Management of Tuberculosis: A guide for clinicians (eBook edition)

CHAPTER 1

Diagnostic evaluation of individuals with presumptive TB

Tuberculosis (TB) is a transmissible infectious disease caused by Mycobacterium tuberculosis and other members of the M. tuberculosis complex (e.g. M bovis, M orygis, M africanum). It is mainly spread by inhalation of aerosolised organisms generated through coughing and talking or singing. While curable with the use of multiple antibiotics, treatment duration is lengthy and morbidity and mortality are high without prompt and effective management. TB is the number 1 infectious disease killer globally and presents important clinical and public health challenges to Australia and the Asia-Pacific region.

In 2015, an estimated 10.4 million people developed active TB worldwide, with 1.8 million deaths occurring as a direct result of TB disease. Within Australia effective public health interventions have resulted in both a low incidence of TB and a low risk of community transmission. In 2014, 1,260 cases of TB were notified in Australia. This equates to a TB incidence of around 6/100 000 population; approximately 1/20th the global average. Nearly 90% of TB cases are diagnosed following exposure overseas, frequently many years after migration. While disease rates among Australian-born individuals are generally very low, some Australian-born individuals are at increased risk of developing TB (particularly Indigenous Australians in remote communities). Effective approaches to both prevention and cure are widely available, case fatality rates are low (<5%) and TB diagnosis and care is available free of charge.

Around half of TB cases in Australia are pulmonary, with disease affecting the lung parenchyma. The typical presentation of productive cough, low-grade fever and weight loss occurring for more than 2 weeks should prompt consideration of the diagnosis in individuals with appropriate epidemiologic risk factors. Tuberculosis can have myriad presentations, with textbook symptoms of pulmonary TB, such as chronic sputum production and haemoptysis, frequently absent.

Surveys of the general community in TB endemic areas have shown that many individuals lack typical symptoms, and appropriate investigation to diagnose or exclude TB may be required even in the absence of symptoms.

Peripheral lymphadenitis is the most common form of extra-pulmonary disease, but M. tuberculosis has been reported in every body organ, including osteo-articular, renal, ovarian, ocular and cutaneous presentations. Extrapulmonary forms of the disease are often indolent and have a protracted clinical course. However, disseminated forms of TB, such as miliary disease and TB meningitis, may occur rapidly and diagnostic delay is associated with high morbidity and mortality.

Performing M. tuberculosis culture requires specialised media that supports the specific nutritional needs of slowly growing mycobacteria. The routine use of liquid culture media has shortened the time of organism identification compared to traditional solid culture methods. However, turnaround times remain slow and 4-6 weeks may still be required for growth depending on the initial organism burden/inoculum.

Rapid molecular tests incorporating TB polymerase chain reaction (PCR) and genotypic assessment of rifampicin resistance mutations (rpoB) should be routine for presumptive pulmonary TB cases. Globally, these PCR tests are most commonly performed using the commercially available GeneXpert platform. The Gene Xpert MTB/RIF® assay allows for rapid identification of both the presence of M tuberculosis and rpoB mutations indicative of clinical and phenotypic rifampicin resistance. Where the GeneXpert platform is not available, (PCR) for specific gene targets may also be performed.

Increasingly, whole genome sequencing (WGS) of M. tuberculosis isolates is conducted following culture. This method allows for M. tuberculosis confirmation, the detection of gene mutations associated with resistance against a wide range of antituberculous drugs and the assessment of likely transmission chains. However, current approaches to performing WGS require concentrated volumes of the organism, which means that sequencing normally is possible only after culture confirmation has been obtained.

Histologic diagnosis of TB includes visualisation of acid-fast bacilli (AFB) and/or suggestive granulomas (usually with some central caseation/necrosis) within appropriate clinical samples. While both the presence of AFB or typical histological changes are consistent with TB, they have poor sensitivity and suboptimal specificity when compared with culture (eg AFB may be absent in clinical specimens which are ultimately culture positive or be indicative of non-tuberculous mycobacteria, while granulomatous inflammation may be caused by sarcoidosis or syphilis). Hence, where possible, confirmation by other methods should be sought.

