Tuberculosis is on the increase particularly where immunosuppressive drugs have altered the host defence mechanisms, or in AIDS. In developing countries, it still remains a problem partly because of inadequately supervised treatment.
For the last 20 years tuberculosis was thought to be under control, but it is now the world’s leading cause of death from a single infectious disease due to:
• Inadequate programmes for disease control
• Multiple drug resistance
• Co-infection with HIV
• Rapid rise in the world’s population of young adultsthe age group with the highest mortality from tuberculosis
Although the risk of contracting tuberculosis is between 20 and 50 times greater in the developing countries compared to the Western World even there the disease is on the increase. In the last 5 years there has been a 12% increase in the USA, a 33% increase in Switzerland and a 25% increase in Italy.
In the UK, there has been no decline in the number of cases with 7000 new cases per year. In the UK the incidence of tuberculosis in immigrants from the Asian subcontinent and West Indies is 40 and four times as common, respectively, as in the native White population. This has led to great variation in the frequency of the disease in different areas of the UK. It is a notifiable disease.
The first infection with M. tuberculosis is known as primary tuberculosis. It is usually subpleural, often in the mid to upper zones. Within an hour of reaching the lung, tubercle bacilli reach the draining lymph nodes at the hilum of the lung and a few escape into the bloodstream. The initial reaction comprises exudation and infiltration with neutrophil granulocytes. These are rapidly replaced by macro phages that ingest the bacilli. These interact with T lymphocytes with the development of cellular immunity that can be demonstrated 3-8 weeks after the initial infection by the development of a positive reaction in the skin to an intradermal injection of protein from tubercle bacilli (tuberculin).
At this stage the classical pathology of tuberculosis can be seen. Granulomatous lesions consist of a central area of necrotic material of a cheesy nature, called caseation, surrounded by epithelioid cells and Langhans’ giant cells with multiple nuclei, both cells being derived from the macrophage. Lymphocytes are present and there is a varying degree of fibrosis. Subsequently the caseated areas heal completely and many become calcified. It is now known that at least 20% of these calcified primary lesions contain tubercle bacilli, initially lying dormant but capable of being activated by depression of the host defence system. Reactivation leads to typical post-primary pulmonary tuberculosis with cavitation, usually in the apex or upper zone of the lung. ‘Post-primary tuberculosis’ refers to all forms of tuberculosis that occur after the first few weeks of the primary infection when immunity to the mycobacterium has developed.
CLINICAL FEATURES AND INVESTIGATION
Primary tuberculosis is symptomless in the great majority of individuals. Occasionally there may be a vague illness, sometimes associated with cough and wheeze. A small transient pleural effusion or erythema no do sum may occasionally occur, both representing allergic manifestations of the infective process. Enlargement of lymph nodes compressing the bronchi can give rise to collapse of segments or lobes of the lung. Apart from cough and a monophonic wheeze, the individual remains remarkably well and the collapse disappears as the primary complex heals. Occasionally, persistent collapse can give rise to subsequent bronchiectasis, often in the middle lobe (Brock’s syndrome).
The manifestations of primary and post-primary tuberculosis, together with the times when they usually occur. Extrapulmonary manifestations are summarized. Miliary tuberculosis can occur within 3 years of the primary infection, or can occur much later as a manifestation of reactivation or, rarely, reinfection with tubercle bacillus. Reactivation in the lung, or indeed in any extrapulmonary location, can occur as immunity wanes, usually with age and chronic ill-health and all manifestations.
This disease is the result of acute diffuse dissemination of tubercle bacilli via the bloodstream. It can be a difficult diagnosis to make, especially in older people, where it is particularly covert. This form of disseminated tuberculosis is universally fatal without treatment. It may present in an entirely non-specific manner with the gradual onset of vague ill-health, loss of weight and then fever. Occasionally the disease presents as tuberculosis meningitis. Usually there are no abnormal physical signs in the early stages, although eventually the spleen and liver become enlarged. Choroidal tubercles are seen in the eyes. These lesions are about one-quarter of the diameter of the optic disc and are yellowish and slightly shiny and raised in nature, later becoming white in the centre. There may be one or many in each eye. The chest X-ray may be entirely normal in miliary tuberculosis as the tubercles are not visible until the miliary shadows are 1 or 2 mm in diameter; they have a hard outline. The lesions can increase in size up to 5-10 mm. Sarcoidosis and staphylococcal or Mycoplasma pneumonia can mimic the chest X-ray appearance of miliary tuberculosis.
The Mantoux test is positive but is occasionally negative in people with very severe disease. Transbronchial biopsies are frequently positive before any abnormality is visible on the chest X-ray. CT scanning may reveal lung parenchymal abnormalities at an earlier stage. Biopsy and culture of liver and bone marrow may be necessary in patients presenting with a pyrexia of unknown origin (PUQ). In the past, a trial of antituberculous therapy was often used in individuals with a PUQ. The fever should settle within 2 weeks of starting chemotherapy if it is due to tuberculosis. This approach is still occasionally used in susceptible individuals when a diagnosis cannot be confirmed.
