Tuberculosis

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40 Tuberculosis

L.K. Nehaul

Key points

• In 2008, there were an estimated 9 million cases of tuberculosis (TB) and 2 million deaths from the disease worldwide.
• One-third of the world’s population is infected with the tubercle bacillus.
• Adequate and effective treatment is essential to treat the individual, control the spread of TB and minimise the occurrence of drug-resistant disease.
• TB is caused by infection with Mycobacterium tuberculosis, M. bovis and M. africanum. M. tuberculosis accounts for around 99% of isolates in the UK.
• TB infection usually occurs by the respiratory route.
• People with HIV infection have an increased risk of developing active TB disease if co-infected with tubercle bacilli.
• Certain medical risk factors increase the risk of TB.
• Most treatment regimens in the developed world are of 6 months’ duration and contain isoniazid, rifampicin and pyrazinamide, with ethambutol or streptomycin.
• Rifampicin, isoniazid and pyrazinamide are all potentially hepatotoxic. Isoniazid may cause a dose-dependent peripheral neuropathy, while ocular toxicity is the most important side effect of ethambutol.
• Multidrug-resistant TB is a problem in many parts of the world; extensively drug-resistant TB was first reported in 2006.

Introduction

Tuberculosis (TB) is a bacterial infection, treatable by anti-TB drugs. It is a global problem, with the incidence varying across the world. In 1993, an increase in reported cases of TB in countries across all continents led the World Health Organization (WHO) to declare TB a global emergency. The burden of TB in many countries is compounded in those who have co-infection with the human immunodeficiency virus (HIV). Of additional concern has been the increase in multidrug-resistant tuberculosis (MDR-TB), with outbreaks in different parts of the world. In 2006, the emergence of extensively drug-resistant tuberculosis (XDR-TB) was first reported. The treatment of drug-resistant TB is complex, costlier and of a longer duration than drug-susceptible cases.

Adequate and effective treatment is essential, both clinically for patients and also to control TB, as the BCG vaccine does not prevent infection. Successful control depends on a close working collaboration between clinical, microbiological, pharmacy, infection control and public health teams in managing patients and their contacts, and a shared understanding with primary care teams as to the role of all health professionals involved in TB.

Clinical and public health practice for bringing TB under control in the UK is underpinned by guidance from National Institute for Health and Clinical Excellence (2006) and the Joint Committee on Vaccination and Immunisation (Department of Health, 2006).

Aetiology

TB is caused by tubercle bacilli, which belong to the genus Mycobacterium. These form a large group but only three relatives are obligate parasites that can cause TB disease. They are part of the Mycobacterium tuberculosis complex. The UK data for 2008 show that M. tuberculosis was isolated in 99% of confirmed cases, M. bovis in 0.4% and M. africanum in 0.5% that year (Health Protection Agency, 2009).

Mycobacterium species include:

• M. tuberculosis complex: M. tuberculosis, M. bovis, M. africanum
• Mycobacteria other than tuberculosis: Around 15 are recognised as pathogenic to humans and some cause pulmonary disease resembling TB. They have been found in soil, milk and water. They are also referred to as atypical mycobacteria.
• Mycobacterium leprae: The cause of leprosy.

Clinical aspects

Infection with tubercle bacilli occurs in the vast majority of cases by the respiratory route. The lung lesions caused by infection commonly heal, leaving no residual changes except occasional pulmonary or tracheobronchial lymph node calcification (Heymann, 2004). About 5% of those initially infected will develop active primary disease (Hawker et al., 2005). This can include pulmonary disease, through local progression in the lungs, or by lymphatic or haematogenous spread of bacilli, to pulmonary, meningeal or other extrapulmonary involvement, or lead to disseminated disease (miliary TB). In the other 95%, the primary lesion heals without intervention but in at least one-half of patients, the bacilli survive in a latent form, which may then reactivate later in life. Infants, adolescents and immunosuppressed people are more susceptible to the more serious forms of TB such as miliary or meningeal TB.

