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.

In the absence of specific risk factors for TB, induration of between 6 and 15 mm diameter may be due to previous TB infection, or BCG vaccination or exposure to non-tuberculous mycobacteria. An induration of more than 15 mm is strongly suggestive of TB infection or disease.

Chest radiography

The chest radiograph is a non-specific diagnostic tool, as TB may present as virtually any abnormality on chest radiography. This is why microbiological evidence of confirmation should be sought. Pulmonary TB may appear as bronchopneumonia with confluent shadowing, without cavitation. Cavitation may be seen, the incidence can vary between 10% and 30%. Uncharacteristic radiological patterns may occur in the presence of HIV infection (Davies, 2003).

Diagnosis in people with HIV

TB can occur early in the course of HIV infection and may therefore be diagnosed before the patient is known to be HIV positive. The possibility of HIV infection in people with TB should therefore be considered, and testing for the virus is appropriate in those with risk factors for HIV.

Early in the course of HIV infection, before serious immunodeficiency occurs, TB is more likely to present with typical clinical features, and a positive tuberculin skin test, with cavitation and/or pleural disease on chest radiography. In the late stages of HIV infection, atypical presentations are more likely with unusual chest findings and extrapulmonary disease. The chest radiograph may be normal in up to 40% of cases.

Public health action

TB is a statutorily notifiable communicable disease in the UK. Cases should be notified on clinical suspicion by the attending doctor to the ‘Proper Officer’ for communicable disease control of the local authority where the patient resides. This is usually the local Consultant in Communicable Disease Control. In Scotland, notifications are made to the Health Board. Notification enables public health action to be initiated and involves investigation of prolonged, close contacts who might be at risk of infection, mainly those living in the same household as the patient, to assess them for LTBI or active TB disease. It may also enable the source of the infection to be found and treated.

Latent TB infection (LTBI) is not notifiable. Public health action is not taken for infections caused by ‘mycobacteria other than TB’.

Treatment

In treating TB, a number of factors are important:

• Choice of drugs
• Length of treatment
• Co-morbidity especially HIV infection, liver and renal diseases
• Adherence to treatment by the patient.

It is important to tailor the management of the patient according to his or her situation, rather than just focus on the drug treatment of TB, as other factors in the patient’s life may affect adherence.

Drug treatment

Treatment with anti-TB drugs has two main purposes:

• to cure people with TB, provided the bacilli are drug sensitive;
• to control TB, by either preventing the development of infectious forms or reducing the period of infectivity of people with infectious disease.

TB had started to decline in the UK before the advent of chemotherapy, probably due to improved nutrition and social conditions. With the advent of effective anti-TB chemotherapy, patients no longer needed treatment in a sanatorium. Results with regimens containing isoniazid together with p-aminosalicylate (PAS) or ethambutol, and sometimes streptomycin, gave excellent results. Treatment was required for 18–24 months if relapse was to be prevented. The availability of pyrazinamide and, more importantly, rifampicin made shorter courses of treatment a possibility. Most regimens in the developed world now contain isoniazid and rifampicin, which are the two most important drugs. These are prescribed together with pyrazinamide and possibly with another agent, such as ethambutol.

Bacterial characteristics

There are three populations of the M. tuberculosis (MTB) organism. The first population is that of the actively growing extracellular bacilli. Large numbers of bacilli can grow extracellularly in pulmonary cavities within liquefied caseous debris. This is the population in which drug resistance develops most rapidly. The second population consists of slow-growing or intermittently growing bacilli, which are inside macrophages. These are fewer in number, but the intracellular environment is acidic and many drugs are not active in these conditions. The third population is made up of slower-growing bacilli, which grow in solid caseous material. This environment is neutral in pH, but the penetration of drugs into this area can be compromised by a poor blood supply.

