Beruflich Dokumente
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Bacterial Infections
Chapter 56
Tuberculosis
AETIOLOGY OF TUBERCULOSIS
The causative organism of tuberculosis, the tubercle bacillus, was
isolated and described by Robert Koch in 1882 (Figure 56.1). It
was subsequently included in the genus Mycobacterium and named
Mycobacterium tuberculosis. A closely related species isolated from
cattle but also able to cause human tuberculosis is termed M. bovis
and strains with rather variable properties principally encountered
in Equatorial Africa are collectively termed M. africanum. These
species are included in the Mycobacterium tuberculosis complex, the
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56.
Tuberculosis
Clinical type of
tuberculosis
Consumption
Pulmonary
Pthisis
Pulmonary
Tabes pulmonalis
Pulmonary
Tissic
Pulmonary
Hectic fever
Pulmonary
Asthenia
Pulmonary
Galloping consumption
Pulmonary
Scrofula
Cervical lymphadenitis
Struma
Cervical lymphadenitis
Kings evil
Cervical lymphadenitis
Tuberculous meningitis
Potts disease
Spinal/vertebral tuberculosis
Tuberculous chancre
Skin
Scrofuloderma
Skin
Lupus vulgaris
Skin
Figure 56.1
Professor Robert
Koch, discoverer of
Mycobacterium
tuberculosis.
B
Figure 56.2 (A) ZiehlNeelsen staining of a sputum sample and
(B) a bronchoalveolar lavage washing showing acid-fast bacilli.
PATHOGENESIS
Infection of humans with M. tuberculosis occurs by inhalation,
ingestion or traumatic inoculation. Intrauterine infection resulting
in congenital tuberculosis is extremely rare.
In most cases infection is by inhalation of small droplets of
cough spray containing a few bacilli. These particles, around 5 m
in diameter, lodge in the alveolae or small airways, mostly in the
lower regions of the lung. The usual sources of such infectious
particles are other human beings with open pulmonary tuberculosis but those working with cattle may be infected by M. bovis in
the cough spray of diseased animals. A less frequent mode of
infection is consumption of milk or food contaminated by M.
bovis, in which case the bacilli often lodge in the tonsil or intestinal wall. Rarely, tubercle bacilli enter the skin through cuts and
abrasions (Figure 56.3) and primary skin tuberculosis was an
occupational hazard of butchers, anatomists and pathologists.
Traditionally, tuberculosis has been divided into two forms,
primary and post-primary. In the past it was usually assumed that
post-primary tuberculosis was always the result of endogenous
reactivation of latent or dormant primary lesions but DNA fingerprinting has shown that many cases, particularly among immunosuppressed persons, are due to exogenous reinfection.5
The natural history of infection with M. tuberculosis and its
sequelae are shown diagrammatically in Figure 56.4. Most people
infected by tubercle bacilli do not develop symptoms and the
primary infection may go unnoticed. In most cases, effective
immune responses lead to containment of the disease process and
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Pathogenesis
Primary infection
(lung, tonsil, gut or skin)
Lung
Ghons focus
Lymphangitis
Lymphadenitis
= primary complex
Resolution
(heals)
Bloodstream
spread
Extensive pulmonary
tuberculosis
Miliary tuberculosis
Organ tuberculosis
Local
spread
Reactivation of
disease due to:
HIV, old age, diabetes,
cytotoxics, steroids,
stress, malnutrition,
malignancies, chronic
liver and renal disease
etc.
Obstruction
of bronchus
Ruptures
into bronchus
Lobar
collapse
TB
bronchopneumonia
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56.
Tuberculosis
Duration
Features
38 weeks
About 3 months
34 months
Up to 3 years
Up to 12 years
B
Figure 56.5 (A) Postmortem lung specimen showing the primary
complex: caseating primary lesion (Ghons focus) with regional
lymphadenitis. (B) Chest X-ray of an infant with primary tuberculosis
showing right hilar node involvement.
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Pathogenesis
Figure 56.6 (AC) The complications and sequelae of primary pulmonary tuberculous lesions.
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56.