Pulmonary (respiratory) TB is more common in the UK than extrapulmonary (non-respiratory) TB. Sites of extrapulmonary disease include the pleura, lymph nodes, pericardium, kidneys, meninges, bones and joints, larynx, skin, intestines, peritoneum and eyes. In the UK, the lymph nodes are the most common site for extrapulmonary disease. In 2008, 55% of cases were pulmonary and 21% involved the extrathoracic lymph nodes.

Pulmonary TB may arise from exogenous reinfection or endogenous reactivation of a latent focus remaining from the initial infection. If untreated, about 65% of patients will die within 5 years, the majority of these within 2 years. Completion of chemotherapy using drugs to which the tubercle bacilli are sensitive almost always results in a cure, even with HIV infection.

Incubation period

The incubation period from infection to demonstrable primary lesion or significant tuberculin reaction ranges from 2 to 10 weeks. Latent infection may persist for a lifetime. HIV infection appears to shorten the interval for the development of clinically apparent TB.

Transmission

Transmission occurs through exposure to tubercle bacilli in air-borne droplet nuclei produced by people with pulmonary or respiratory tract TB during expiratory efforts such as coughing or sneezing. In general, only the respiratory forms of TB (tuberculosis of the larynx is highly contagious but rarely seen in the UK) are infectious. Most infections are acquired from adults with post-primary pulmonary TB. The greatest risk of infection is to close, prolonged contacts, mainly household contacts. Between 90% and 95% of cases of TB in children are non-infectious (Davies, 2003). TB cannot be acquired from individuals with latent TB infection (LTBI).

Patients should be considered infectious if they have sputum smear-positive pulmonary disease (i.e. they produce sputum containing sufficient tubercle bacilli to be seen on microscopic examination of a sputum smear) or laryngeal TB. Patients with smear-negative pulmonary disease (three sputum samples) are less infectious than those who are smear positive. The relative transmission rate from smear-negative compared with smear-positive patients has been estimated to be 0.22 (British Thoracic Society, 2000).

Risk groups

Certain groups are at increased risk of LTBI and possibly TB disease if exposed. These include:

• close contacts of patients with TB, especially those with sputum smear-positive pulmonary disease
• casual contacts (e.g. work colleagues) if they are immunosuppressed
• people from countries with a high incidence of TB (40/100,000 population or greater).

People with certain medical conditions are at increased risk of developing active TB if they have LTBI. These medical risk factors are set out in Box 40.1.

Box 40.1 Examples of factors that increase risk of developing active tuberculosis if infected

• HIV positive
• Injecting drug users
• Solid organ transplantation, jejunoileal bypass or gastrectomy
• Haematological malignancy, for example leukaemia and lymphomas
• Chronic renal failure or receiving haemodialysis
• Receiving anti-TNFα treatment
• Silicosis

Impact of HIV infection

People with HIV infection have an increased risk of developing TB if exposed to infection. The estimated annual risk of TB in those with HIV infection and TB co-infection is around 10% as opposed to a 10% lifetime chance in someone infected with TB, but not HIV.

Drug-resistant TB

MDR-TB is caused by bacteria that are resistant to at least isoniazid and rifampicin, the most effective anti-TB drugs. MDR-TB results from either primary infection with resistant bacteria or may develop in the course of a patient’s treatment.

XDR-TB is a form of TB caused by bacteria that are resistant to isoniazid and rifampicin, that is, MDR-TB, as well as any fluoroquinolone and any of the second-line anti-TB injectable drugs including amikacin, kanamycin or capreomycin (WHO, 2010).

Epidemiology

Epidemiology is a measure of the occurrence of a disease in different populations. It helps to identify population groups at increased risk of TB. The key measures for TB are the number of new cases in a specified period of time, usually 1 year, and the incidence rates, that is, new cases per 100,000 of the population. Incidence rates are a good comparative measure of differences in the occurrence of TB between countries or different sub-groups in the population, as they take into account the size of those groups. TB surveillance, which involves monitoring its occurrence and epidemiology, is an essential component of TB control programmes, because it helps to evaluate their effectiveness in reducing disease rates.