Rifampicin is the only drug that is bactericidal against all three populations. Isoniazid, streptomycin and the other aminoglycosides are bactericidal against extracellular bacilli. Isoniazid is also bactericidal against intracellular organisms. Pyrazinamide is bactericidal only against intracellular organisms and works well in an acidic pH. All other first-line TB drugs are bacteriostatic. Of the alternative drugs, which can be used in the treatment of drug-resistant TB, the quinolones have the highest bactericidal activity against M. tuberculosis.

When considering a treatment regimen for TB, it must be remembered that viable bacilli for slow-growing or intermittently growing populations may persist if drugs are not continued for an adequate period of time. The patient’s condition can then relapse after chemotherapy is completed.

Treatment

The recommended standard treatment regimen for respiratory and most other forms of TB in the UK is:

• rifampicin, isoniazid, pyrazinamide and ethambutol for the initial 2 months (initial phase)
• a further 4 months of rifampicin and isoniazid (continuation phase).

A longer period of treatment than the standard 6 months is needed for meningeal TB and where there is direct spinal cord involvement.

Patients should be started on the standard treatment regimen on clinical diagnosis and the doses of the first-line anti-tuberculous agents are shown in Table 40.3. The drugs used can be changed if drug-susceptibility testing shows evidence of resistance.

Table 40.3 Dosages of first-line anti-tuberculous agentsa

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The purpose of the concurrent use of four drugs in the initial phase is to reduce the bacterial population as rapidly as possible and prevent the emergence of drug-resistant bacteria. In general, daily dosing schedules are recommended. Combination tablets can be used and have the advantage of preventing accidental or inadvertent single drug therapy, which can lead to acquired drug resistance within weeks in active TB. It is important, however, to ensure the combination product contains the required dose of the constituent drugs.

Patients with suspected drug reactions or drug-resistant TB should always be referred back to the specialist physician and the healthcare team supervising their treatment.

Respiratory TB

Respiratory TB is defined as active TB affecting any of the following:

• lungs
• pleural cavity
• mediastinal lymph nodes
• larynx.

The standard 6-month regimen, as set out earlier, is recommended for the treatment of active respiratory TB in:

• adults not known to be HIV positive
• adults who are HIV positive
• children.

TB of peripheral lymph nodes

Trials have shown that 6 months of treatment are just as effective as 9 months for fully susceptible bacilli. The standard 6-month treatment regimen is recommended.

Meningeal TB

Patients with active meningeal TB (tuberculous meningitis) should be treated with rifampicin and isoniazid for 12 months together with pyrazinamide, and normally ethambutol, for the first 2 months. Ethambutol (and streptomycin if used in preference) only reach cerebrospinal fluid through inflamed meninges.

Care must be exercised when ethambutol is used in unconscious patients as a decline in visual acuity, a known side effect of ethambutol, cannot be assessed.

Meningeal TB is a serious disease and treatment must be started promptly. The stage at which the disease is diagnosed, and treatment started, most affects prognosis. Therefore, it is often justified to start a therapeutic trial of anti-TB drugs in the absence of a definite diagnosis.

The use of glucocorticoids is also recommended in the management of meningeal TB and is commenced at the same time as anti-tuberculous drugs. Consideration should be given to their gradual withdrawal within 2–3 weeks of initiation. The recommended doses (National Institute for Health and Clinical Excellence, 2006) are:

• Adults: equivalent to prednisolone 20–40 mg if on rifampicin, otherwise 10–20 mg
• Children: equivalent to prednisolone 1–2 mg/kg, maximum 40 mg

The more recent British Infection Society (BIS) guidelines for the diagnosis and treatment of TB of the central nervous system (CNS) in adults and children (Thwaites et al., 2009) recommend all patients with meningeal TB should receive adjunctive corticosteroids (dexamethasone) regardless of disease severity at presentation.

Bone and joint TB

The spine is the most common site for bone TB. Bone and joint TB are treated effectively with standard agents such as isoniazid and rifampicin for 6 months, together with pyrazinamide and a fourth drug, usually ethambutol in the initial phase (for 2 months). This recommendation covers active spinal TB and active TB at other bone and joint sites. Occasionally, surgery may be needed to either relieve spinal cord compression or correct spinal deformities.

