

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