Global

Globally, it is estimated that TB causes about 2 million deaths worldwide each year. One-third of the world’s population is infected with the tubercle bacillus. It is becoming the leading cause of death among HIV-positive people. Over 4 million cases of TB disease are notified annually although the estimated number of new cases is put at 9 million. The majority of cases occur in poor countries in the southern hemisphere (WHO, 2009).

The numbers of cases estimated to have occurred in 2008, globally and by WHO region, is presented in Table 40.1. Most cases of TB are in South East Asia, although the highest rates are in Africa.

Table 40.1 Estimated epidemiological burden of tuberculosis incidence globally and by WHO region (Source: WHO, 2010)

WHO region Numbers (000s), 2008 (lower and upper bounds) Rates per 100,000 population, 2008 (lower and upper bounds)
Africa 2800 (2700–3000) 350 (330–370)
Americas 280 (260–300) 31 (29–33)
Eastern Mediterranean 650 (580–740) 110 (99–130)
Europe 430 (400–460) 48 (45–51)
South-East Asia 3200 (2800–3700) 180 (160–210)
Western Pacific 1900 (1700–2200) 110 (95–130)
Global 9400 (8900–9900) 140 (130–150)

In 2008, it was estimated that 440,000 people had MDR-TB worldwide, and one-third of these died. The brunt of the MDR-TB epidemic is borne by Asia, with almost 50% of cases worldwide estimated to occur in China and India. However, in some areas of the world, up to one in four people have drug-resistant TB. For example, 28% of all people newly diagnosed with TB in one region of North-Western Russia had the multidrug-resistant form of the disease (WHO, 2010).

UK

In the UK, since the late 1980s, there have been changes in the epidemiology of TB. Following a decrease in notifications over several decades, from the late 1980s cases of TB started to increase again.

A total of 8655 cases were reported in 2008 (Health Protection Agency, 2009). The overall rate across all population groups was 14.1 per 100,000 population. Of all cases, 39% occurred in the London region, where the rate was 44.3 per 100,000 population. Nineteen primary care organisations in England had a rate of 40 per 100,000 or over, all of which were in major urban areas. Rates of TB in England outside London varied from 5.7 per 100,000 in South-West England to 18.7 per 100,000 in the West Midlands. Incidence rates per 100,000 population were 8.7 in Scotland, 5.8 in Wales and 3.3 in Northern Ireland. The majority of cases (72%) were in the population born outside the UK and in those aged 16–44 years (61%). The TB rate was higher in those born abroad than among those born in the UK (86 compared with 4.4 per 100,000). This reflected higher rates of TB in people from high-incidence countries, mainly South Asia. The risk of TB is highest in the 5 years after arrival in the UK. TB can also occur as a travel-related disease in UK residents from high-incidence countries, who return to visit their country of birth and are exposed to TB. The numbers of cases by region in England, Wales and Northern Ireland, in 2008, is shown in Table 40.2.

Table 40.2 Tuberculosis case reports and rates by UK region/country 2008 (adapted from Health Protection Agency, 2009)

UK region/country Number of cases Rate per 100,000 population
London 3376 44.3
West Midlands 1012 18.7
North West 745 10.8
Yorkshire and the Humber 647 12.4
East Midlands 517 11.7
South East 719 8.6
East of England 478 8.3
South West 297 5.7
North East 179 7.0
England 7970 15.5
Scotland 452 8.7
Wales 174 5.8
Northern Ireland 59 3.3

Diagnosis

Symptoms

The symptoms and signs of TB include:

• Cough for 3 weeks or more/productive cough
• Sputum usually mucopurulent or purulent
• Haemoptysis not always a feature
• Fever may be associated with night sweats
• Tiredness
• Weight loss variable
• Anorexia variable
• Malaise.