Disseminated TB

Generalised (disseminated or miliary) TB must be treated promptly as there is appreciable mortality from delayed diagnosis and treatment. The standard 6-month regimen containing both isoniazid and rifampicin, with pyrazinamide and ethambutol in the first 2 months, is used. If there is evidence of CNS involvement, treatment should be the same as for meningeal TB.

Pericardial TB

Although TB of the pericardium is rare in the UK, it is potentially important because of the possibility of cardiac tamponade and constrictive pericarditis, which are associated with a significant morbidity and mortality. The standard 6-month treatment regimen is recommended for patients with active pericardial disease. Glucocorticoids should also be prescribed at the following doses (National Institute for Health and Clinical Excellence, 2006):

• Adults: a glucocorticoid equivalent to prednisolone at 60 mg/day
• Children: a glucocorticoid equivalent to prednisolone 1 mg/kg/day (maximum 40 mg/day), with gradual withdrawal of the glucocorticoid, starting within 2–3 weeks of initiation.

Treatment of TB in special circumstances

TB in children

The doses of drugs used in children are shown in Table 40.3. Doses are generally estimated to facilitate prescription of easily administered volumes of liquid or tablets of appropriate strength. Ethambutol should not routinely be used in young children, who would be unable to report visual disturbances should they occur. However, it may be used if there is toxicity or resistance to other agents.

Pregnancy

As there is a risk of TB to the fetus, treatment should be commenced whenever it is moderately or highly probable that a pregnant woman has TB. Standard therapy should be given, although streptomycin should not be used as it may be ototoxic to the fetus. It is considered safe for mothers to breast feed while taking anti-tuberculous treatment. Pyridoxine (vitamin B6) supplementation (10–25 mg/day) is recommended for breastfeeding women taking isoniazid. Patients should be warned of the reduced effectiveness of oral contraceptives in regimens containing rifampicin, and advised to use other, non-hormonal contraceptives.

Renal disease

Patients with renal disease may be given isoniazid, rifampicin and pyrazinamide in standard doses as these drugs are predominantly eliminated by non-renal routes. Ethambutol undergoes extensive renal elimination and therefore dose reduction is needed. Monitoring serum concentrations has been suggested, but this might not be readily available in many centres. Streptomycin must be used with considerable caution to prevent toxicity and is best avoided in renal failure. Rifampicin may be given in standard doses to patients on dialysis. However, doses of the other agents need to be modified, and a number of different regimens have been suggested.

Liver disease

Monitoring of liver enzymes is recommended in patients with liver failure or in alcoholics because rifampicin, isoniazid and pyrazinamide are all potentially hepatotoxic. However, increases in transaminases at the start of anti-tuberculous treatment occur frequently. These are usually transient and not a reason for stopping treatment unless frank jaundice or hepatitis develops, in which case all drugs should be stopped. It is usually possible to restart treatment when transaminases have returned to pre-treatment levels.

Immunocompromised patients

Patients who are immunocompromised, including those with HIV infection, should be treated with normal first-line agents unless multidrug-resistant TB is suspected. Theoretically, these patients have a greater risk of relapse and may need to be treated for longer than the normal 6 months.

TB and HIV co-infection

Guidelines for the treatment of TB/HIV co-infection (Pozniak et al., 2009) recommend that co-infected patients are managed by a multidisciplinary team which includes physicians with expertise in the treatment of both TB and HIV.

If patients on anti-tuberculous therapy are started on highly active antiretroviral therapy (HAART), then antiretrovirals should be chosen to avoid interactions with TB therapy. The treatment for TB should only be modified when drug interactions with antivirals do not allow the optimal TB treatment regimen. In some cases, a longer duration of treatment for the TB may be needed.

Chemo-preventive therapy for TB is not recommended in HIV-infected patients. However, as HIV-infected people with LTBI are more likely to progress to active TB disease than people without HIV, the detection and treatment of a latent infection is important.

