Tuberculosis
TB is caused by infection with Mycobacterium tuberculosis (MTB),
which is part of a complex of organisms that also includes M. bovis
(reservoir cattle) and M. africanum (reservoir human).
Recent figures suggest a decline in the incidence of TB but, despite
this, an estimated 8.8 million incident cases occurred in 2010 and TB
accounted for nearly 1.5 million deaths. One-third of the world’s
population has latent TB. The majority of cases occur in the poorest
nations, who struggle to cover the costs of management and control
programmes. In Africa, the resurgence of TB has been driven largely
by HIV disease. Drug resistance is an increasing problem, especially
in Africa, the former Soviet states and the Baltic, caused by incomplete
treatment of cases.
The formation of a mass of granulomas surrounding an area of
caseation leads to the appearance of the primary lesion in the lung,
referred to as the ‘Ghon focus’. The combination of a primary lesion
and regional lymph node involvement is termed the ‘Ghon complex’.
If the bacilli spread (either by lymph or blood) before immunity
is established, secondary foci may be established in other organs,
including lymph nodes, serous membranes, meninges, bones, liver,
kidneys and lungs. These foci resolve once an immune response
is mounted and the organisms gradually lose viability. However,
‘latent bacilli’ may persist for many years. The estimated lifetime
risk of developing disease after primary infection is 10%, with
roughly half of cases occurring in the first 2 yrs after infection.
Clinical features
Primary pulmonary TB: This refers to infection of a previously
uninfected (tuberculin-negative) individual. In most cases, infection
of a healthy individual is subclinical and indicated only by the
appearance of a cell-mediated, delayed-type hypersensitivity reaction
to tuberculin (demonstrated by tuberculin skin testing). If the
organism cannot be contained, primary progressive disease ensues.
Post-primary pulmonary TB: This is the most frequent form of
post-primary disease. Onset occurs insidiously over several weeks.
Systemic symptoms include fever, night sweats, malaise, and loss of
appetite and weight, and are accompanied by cough, often with
haemoptysis. CXR typically shows an ill-defined opacity situated in
one of the upper lobes. As disease progresses, consolidation, collapse
and cavitation may develop. A miliary pattern or cavitation
suggests active disease.
Miliary TB: Blood-borne dissemination gives rise to miliary TB,
which may present acutely but is often characterised by 2–3 wks of
fever, night sweats, anorexia, weight loss and dry cough.
Hepatosplenomegaly may be present and headache may indicate
coexistent tuberculous meningitis. Auscultation is frequently
normal, although with more advanced disease widespread crackles
occur. Fundoscopy may show choroidal tubercles. CXR demonstrates
fine 1–2-mm lesions (‘millet seed’) distributed throughout the
lungs. Anaemia and leucopenia may be present.
Extrapulmonary disease (Fig. 9.6): This accounts for ~20% of cases
in HIV-negative individuals and is more common in HIV-positive
individuals. Cervical or mediastinal lymphadenitis is the most
common extrapulmonary presentation. Meningeal disease represents
the most important form of CNS TB, as it is rapidly fatal if
unrecognised and untreated.
Investigations
Mycobacterial infection is usually confirmed by direct microscopy
(Ziehl–Neelsen or auramine staining) and culture of sputum or other
samples from the respiratory tract or other infected site. An estimated
5000–10 000 acid-fast bacilli must be present for sputum to be
smear-positive, whereas only 10–100 viable organisms are required
for sputum to be culture-positive. Standard culture takes up to
8 wks. Liquid culture media (e.g. BACTEC) can expedite growth and
drug sensitivity testing (7–21 days). Where multiple drug-resistant
TB (MDRTB) is suspected, molecular tools may be employed to test
for the presence of the rpo (rifampicin resistance) gene.