Typically there is gradual onset of symptoms over weeks or months. Tiredness, malaise, anorexia and loss of weight together with a fever and cough remain the outstanding features of pulmonary tuberculosis. Drenching night sweats are now rather uncommon and are more usually due to anxiety. Sputum in tuberculosis may be mucoid, purulent or blood-stained. Many patients suffer a dull ache in the chest and it is not uncommon for patients to complain of recurrent colds. A pleural effusion or pneumonia can be the presenting feature of tuberculosis. Physical examination is of little value. Finger clubbing is only present if the disease is advanced and associated with considerable production of purulent sputum. There are often no physical signs in the chest even in the presence of extensive radiological changes, though occasionally persistent crackles may be heard. Physical signs of an associated effusion, pneumonia or fibrosis may be present.
An abnormal chest X-ray is often found with no symptoms, but the reverse is extremely rare-pulmonary tuberculosis is unlikely in the absence of any radiographic abnormality. The chest X-ray (Fig. 12.36) typically shows patchy or nodular shadows in the upper zones, loss of volume, and fibrosis with or without cavitation. Calcification may be present. The X-ray appearances alone may strongly suggest tuberculosis, but every effort must be made to obtain microbiological evidence. A single X-ray does not give an indication of the activity of the disease. Very similar chest X-ray appearances occur in histoplasmosis and other fungal infections of the lung,
including cryptococcosis, coccidioidomycosis and aspergillosis. Lymph node tuberculosis manifestation The patient presents with a tender lump, usually supraclavicular or in the anterior triangle of the neck. This form of tuberculosis.
Tuberculosis in patients with AIDS
Intrathoracic lymphadenopathy and diffuse or miliary infiltrates is common in patients with AIDS, and cavitation less common than in patients without AIDS. Disseminated tuberculosis is particularly frequent, occurring in over one-third of cases.
STAINING. The sputum is stained with Ziehl-Nielsen (ZN) stain for acid and alcohol-fast bacilli (AAFB). CULTURE. The sputum is cultured on Dover’s or Lowenstein- Jensen medium for 4-8 weeks. Cultures to determine the sensitivity of the bacillus to antibiotics talce a further 3-4 weeks.
FIBREOPTIC BRONCHOSCOPY with washings from the affected lobes is useful if no sputum is available. This has replaced techniques such as gastric washings. BIOPSIES of the pleura, lymph nodes and solid lesions within the lung (tuberculomas) may be required to malce the diagnosis.
The slow growth of M. tuberculosis in culture has hindered the ability to malce a rapid definitive diagnosis. Newer techniques are being developed which should play an increasing role in rapid diagnosis. Radiolabelled DNA probes specific for various mycobacterial species can identify organisms in culture. The sensitivity of these methods has been enhanced by amplifying target DNA using the polymerase chain reaction. This allows direct testing of sputum and other fluids providing a laboratory diagnosis within 48 hours; it is still being evaluated.
Vaccination with BeG (Bacille Calmette-Guerin) has been given to schoolchildren in the UK since 1954. BeG is a bovine strain of M. tuberculosis that lost its virulence after growth in the laboratory for many years. Early trials showed that it decreases the risk of developing tuberculosis by about 70%. With the continuing decrease in the incidence of tuberculosis it is becoming less cost-effective to administer this vaccine, and the procedure is being stopped in certain areas of the UK. However, in other areas with a high immigrant population, the vaccine is being administered 6 weeks after birth rather than at the traditional age of 13 years. This is to prevent the disease from developing in young children, where it can progress extremely rapidly and in whom any delay in diagnosis can be fatal. BeG is only given to individuals who are tuberculin-negative; those with positive tests are further screened by a chest X-ray. BeG should be given at a dose of 0.1 ml intradermally to children and adults, but at a dose of 0.05 ml to infants. The practice of BCG vaccination in the UK, thereby producing cellular immunity and a positive tuberculin test, is an important reason why the Mantoux test is of little value in clinical practice for subsequent diagnosis of active disease.
Tuberculosis is spread from person to person and effective tracing of close contacts has helped to limit spread of the disease as well as to identify diseased individuals at an early stage. Screening procedures involve screening all close family members or other individuals who share the same kitchen and bathroom facilities. Occasionally, close contacts at work or school may also be screened. Contacts who are ill should be thoroughly investigated for tuberculosis. If they are well, a chest X-ray is talcen and a tuberculin test is performed. In adults, even if the tuberculin test is positive, provided the chest X-ray is negative nothing more need be done. In patients with HIV infection, who have not had BCG, chemoprophylaxis with isoniazid is often given. In children, a positive tuberculin test is usually taken as evidence of infection, and treatment is instituted. If the tuberculin test is negative in children and young adults «35 years) it is repeated at 6 weeks, and if it remains negative then BeG is administered. If it has become positive (without BeG), this is again taken as an indication of active disease and the individual is treated. Children under the age of 1 year who have a family member with tuberculosis are given chemoprophylaxis with a daily dose of isoniazid 5-10 mg kg:” for 6 months together with immunization with a strain of BeG that is resistant to isoniazid.