HAART is effective at reducing the incidence of new TB in HIV-infected people. HIV-positive patients should therefore be offered HAART.

Drug-resistant TB

Drug-resistant TB is a considerable problem worldwide. In the UK, however, the proportion of TB isolates showing resistance is low (in 2008, 6% were resistant to isoniazid, 1.5% resistant to rifampicin, and 6.8% resistant to any first-line drug). Drug resistance is an important issue in the management of TB as it may compromise the effectiveness of treatment and prolong the period during which patients are infectious to others. Isoniazid is the most usual agent to which resistance is seen. Multi-drug resistance is important because the main bactericidal drugs, isoniazid and rifampicin, are ineffective. Treatment has to be individualised, requires a complex regimen involving the use of multiple reserve drugs and can cost at least £50,000 to £70,000 each to treat (Table 40.4). It is recommended that treatment of these individuals is only carried out by physicians with experience in drug-resistant TB; in hospitals, when inpatient treatment is necessary, with appropriate isolation facilities (negative pressure rooms); and in close conjunction with specialist centres.

Table 40.4 Reserve drugs: dosages and side effects (British Thoracic Society Joint Tuberculosis Committee, 1998)

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Monitoring treatment

In pulmonary TB, sputum examination and culture are the most sensitive markers of treatment success. Patients taking regimens containing rifampicin and isoniazid should be non-infectious within 2 weeks. If a patient does not become culture negative, it may be due to either drug resistance or non-adherence, the latter being more likely. Good adherence is essential if treatment is to be successful and checking this can be difficult, especially when a patient is unwilling to cooperate.

Adverse reactions

The major adverse reactions of the first-line drugs are shown in Table 40.5. Rifampicin, isoniazid and pyrazinamide are all potentially hepatotoxic, and liver function should be checked before treatment commences with these drugs. Transient increases in transaminases and bilirubin commonly occur at the start of treatment although there is no need to continue to monitor liver function in patients where pre-treatment liver function was normal. However, liver function tests must be measured if fever, malaise, vomiting or jaundice develop and all drugs should be stopped. Liver function should be allowed to return to normal, at which time treatment can be recommenced one drug at a time. Clinical hepatitis is rare although patients may complain of vague symptoms such as abdominal pain and malaise which may indicate impending hepatitis.

Table 40.5 Major adverse reactions of first-line anti-tuberculous drugs

Drug Common reaction Uncommon reaction
Isoniazid   Hepatitis, cutaneous hypersensitivity, peripheral neuropathy
Rifampicin   Hepatitis, cutaneous reactions, gastro-intestinal reactions, thrombocytopaenic purpura, febrile reactions, ‘flu syndrome’
Pyrazinamide Anorexia, nausea, flushing Hepatitis, vomiting, arthralgia, hyperuricaemia, cutaneous hypersensitivity
Ethambutol   Retrobulbar neuritis, arthralgia

Rifampicin is usually well tolerated, but gastro-intestinal upsets, fever and rash can occur. It interacts with many medications, including methadone, protease inhibitors and non-nucleoside reverse transcriptase inhibitors used to treat HIV infection, macrolide antibiotics, warfarin and hormonal contraceptives. It will colour the urine orange-red within approximately 4 h of a dose.

Hypersensitivity reactions or rashes may occur with any of the drugs. However, the most important, although rare, is caused by rifampicin and can be quite severe. It is more prevalent during intermittent treatment and presents as a flu-like syndrome, sometimes with abdominal pain and respiratory symptoms. This usually resolves on reverting to a daily dosage. However, if more serious effects occur, such as renal impairment or haematological abnormalities, the drug should be stopped and never restarted.

Isoniazid can cause fever, skin rashes and a dose-dependent peripheral neuropathy, probably due to depletion of vitamin B6. This reaction is rare at recommended doses, but certain patient groups which include problem drinkers (‘alcoholics’) and pregnant women are at greater risk and should receive pyridoxine supplementation at a dose of 10–25 mg/day.