Chemotherapy
Standard therapy involves 6 mths’ treatment with isoniazid and
rifampicin, supplemented in the first 2 mths with pyrazinamide and
ethambutol. Fixed-dose tablets combining two or three drugs are
preferred. Treatment should be commenced immediately in any
patient who is smear-positive or smear-negative but with typical
CXR changes and no response to standard antibiotics. Six mths of
therapy is appropriate for pulmonary TB and most extrapulmonary
TB; however, 12 mths of therapy is recommended for meningeal TB,
including spinal TB with spinal cord involvement – in these cases,
ethambutol may be replaced by streptomycin. Pyridoxine should be
prescribed in pregnant women and malnourished patients to reduce
the risk of peripheral neuropathy with isoniazid. Where drug resistance
is not anticipated, patients can be assumed to be non-infectious
after 2 wks of appropriate therapy.
Regular monitoring of LFTs is important, as several antituberculous
drugs are potentially hepatotoxic. Corticosteroids reduce
inflammation and limit tissue damage, and are currently recommended
when treating pericardial or meningeal disease, and in children
with endobronchial disease. They may also be of benefit in
pleural effusion, ureteric TB and severe pulmonary TB.
Control and prevention
Detection of latent TB: Contact tracing entails identifying an
index case, other persons infected by the index patient, and close
contacts who should receive BCG vaccination or chemotherapy.
Approximately 10–20% of close contacts of smear-positive patients
and 2–5% of those with smear-negative, culture-positive disease
have evidence of TB infection.
An otherwise asymptomatic contact with a positive tuberculin
skin test but a normal CXR may be treated with chemoprophylaxis
(e.g. rifampicin and isoniazid for 3 mths) to prevent progression to
clinical disease. Chemoprophylaxis is also recommended for:
● Contacts aged under 16 with a strongly positive tuberculin test.
●Children under 2 in close contact with smear-positive disease.
● Those with recent confirmed tuberculin conversion. ● Babies of
mothers with pulmonary TB. ● HIV-infected close contacts of a
patient with smear-positive disease.
Tuberculin skin testing may be falsely positive in BCG-vaccinated
patients and those exposed to non-tuberculous mycobacteria. Falsenegative
skin tests occur with immunosuppression or overwhelming
infection. These limitations may be overcome by employing
interferon-gamma release assays (IGRAs) that are specific to MTB.
Directly observed therapy (DOT): Poor adherence to therapy
causes prolonged illness, risk of relapse, and drug resistance. DOT
involves the supervised administration of therapy 3 times weekly.
In the UK, it is recommended for at-risk groups, including homeless
people, alcohol or drug users, patients with serious mental illness
and those with a history of non-adherence.
TB and HIV/AIDS
The close links between HIV and TB, particularly in sub-Saharan
Africa, are a major challenge. Programmes that link detection and
treatment of TB with detection and treatment of HIV are important,
and all patients with TB should be tested for HIV. Mortality is high
and TB is a leading cause of death in HIV patients.
Multidrug-resistant TB
There has been a marked increase in drug-resistant strains, particularly
in the poorest countries, which is closely linked to inadequate
treatment. Cure is possible but prolonged treatment with less effective,
more toxic and more expensive therapies is often necessary.
BCG (the Calmette–Guérin bacillus): This is a live attenuated
vaccine used to stimulate protective immunity. It prevents disseminated
disease in children but efficacy in adults is inconsistent.
Vaccination policies vary worldwide; in the UK, vaccination is recommended
for infants in high-prevalence communities, health-care
workers and selected contacts.
Prognosis:
Cure should be anticipated in the majority of patients. There is a
small (< 5%) risk of relapse and most recurrences occur within
5 mths. Without treatment, a patient with smear-positive TB will
remain infectious for ~2 yrs; in 1 yr, 25% of untreated cases will die.
Opportunistic mycobacterial infection
Other species of environmental mycobacteria (often termed ‘atypical’)
may cause human disease. These mycobacteria are low-grade
pathogens (with the exception of M. malmoense and M. ulcerans),
tending to cause disease in the setting of immunocompromised or
scarred lungs. M. kansasii, M. avium complex (MAC), M. malmoense
and M. xenopi are the species that most often cause lung disease.
These organisms are not communicable but prolonged treatment is
needed.
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