Awareness of the disease

Awareness of TB on the part of health care professionals and of people in high-risk communities is essential to its control. Early diagnosis, especially of pulmonary TB, followed by prompt commencement of treatment can reduce the period of infectivity to other people, especially susceptible contacts, who might be at risk of the more serious forms of TB disease. Such contacts can include children in nurseries or schools or immunosuppressed patients in a hospital setting. Health care professionals should be particularly alert to symptoms suggestive of TB in health care workers or people working in childcare or institutional settings, and initiate investigations at the earliest possible opportunity. Such action can lead to the diagnosis of TB before it becomes infectious, thereby protecting vulnerable contacts.

TB should be considered in the differential diagnoses of patients with a chronic cough for which there is no other likely cause, or in individuals with chest infections not responding to treatment.

Clinical diagnosis

The clinical diagnosis of TB disease is based on the symptoms and signs in the patient together with chest radiography, microscopy of sputum (for acid-fast bacilli) followed by culture and tuberculin skin testing. Blood-based immunological tests, introduced in the last few years, will play an increasingly important role in TB diagnosis. These tests can distinguish between TB infection and previous BCG vaccination.

Investigations

Investigations are essential to confirm clinically suspected TB and should be arranged even if the diagnosis is strongly suspected on clinical grounds. Microbiological tests are crucial, especially for pulmonary disease, as they facilitate both the clinical and public health management of TB and ensure the appropriate implementation of infection control procedures for cases managed in healthcare settings.

Microbiological

Microbiological investigations are undertaken to assess the infectious state of the patient, and distinguish between infection with mycobacteria causing TB and other mycobacteria. They also determine the drug-susceptibility patterns of the infecting organisms, to ensure that the drugs prescribed will be effective in treating the individual patient. Investigations comprise microscopy, culture, drug-susceptibility testing and strain typing.

Direct microscopy of sputum is the simplest and quickest method of detecting the infectious patient, by looking for acid-fast bacilli. A minimum of three sputum samples, one of which should be early morning, should be collected from patients with suspected respiratory TB.

Direct microscopy is not as useful in non-pulmonary disease, any specimens taken should be sent for culture.

If conventional culture methods are used, such as the Lowenstein–Jensen medium, growth may take up to 6 weeks. Modern liquid cultures can produce results more quickly. Polymerase chain reaction (PCR)-based tests can also detect M. tuberculosis complex in clinical specimens.

A rapid test is available for assessing rifampicin resistance in individuals thought to have drug-resistant TB. A positive result indicates the need to assess susceptibility to other first-line anti-TB drugs. Drug-susceptibility testing still needs to be done on isolates grown on culture media.

DNA fingerprinting, or strain typing, is useful in the public health management of TB. In 2010, a new method, mycobacterial interspersed repetitive unit/variable number of tandem repeats (MIRU/VNTR) 24-loci strain typing, became available in the UK. Strain typing will help in establishing links between cases not previously identified, disproving links between apparent clusters of cases, and also in detecting cross-contamination in laboratories.

Tuberculin testing

Tuberculin testing is used to detect LTBI. Only the Mantoux test is now used but it should be carried out by health care professionals trained and experienced in its use. The standard Mantoux test consists of an intradermal injection of 2 TU of Statens Serum Institute (SSI) tuberculin RT23 in 0.1 mL solution for injection. In this test, 0.1 mL of the appropriate solution is injected intradermally, usually on the forearm, so that a bleb of around 7 mm is produced. The results are read 48–72 h later, although a valid reading can be obtained up to 96 h later. The transverse diameter of the area of induration is measured with a ruler and the result recorded in millimetres.

The interpretation of the test will depend on the clinical circumstances, including a past history of TB or exposure to TB. A diameter of induration of less than 6 mm is negative, that is, there is no significant hypersensitivity to tuberculin protein.

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