Pyrazinamide can cause hepatitis. This is not increased when the drug is given with isoniazid and rifampicin in the standard 6-month treatment regimen. However, when hepatic toxicity occurs, liver enzymes are elevated for a longer time than with rifampicin or isoniazid. If patients have known pre-existing hepatic dysfunction, the use of pyrazinamide should be carefully considered.

Ethambutol ocular toxicity (optic neuritis) is by far the most important side effect of ethambutol. Some patients with pre-existing ocular problems, for example those with diabetes, may be at greater risk of toxicity. Daily doses of 30 mg/kg or more increase the likelihood of toxicity, as does the administration of standard daily doses (15–25 mg) to patients with impaired renal function.

Patients should be tested for both visual acuity and red-green colour discrimination before treatment. If toxicity develops, the drug must be stopped promptly. This should lead to a gradual improvement in vision. Permanent damage may occur if the drug is continued.

In children older than 5 years of age, a dose of ethambutol of 15 mg/kg has been shown to be safe (Trebucq, 1997). A baseline ophthalmological assessment is important in children as in adults and should be repeated after 1–2 months.

Chemoprophylaxis

The use of chemoprophylaxis is important in preventing vulnerable individuals with LTBI from developing active TB disease. Without chemoprophylaxis, 40–50% of infants and 15% of older children with LTBI will develop active TB disease in 1–2 years. Prophylaxis is usually with isoniazid alone for 6 months or rifampicin and isoniazid for 3 months. Detailed guidance as to when isoniazid or rifampicin and isoniazid should be used has been produced by National Institute for Health and Clinical Excellence (2006).

BCG vaccine

BCG vaccine contains a live, attenuated strain derived from M. bovis. It does not protect against infection, but it prevents the more serious forms of disease such as miliary TB and meningeal TB. The BCG immunisation programme in the UK is now a risk-based programme, the key part being a neonatal programme targeted at protecting those children most at risk of exposure to TB, particularly from the more serious forms of the disease (Department of Health, 2006). Most age groups require a Mantoux test prior to being offered BCG vaccine.

Patient care

It is possible to cure virtually all patients with TB infection or disease provided that an adequate regimen, to which the bacilli are susceptible, is prescribed and the patient complies with treatment. By far the largest cause of treatment failure is non-adherence by the patient. This has serious consequences: treatment may fail and disease may relapse, in some cases with resistant organisms. A patient with infectious TB who does not adhere to treatment is a public health hazard.

Factors affecting adherence

A number of studies have shown that adherence falls as the number of tablets to be taken per day increases, and falls still further if doses have to be taken frequently through the day. Ideally, the least number of tablets should be given. Patients may fail to adhere because they feel better and do not appreciate the need to continue with their medication. Lack of clarity of instructions, written, verbal or other, may compromise adherence, particularly if the patient is confused by conflicting advice from different health care professionals. Finally, adverse effects, or symptoms perceived to be adverse effects, may reduce adherence.

Improving patient adherence

Anti-TB therapy should be prescribed once a day using as few tablets as possible. Single daily dosing enables patients to fit their medication into their daily routine. Rifampicin and isoniazid are both well absorbed when taken on an empty stomach. However, absorption is reduced and delayed when taken with or after food. It is therefore recommended that both should be taken 1 h before food to rapidly achieve peak blood levels. It is usually recommended that patients take their medication before breakfast. Cueing tablet taking to a regular activity may improve adherence in some patients.

The number of tablets to be taken each day may be reduced by using combination preparations of which several are available. Some, for example Rifater®, contain ratios of rifampicin, isoniazid and pyrazinamide that differ slightly from the dosages recommended by the British Thoracic Society. Combination preparations may not be suitable for use in children as the required dose regimens differ from those of adults.

Formulation

With the exception of streptomycin, first-line agents are usually administered orally. There is a liquid preparation of rifampicin available for patients who cannot take tablets or capsules. In patients who are severely ill, and cannot take oral medication, rifampicin may be given intravenously, and isoniazid can be administered by both the intravenous and intramuscular routes.