In general, much greater emphasis is placed on contact tracing and investigation of those under the age of 35 years and in some immigrant groups (Irish and Asian) in whom the disease is more virulent and prevalent.
Bed rest does not affect the outcome of the disease. Some patients will require hospitalization for a brief period; these include ill patients, those in whom the diagnosis is uncertain and, most importantly, those individuals from whom it is essential to gain cooperation. The most important factor in the successful treatment of tuberculosis lies in the continual self-administration of drugs for 6 months; lack of patient compliance is a major reason why 5% of patients do not respond to treatment. In vitro resistance to one or more of the antituberculous drugs occurs in less than 1% of patients in the UK. Long stay in hospital is now only required for persistently uncooperative patients, many of whom are homeless and abuse alcohol.
This is now standard practice for patients with pulmonary and lymph node disease: daily administration of rifampicin 600 mg and isoniazid 300 mg. (For those whose body weight is below 55 kg, rifampicin is reduced to 450 mg daily.) These are given as combination tablets and are taken 30 min before breakfast, since the absorption of rifampicin is influenced by food. This is supplemented for the first 2 months by pyrazinamide at a dose of 1.5 g (body weight <55 kg) or 2.0 g daily. Studies have indicated that pyrazinamide is of particular value in treating mycobacteria present within macrophages and for this reason it may have a very valuable effect on preventing subsequent relapse.
Treatment of bone tuberculosis should be continued for a total of 9 months and of tuberculous meningitis for 12 months. The drugs used are the same as for pulmonary tuberculosis with pyrazinamide prescribed for the first 2 months only.
The development of resistance after initial drug sensitivity (secondary drug resistance) occurs in patients who do not comply with the treatment regimens. Primary drug resistance is seen in immigrants and those exposed to others infected with resistant organisms. Multidrug resistance occurring particularly in patients with HIV infection is a major therapeutic problem with a high mortality. Nosocomial transmission of multidrug-resistant tuberculosis to health care workers and to other patients is recognized and poses a major public health problem. The drug treatment of suspected drug resistance in HIV -positive and HIV-negative patients is:
• With multiple drug resistance use at least three drugs to which the organism is sensitive.
• With resistance to one of the four main drugs, use the other three.
Therapy should be continued for up to 2 years and in HIV-positive patients for at least 12 months after negative cultures.
Unwanted effects of drug treatment
RIFAMPICIN. This drug induces liver enzymes, which may be transiently elevated in many patients. The drug should only be stopped if the serum bilirubin becomes elevated, which is extremely rare. Thrombocytopenia has been reported. Rifampicin stains body secretions pink and the patients should be warned of the change in colour of their urine, tears and sweat. Induction of liver enzymes means that concomitant drug treatment may be made less effective (see Chapter 14) and oral contraception should not be used.
ISONIAZID. This gives rise to very few unwanted effects. At high doses it may produce a peripheral neuropathy but this is extremely rare when the normal dose of 200- 300 mg is given daily. Nevertheless, it is customary to prescribe pyridoxine 10 mg daily to prevent this effect Occasionally, isoniazid gives rise to allergic reactions in the form of a skin rash and fever, with hepatitis occuring in less than 1% of cases. The latter, however, may be fatal if the drug is continued.
PYRAZINAMIDE. The main unwanted effect of this drug is severe hepatic toxicity, though recent experience suggests that this is much rarer than initially thought using present dosage schedules. Gout due to hyperuricaemia may occur.
ETHAMBUTOL. This drug can cause a dose-related retrobulbar neuritis that presents with colour blindness for green, reduction in visual acuity and a central scotoma. It usually reverses provided that the drug is stopped when symptoms develop; patients should therefore be warned of its effects. Because of this problem ethambutol is rarely used unless resistance of M. tuberculosis is present to one or more of the other drugs. All patients should be seen by an ophthalmologist prior to treatment.
STREPTOMYCIN. The main unwanted effect of streptomycin is irreversible damage to the vestibular nerve. It is more likely to occur in the elderly and in those with renal impairment. Allergic reactions to streptomycin are more common than to rifampicin, isoniazid and pyrazinamide. This drug is only used if patients are very ill and not responding adequately to therapy.
Patients should be seen regularly for the duration of chemotherapy and once more after 3 months, since relapse, though very unlikely, usually occurs within this period of time.
Patients who have any chest X-ray changes compatible with previous tuberculosis and who are about to undergo long-term treatment that has an immunosuppressive effect, such as renal dialysis or treatment with corticosteroids, should receive chemoprophylaxis with isoniazid 200-300 mg daily.