Reliance on radiological and/or clinical criteria, in the absence of bacteriological testing, may be necessary when clinical specimens cannot be obtained or tests are negative despite high clinical suspicion. Individuals with a high clinical probability of disease may sometimes be treated in the absence of bacteriological confirmation (such as unwell young children with recent household contact with an infectious TB case), but only after careful consideration and with close monitoring of clinical treatment response.

Tests for M. tuberculosis infection, such as interferon-gamma release assays or the tuberculin skin test, evaluate T-cell mediated immunologic responses. These tests are generally unhelpful in establishing diagnosis of TB, on account of their poor specificity and sensitivity for disease, and may indeed be falsely negative in the setting of significant disease. Hence, use of LTBI testing in the context of suspected disease is not encouraged.

Definitive diagnosis of active TB requires the demonstration of viable M. tuberculosis in the context of clinical findings consistent with active disease. Ideally, all cases of TB should be diagnosed by culture conducted on appropriate clinical specimens (such as sputum, bronchoscopic washings, lymph node biopsy or other site as clinically appropriate). In addition to confirmation of active TB, positive cultures also allow for phenotypic drug susceptibility testing, which is critical to tailoring an appropriate individualised treatment regimen (Chapter 2). Although not always attainable, establishing a bacteriological diagnosis and antibiotic resistance profile should be a priority. In the following diagnostic schema, there is a ‘hierarchy’ of preferred methods for confirming tuberculosis, in which establishing a diagnosis by culture confirmation is superior to molecular (PCR) methods alone, and so forth (culture>molecular>histology>radiological>clinical), more details on which follow below.

In addition to morbidity and mortality associated with developing TB, individuals may also present a risk of transmission to others in the community. Priority is given to screening contacts of patients with infectious pulmonary TB. Extrapulmonary forms of TB are generally not contagious, as TB is usually spread via the respiratory/aerosol route. Concomitant pulmonary disease should always be excluded in patients treated for extrapulmonary forms of the disease.

In general, the concentration of organisms found in sputum correlates with risk of transmission, with individuals who are sputum ‘smear-positive’ (for AFBs on light microscopy), being substantially more likely to transmit infection than those who are ‘sputum smear-negative’.

In general, TB is less transmissible than many common respiratory infections (such as influenza). Hours or days of close contact with an infectious individual are usually required before the risk of infection becomes significant. However, this may vary considerably depending upon the extent of disease and proximity of contact.

Once a case of potentially infectious TB has been notified to health authorities, contacts judged to be at sufficient risk of infection should undergo clinical review and TB testing. Such contact follow-up is the responsibility of state and territory TB programs in Australia. Contact tracing serves two purposes. First, it identifies contacts with previously unrecognised active disease (co-prevalent cases), facilitating early introduction of treatment and preventing further TB transmission. Second, it identifies asymptomatic contacts with TB infection who may benefit from preventive therapy or ongoing surveillance. For additional detail on diagnosis and management of LTBI, see Chapter 7.

References and further reading

Bates M, Zumla A. The development, evaluation and performance of molecular diagnostics for detection of Mycobacterium tuberculosis. Expert Review of Molecular Diagnostics. 2016 Mar 3;16(3):307-22.

Horsburgh Jr, C. Robert, Clifton E. Barry III, and Christoph Lange. Treatment of tuberculosis. New England Journal of Medicine 373.22 (2015): 2149-2160.

Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, Keane J, Lewinsohn DA, Loeffler AM, Mazurek GH, O’Brien RJ. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clinical Infectious Diseases. 2017; 64(2): e1-e33.

Sotgiu G, Nahid P, Loddenkemper R, Abubakar I, Miravitlles M, Migliori GB. The ERS-endorsed official ATS/CDC/IDSA clinical practice guidelines on treatment of drug-susceptible tuberculosis. European Respiratory Journal. 2016 Oct 1;48(4):963-71.

World Health Organization. Global tuberculosis report 2016. World Health Organization, 2016.