Information for patients

Written instructions and/or patient information leaflets (PILs) may be offered to support verbal counselling if there is any doubt as to the patient’s understanding. It should be emphasised that the disease will be cured, but this will take some months and the tablets will need to be taken as prescribed even if the patient feels better. Some patients will adhere initially while they are unwell but will fail to adhere later as they begin to feel better.

The occurrence of some adverse effects may require discontinuation of a drug, but others are harmless. The patient should be told which side effects to expect and which require referral to a member of the healthcare team. Again, written instructions may be helpful.

A number of patients from abroad have a poor command of English. TB Alert has produced leaflets on the treatment of TB for patients. These can be found at the TB Alert website (http://www.tbalert.org/), and are available in languages other than English.

On occasion, drugs which are not licensed for use in the UK although licensed abroad are prescribed for TB. These may be obtained on a named-patient basis through recognised specialist wholesalers. Patients who receive these medicines require specific counselling to help them understand the special circumstances surrounding their use and receive appropriate patient information.

Directly observed therapy (DOT)

DOT, where the patient is observed taking their anti- tuberculous medication by a health care professional, is not needed for most cases of active TB. A risk assessment for treatment adherence should be undertaken in all patients, and DOT regimens considered where non-adherence to treatment might be a problem, for example in street- or shelter-dwelling homeless people with active TB and patients with a history of non-adherence. This latter group includes individuals with chronic alcohol or other social problems.

DOT regimens may be fully or partially intermittent. In the latter, four drugs (isoniazid, rifampicin, pyrazinamide and either ethambutol or streptomycin) are given daily for 2 months followed by rifampicin and isoniazid two or three times weekly for the subsequent 4 months. For most drugs, the doses are increased when given intermittently and these are shown in Table 40.3. Trials of intermittent regimens have shown treatment is as effective when given intermittently as when given daily.

Counselling points

It is now a requirement for patients to be provided with a PIL for medication they are taking. Patients should be advised to read the PIL. The TB doctor, nurse and pharmacist should provide them with other relevant information orally. Patients taking rifampicin should be told that the drug will cause a harmless discolouration of their urine and other body fluids, for example sweat and tears. The staining of tears is important if the patient uses soft contact lenses as these may be permanently stained. Gas-permeable and hard lenses are unaffected. Women using the oral contraceptive pill should be advised to use other non-hormonal methods of contraception for the duration of rifampicin treatment and for 8 weeks afterwards as the effectiveness of hormonal contraceptives is reduced by rifampicin.

Although ocular side effects are rare when ethambutol is taken in normal dosages, patients should be warned of this potentially serious side effect. They should be advised to stop the drug and report to their doctor if they notice any changes in vision, such as a reduction in visual acuity or changes in colour vision. This is especially important because visual changes are usually reversible on discontinuation of the drug but may be permanent if the drug is not stopped.

Case studies

Case 40.1

A man in his 40s is referred to a chest physician with a cough productive of sputum and a fever. A chest x-ray indicates bilateral pneumonia with apical involvement. A sputum smear reveals the presence of acid, alcohol-fast bacilli. His physician considers that TB is the most likely clinical diagnosis. This is subsequently confirmed microbiologically. The patient does not comply with treatment and needs to be admitted to hospital, but refuses. There are indications he might be disruptive if admitted into hospital.

Questions

1. What form of TB does this patient have?
2. What can be done to compel his admission to hospital?
3. Which groups of healthcare staff should be involved in arrangements for his admission to hospital?

