Sahar Mahmoud, aged 41 years, has come to see you for her regular review. You have been seeing her for eight weeks and she is feeling a lot better. However, you note that she is now presenting with a tremor. It has only started this week.
Tuberculosis (TB) caused by Mycobacterium tuberculosis is a disease of antiquity but remains a major cause of morbidity and mortality world-wide. Although the number of deaths from TB is falling and currently estimated by the WHO to be 1.6 million per year, it remains an enormous public health problem, with about 9.2 million new cases per year and over 3 billion people (approximately half the world's population) at risk or infected. In some sub-Saharan African countries where TB is endemic and there is a high prevalence of HIV, up to 10% of the population develops TB each year. TB contributes to poverty by affecting young and middle-aged adults in their productive years.
M. tuberculosis is spread predominantly by aerosolised droplet nuclei and only rarely by ingestion of unpasteurised milk or via the skin.
Primary tuberculosis
After inhalation, tubercle bacilli usually lodge in the subpleural region of the upper or lower lobes and establish an infection. Bacilli that enter the blood stream seed many organs of the body (subclinical bloodstream spread) and over 95% of infected individuals mount an effective immune response and the foci of infection heal. Occasionally, primary infection may progress directly to disease in the lung or at extrapulmonary sites.
Latent tuberculosis
In most people a small number of viable bacteria persist indefinitely in these quiescent primary foci. These individuals have asymptomatic latent tuberculosis and may remain well for the rest of their lives. However, approximately 5-10% of latent infections reactivate later in life causing post-primary TB.
Post-primary tuberculosis
This can occur at any time from a few weeks to many decades after the primary infection. It can arise by reactivation of a previous focus of infection or by reinfection. Around half of all cases of post-primary pulmonary TB occur in the 10 years following the primary infection; the incidence is greatest when the primary infection has occurred in adolescence.
Pulmonary post-primary TB typically affects the apex of the upper lobe or the apex of the lower lobe. Viable bacteria initiate a local inflammatory reaction characterised by accumulation of activated macrophages (epithelioid cells) with lymphocytes around the periphery. The appearances of the characteristic lesion of TB, the granuloma, reflect an effective cell-mediated immune response. Enlargement and multiplication of granulomas leads to confluent granulomatous consolidation. Tissue necrosis is prominent and the centre of the granulomatous mass often has a cheesy consistency, hence the term 'caseation'. In some cases the caseating material liquefies and is discharged into a bronchus, where it may spread to other parts of the lung or be coughed up, often leaving a cavity.
Most often, a person develops primary TB asymptomatically. The diagnostic significance of the tuberculin skin test changing from negative to positive (known as tuberculin conversion) may only become apparent if a patient has routine testing or happens to be tested before and after developing TB.
In the majority of cases the consolidation or pleural effusion of primary TB either resolves spontaneously or is discovered accidentally when a chest x-ray is performed for some other reason. Occasionally, a primary focus may enlarge and cavitate or progress directly to tuberculous bronchopneumonia or miliary TB.
Symptoms of post-primary TB are often insidious and may be present for several months before presentation. Weight loss, night sweats, malaise and anorexia are common but may initially be ascribed to 'overwork' or 'stress'. A chronic, productive cough, sometimes with blood-stained sputum, shortness of breath or chest pain usually prompts medical attention.
In advanced disease there may be progressive dyspnoea with the development of respiratory failure, diffuse crackles and evidence of cor pulmonale.
Establishing the diagnosis of TB may be difficult.
Microscopy and culture
The aim is to obtain histological and bacteriological confirmation of the diagnosis. Several (usually three) deep cough specimens of sputum should be sent for microscopy and culture. Examination of gastric juice in the morning may aid diagnosis, particularly when cough is absent in children. Fibreoptic bronchoscopy is indicated in the absence of sputum or the presence of undiagnosed lung lesions. Bronchoalveolar lavage and bronchial brushings, washings and biopsies may provide samples in which organisms can be identified by microscopy or culture. Needle biopsy specimens taken during bronchoscopy can help confirm the diagnosis if histological material is obtained showing classical caseating granulomas. Even when not caseating, histological appearances of granulomas are often highly suggestive of TB. In countries where TB is common, empirical treatment (after appropriate sputum or tissue specimens for culture have been obtained) is often initiated for granulomatous or caseating lesions.
Mycobacteria have a lipid-rich cell wall, which means they retain certain stains after acid or alcohol treatment, and are therefore known as acid- and alcohol-fast bacilli (AAFB). Microscopy of sputum gives rapid results and is invaluable in high-prevalence areas with limited resources, although it is less sensitive than culture. Culture is considered the gold standard for diagnosis, allowing both identification of the organism and antibiotic sensitivity testing; however, it can take several weeks. New molecular tests such as GeneXpert MTB/RIF can rapidly identify both the presence of M. tuberculosis and rifampicin resistance. Such assays are now widely available and will become invaluable for the rapid detection and management of TB and drug-resistant TB in high-prevalence areas where laboratory facilities and funding permit.