CHAPTER 2

Treatment of active tuberculosis

Prior to initiation of treatment, patients should be assessed for co-morbid conditions which may affect therapy or TB-related outcomes. This particularly includes testing for conditions which may increase risk of medication-related hepatotoxicity, such as Hepatitis B or C, pregnancy testing where appropriate, and review of existing medication use.

The following is a list of baseline testing which is recommended for all patients initiating TB therapy. Additional tests may also be required for individual circumstances, particularly where second-line medications are being considered.

•Clinical assessment, including weight, visual acuity and Ishihara test (colour vision)

•Radiological evaluation as appropriate to site, but including CXR

•Blood tests: Full Blood Examination (FBE), Liver Function Tests (LFT), Urea, Electrolytes and Creatinine (UEC), Vitamin D, HbA1C, HIV Ag/Ab, HBVsAg/Ab/ cAb, HCV Ab

Patients should be provided with individualised counselling on the importance of medication adherence. Common and important side effects for TB medications and planned monitoring should also be discussed routinely, with strategies for reducing risk (such as avoidance of alcohol) and clear instructions for reporting potential adverse effects provided.

The goals of tuberculosis therapy are to provide curative treatment without relapse; reduce infectivity in the case of infective pulmonary disease; prevent the emergence of drug resistance and minimise treatment adverse effects.

Traditionally, empirical antituberculous treatment has generally been commenced without knowing the full antibiotic susceptibilities of the causal organism. Globally, this is still the case. Increasingly in Australia, access to rapid molecular diagnostic tests can provide at least some guidance in selecting the initial regimen. The standard initial regimen for proven or presumed infection with drug-susceptible M tuberculosis comprises four drugs.

HRZE regimen (the standard four-drug regimen)

Drugs: isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E)

•Isoniazid is the most effective bactericidal drug.

•Rifampicin and pyrazinamide are the most important sterilising drugs and are thought to act by killing different populations of semi-dormant organisms (persisters).

•Isoniazid and rifampicin are the most effective drugs at preventing the emergence of resistance to other drugs.

•Rifampicin may interact with other medications through induction of hepatic metabolism, which should be checked prior to commencement. This is most commonly encountered in relation to the oral contraceptive pill, which may have decreased efficacy with co-administration. Women should be advised to use a barrier contraceptive.

•The metabolism of isoniazid is by acetylation. Individuals may be slow, heterozygous rapid, or homozygous rapid acetylators. Isoniazid acetylator status is not routinely determined and generally does not impact on treatment outcome, but it may be of significance when intermittent regimens are used, and may also impact the frequency of hepatotoxicity.

•Pyrazinamide has good activity against intracellular organisms and is most active in the first 2 months of treatment; it enables the total duration of treatment to be shortened to 6 months (for fully drug-sensitive infections). Mycobacterium bovis (including M. bovis Bacille Calmette Guerin [BCG]) is inherently resistant to pyrazinamide. Pyrazinamide is therefore not included in treatment regimens for tuberculosis known to be caused by M. bovis.

•Ethambutol is a bacteriostatic drug that is given to prevent the emergence of resistance.

Duration of initial (intensive or bactericidal) phase

The minimum duration of intensive phase treatment, usually with HREZ, is 2 months (or 8 weeks). Pyrazinamide should be continued, unless the organism is known to be resistant, until sputum is acid-fast bacillus (AFB) smear-negative or for 2 months, whichever is longer. As intermittent regimens are associated with increased treatment failure and relapse, it is recommended that daily therapy be used whenever possible, particularly during the intensive phase of therapy.

Table 2.2: Initial dosing of antituberculosis therapy.

HRZ regimen

Drugs: Three drugs: isoniazid (H), rifampicin (R) and pyrazinamide (Z)

Ethambutol is given to prevent the emergence of additional resistance in the event that isoniazid resistance is already present. Ethambutol is almost always included in the initial regimen because more than 85% of TB in Australia occurs in individuals born in countries with a high TB incidence where rates of isoniazid resistance are 5–10% (or higher).

Ethambutol is omitted from the initial regimen if the TB isolate is known to be fully susceptible to first-line agents before treatment has been started. If ethambutol is indicated but is unable to be used due