Answers

1. This man has sputum smear-positive pulmonary TB, the infectious form of the disease, and poses a risk of infection to others.
2. Legal measures should be considered to have the patient compulsorily admitted to hospital. These are set out in the Public Health (Control of Diseases) Act 1984 for England and Wales, and the Health Protection Regulations 2010. This will involve an application to the magistrates court for compulsory admission to hospital under a legally binding order, to be signed by the magistrates. The hospital will need to have agreed to his admission.
3. He will need to be admitted to a side room. Given that he may be disruptive, a multidisciplinary team meeting should be held to agree a care plan in preparation for his admission. This should be discussed with the patient, including the reasons why he will need to be kept in isolation. This should take place prior to an application for a court order if the patient refuses admission to hospital.

Case 40.2

A woman in her 40s is admitted to hospital with shortness of breath. She has lived in sub-Saharan Africa. She subsequently develops a non-productive cough. Bronchial washings are smear negative for acid-fast bacilli, but M. tuberculosis is isolated from the sample. Early sputum samples are smear negative, but later samples are smear positive.

Questions

1. What form of TB does this patient have?
2. Should she be in isolation?
3. What treatment should she receive for her TB?
4. Is she at low or high risk for drug-resistant TB?
5. What further microbiological investigations would be essential?

Answers

1. She has pulmonary TB, indicated by her symptoms and chest x-ray.
2. She should be in isolation in a single room. If a risk assessment suggests she may have MDR-TB, advice should be sought from the Infection Prevention and Control Team as to whether she should be transferred to a negative pressure room.
3. She should be commenced on standard quadruple therapy, comprising rifampicin and isoniazid, supplemented with pyrazinamide and ethambutol for the first 2 months.
4. A history of residence in sub-Saharan Africa suggests she could be at risk of drug-resistant TB, in particular multiple drug-resistant TB. The change in sputum smear status, despite being on standard quadruple therapy, would certainly suggest drug resistance.
5. A PCR test should be done on the isolate to determine whether her infecting strains of tubercle bacilli are resistant to rifampicin. Tests should also be done to assess susceptibility to other drugs.

Case 40.3

A woman in her mid-20s is diagnosed as having sputum smear-negative pulmonary TB. Although she initially takes her anti-TB drugs, she does not attend follow-up clinics and her condition deteriorates. Her primary care doctor collects a sputum sample from her and persuades her to attend the chest clinic. The sputum smear is now positive and it is found she has continued to work, despite being advised not to do so.

Questions

1. What type of treatment regimen should be offered to this patient?
2. Who should be involved in planning this treatment regimen, and what arrangements should be put in place to ensure this works?
3. Should the patient’s work contacts be screened?

Answers

1. Patients like this should receive supervised treatment (DOTS) three times a week in a convenient setting, such as at home.
2. There needs to be close collaboration between the physician responsible for treatment, the patient’s primary care physician, TB nurse, pharmacist, the public health team and the health care professionals (often district nurses or health visitors in the UK) who will supervise treatment. The patient needs to be involved in discussions about these arrangements, as treatment will not be successful without her cooperation.
The physician will need to adjust the treatment dosage in line with the thrice-weekly regimen, inform the general practitioner and ensure the correct prescriptions are issued. Those supervising treatment need a clear explanation of what is expected of them, including details of the drugs and dose, and duration of treatment. They also need to know what to do if the patient does not adhere.
3. The question of whether work contacts should be screened must be dealt with on an individual case basis. This usually involves the health protection (public health) team informing the patient of the need to inquire into work contacts, and getting the patient’s agreement to approach a supervisor or manager in the workplace. A telephone conversation will provide initial information on the working environment and should be followed up by a visit if initial inquiries indicate a possible need to screen workplace contacts.

Case 40.4

A 40-year-old man with young children aged under 5 is diagnosed with infectious pulmonary TB, but is not taking his anti-tuberculous drugs. He has mental health problems for which he is on treatment and is a drug misuser. Arrangements are made for him to have home-based directly observed treatment (DOT) for TB, but these break down.

Questions

1. What other arrangements should be considered for his treatment?
2. What other options could be pursued if alternative arrangements cannot be put in place?
3. Might a community pharmacist have a role in assisting with the treatment of such a patient?