Radiology
A chest x-ray should always be obtained at the outset. Typically, pulmonary TB shows patchy or nodular opacities in the apex of the upper lobe or apex of the lower lobe. Cavitation is common. Occasionally, especially in a person infected with HIV, chest x-ray changes may be non-specific or absent in the presence of extensive disease.
Tuberculin skin testing
A strongly positive tuberculin skin test (TST) is supportive of a diagnosis of TB but cannot distinguish between latent TB infection and TB disease. In low-risk populations a strongly positive TST may represent previous BCG vaccination and a negative TST may still occur in active disease in immunosuppressed patients. TSTs are therefore increasingly being replaced by interferon-gamma (IFN-γ) release assays (IGRAs), which detect IFN-γ release by T cells from whole blood exposed to M. tuberculosis-specific antigens. These tests are more specific than TST, as there is no cross-reactivity with BCG.
Investigation flowchart for suspected tuberculosis:
Clinical Suspicion of TB
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Chest X-ray
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Sputum Samples (×3)
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If sputum negative or unable to produce sputum:
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Tuberculin Skin Test or IGRA
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Additional tests if extrapulmonary TB suspected:
The aims of treatment are to achieve cure and to avoid the emergence of drug-resistant organisms. This is best achieved by giving a minimum of three drugs initially and ensuring that treatment is taken for an adequate duration. Poor adherence is the most important cause of relapse and the development of drug-resistant organisms.
Drug therapy for newly diagnosed pulmonary TB should be taken for 6 months. The initial phase of 2 months with four drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) is designed to rapidly reduce the number of organisms and thus minimise the emergence of drug-resistant organisms. In the continuation phase rifampicin and isoniazid are given for a further 4 months to eliminate any remaining organisms.
Organisms that are sensitive to isoniazid and rifampicin at the start of treatment are very likely to be eliminated in 6 months. Prolongation of therapy beyond 6 months is only necessary if the response to chemotherapy is slow (e.g. if patients are still sputum- or culture-positive after 4 months of treatment) or there is extensive disease. In special situations, such as CNS TB, longer courses are indicated.
Monitoring therapy
Clinical review and sputum microscopy and culture should be performed at 2 months. If the patient is responding well, treatment is continued into the continuation phase. If the patient is failing to respond, the possibilities of poor adherence or drug-resistant TB must be considered. Directly observed therapy (DOT) should be instituted if poor adherence is a problem, while drug sensitivity results should guide further treatment of drug-resistant TB.
Patients must be warned to report symptoms suggestive of adverse effects (particularly hepatitis). Biochemical monitoring should be performed at least at the beginning and at 2 months, and more frequently in the elderly, those with liver disease and those known to be hepatitis B or C carriers.
Public health aspects
TB is a notifiable disease and every effort should be made to trace and screen contacts of patients with TB for evidence of either latent or active TB. Chemoprophylaxis or treatment is then given as appropriate.
| Drug | Dose | Most important side-effects |
|---|---|---|
| Isoniazid | 5 mg/kg (max 300 mg) daily | Hepatitis, polyneuropathy (prevent with pyridoxine 10 mg daily), rash, fever, drug-induced lupus |
| Rifampicin | 10 mg/kg (max 600 mg) daily | Hepatitis, orange secretions, flu-like symptoms, rash, thrombocytopenia; accelerated metabolism of warfarin, corticosteroids, contraceptive pill |
| Pyrazinamide | 25 mg/kg (max 2 g) daily | Hepatitis, arthralgia, rash, hyperuricaemia (rarely causes gout) |
| Ethambutol | 15 mg/kg daily | Optic neuritis (causes colour blindness and reduced visual acuity); dose-dependent – less common at 15 mg/kg |
Drug-resistant TB poses a major threat to global TB control. Most cases of drug resistance are due to inappropriate prescription of drugs or patients not adhering to treatment.
Multi-drug resistant TB (MDR-TB) is TB resistant to at least isoniazid and rifampicin and is associated with long, expensive treatment that is complex and much less likely to result in cure. There are an estimated 480 000 cases of MDR-TB per year, with around 210 000 deaths. MDR-TB is found in all countries surveyed but is most common in Eastern Europe and Central Asia, where around 20% of cases are MDR-TB. Treatment of MDR-TB requires the use of second-line drugs for a minimum of 18-24 months under close supervision.
Extensively drug-resistant TB (XDR-TB) is MDR-TB that is additionally resistant to a fluoroquinolone and at least one other second-line injectable drug (amikacin, kanamycin or capreomycin). XDR-TB is more difficult to treat and associated with extremely high mortality, particularly in HIV-infected individuals where survival can be as low as 10%. The treatment of XDR-TB is extremely challenging and expensive, and although new drugs are now in clinical trial there is an urgent need for other drugs and for new diagnostics to rapidly identify drug resistance.
The tremor is likely due to isoniazid treatment and may indicate peripheral neuropathy. Isoniazid can cause peripheral neuropathy, and all patients on isoniazid should be prescribed pyridoxine (vitamin B6) 10 mg daily prophylactically to prevent this complication.
Initial management should have included:
The patient should be examined for signs of peripheral neuropathy, and if confirmed, pyridoxine should be started immediately. If severe, consideration should be given to stopping isoniazid and using alternative second-line drugs.