Answers

1. The mental health team responsible for his care could be asked if they would observe him taking treatment. However, they may be concerned about the possible risk to themselves from exposure to someone with infectious TB. The same difficulties could arise if admission to a secure mental health facility is considered. If the patient is not in contact with the drug service, their involvement is only possible if the patient agrees to engage with them.
2. If none of the options in (1) are possible in practice, the patient remains an infectious risk, especially to his children. The advice of child protection professionals should therefore be sought, and if necessary a referral made to social services. The children will not necessarily be taken into care, alternative ways of supporting child care will be sought but their safety is paramount.
3. Community pharmacists could have a role to play in supervising treatment and this should be discussed with them where appropriate. If they agree, arrangements can be put in place, including a discussion between the pharmacist and the patient as to the ‘rules of engagement’, that is what the patient can expect from the pharmacist and what the pharmacist expects from the patient.

Acknowledgement

The help from TB physicians, specialist TB nurse and pharmacy colleagues in Gwent for advice on the practical and clinical aspects of treatment and assistance with the case studies is gratefully acknowledged.

References

British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom. Thorax. 2000;55:887-901.

British Thoracic Society Joint Tuberculosis Committee. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations. Thorax. 1998;53:536-548. With permission from BMJ Publishing Group Ltd

Davies P.D.O., editor. Clinical Tuberculosis. London: Arnold, 2003.

Department of Health. Immunisation Against Infectious Disease, Chapter 32, Tuberculosis: BCG Immunisation. London: DH. 2006. Available at http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_113027

Hawker J., Begg N., Blair I., et al, editors. Communicable Disease Control Handbook. Oxford: Blackwell, 2005.

Health Protection Agency. Tuberculosis in the UK: Annual Report on Tuberculosis Surveillance in the UK 2009. London: Health Protection Agency Centre for Infections; 2009.

Heymann D.L., editor. Control of Communicable Diseases Manual. Washington, DC: American Public Health Association, 2004.

National Institute for Health and Clinical Excellence. Tuberculosis – Clinical Diagnosis and Management of Tuberculosis and Measures for Its Prevention and Control, CG 33.. London: NICE. 2006. Available at: http://guidance.nice.org.uk/CG33

Pozniak A.L., Collins S., Coyne K.M., on behalf of the BHIVA Guidelines Writing Committee. Guidelines for the Treatment of TB/HIV Co-infection. London: British HIV Association; 2009. Available at: http://bhiva.org/documents/Guidelines/Treatment%20Guidelines/Current/TreatmentGuidelines2009.pdf

Thwaites G., Fisher M., Hemingway C., et al. The British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J. Infect.. 2009;59:167-187.

Trebucq A. Should ethambutol be recommended for routine treatment of tuberculosis in children? A review of the literature. Int. J. Tuberc. Lung Dis.. 1997;1:12-15.

WHO. Multidrug and Extensively Drug-Resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response. Geneva: WHO; 2009. Available at: http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf

World Health Organization. Global Tuberculosis Control. A Short Update to the 2009 Report. Geneva: WHO; 2009. Available at: http://whqlibdoc.who.int/publications/ 2009/9789241598866_eng.pdf

Further reading

American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of Tuberculosis. MMWR; 2003. l52: RR-11

Campbell I.A., Bah-Sow O. Pulmonary tuberculosis: diagnosis and treatment. Br. Med. J.. 2006;332:1194-1197.

Health Protection Scotland. Tuberculosis: Clinical Diagnosis and Management of Tuberculosis and Measures for Its Prevention and Control in Scotland. Glasgow: Health Protection Scotland; 2009.

Schlossberg D., editor. Tuberculosis and Nontuberculous Mycobacterial Infections. New York: McGraw-Hill, 2006.

World Health Organization. Treatment of Tuberculosis Guidelines. Geneva: WHO; 2010. Available at: http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf

Useful websites

Immunisation against infectious disease ‘The Green Book’ http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_079917

The truth about TB http://www.thetruthabouttb.org/

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