Tuberculosis
PATHOLOGY OF TUBERCULOSIS
A wide spectrum of pathological manifestations is seen in tuberculosis. The initial host response to infection consists of an
acute inflammatory reaction with an influx of polymorphonuclear
neutrophil leucocytes. If this acute inflammatory response is
unable to limit the infectious process, a progressive infiltration
with macrophages occurs. The macrophages have a pale eosinophilic cytoplasm and elongated nuclei and as they resemble epithelial cells they are called epithelioid cells. Some macrophages
fuse to form multinucleated Langhans giant cells. A zone of
lymphocytes and fibroblasts surrounds this compact cellular structure which is termed the tubercle as it resembles a small potato
tuber (Figure 56.10A). The tubercle is an example of a granuloma,
a characteristic feature of chronic infections. Within 2 weeks,
caseous necrosis is seen in the centres of the granulomas but this
is also seen in other chronic infections, including deep-seated
fungal infections (e.g. Histoplasma capsulatum) and thus a specific
diagnosis, based on the determination of the aetiological agent,
is important.
Granuloma formation is a central event in the immune response
against M. tuberculosis, but while the granuloma restricts the
spread of the infection, it is a space-occupying lesion that can
damage surrounding normal tissues. Granulomas are dynamic
structures characterized by the accumulation of activated macrophages and an infiltration of T lymphocytes. The extent and morphological features of the granuloma vary considerably from
person to person so that a wide spectrum of granulomatous reactions is seen in tuberculosis. At one end of this spectrum, characterized by compromised immune responses, there is poor
granuloma formation and extensive areas of tissue necrosis containing large numbers of mycobacteria. At the other end, in which
immune responses are relatively intact, indolent non-caseating
granulomas containing few organisms are seen. The latter are
typically seen in chronic skin tuberculosis (lupus vulgaris) and
histologically the lesions resemble those seen in tuberculoid
leprosy and sarcoidosis. Most tuberculosis patients fall between
these two extremes.
The tuberculous process may involve serous cavities, usually
the pleural cavities but sometimes the pericardial cavity. Such
involvement appears to be primarily due to a hypersensitivity
reaction to antigens of the tubercle bacillus and is characterized
by an inflammatory, fibrin-rich exudate containing lymphocytes
and polymorphonuclear leucocytes. Epithelioid and Langhans
giant cells are scanty.
In the majority of cases, effective immune responses limit the
progression of the primary complex which heals by fibrosis and
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A
A
B
Figure 56.10 (A) Classical caseating granuloma due to M.
tuberculosis. Note the central area of caseous necrosis surrounded
by a rim of epithelioid cells, Langhans giant cells and lymphocytic
infiltrate. (B) Lung histopathology illustrating an anergic response to
infection with M. tuberculosis in a lung of a patient with AIDS.
There is widespread granular necrosis and a non-reactive
anergic cellular response with a few lymphocytes and epithelioid
cells and no Langhans giant cells.
B
Figure 56.9 (A) Extensive pulmonary tuberculosis with cavitation.
(B) Postmortem lung showing several cavities and extensive lung
involvement due to tuberculosis.
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56.
Tuberculosis
Geographical origin
Immune suppression
HIV infection
Protein-calorie malnutrition
Steroid therapy
Cytotoxic drugs
Congenital immunodeficiencies
Vitamin D deficiency
Medical conditions
Liver failure
Cancer
Diabetes mellitus
Smoking-related lung damage
Industrial dust disease of the lungs, e.g.
silicosis, asbestosis
Renal failure
Measles
Schistosomiasis
Gastrectomy
Genetic factors
Stress
Environmental factors
Mycobacterial factors
Adapted from Zumla A, Mwaba P, Rook G, et al. Tuberculosis. In: James DG,
Zumla A, eds. The Granulomatous Disorders. Cambridge: Cambridge University
Press; 1999:132160.
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Epidemiology of Tuberculosis
Environmental factors
From the time of birth, humans are exposed to a huge range of
microorganisms in the environment, including many species of
saprophytic mycobacteria and members of related genera. Contact
with these is able to modify the pattern of immune responsiveness
to pathogenic mycobacteria and to BCG vaccine. Indeed, such
environmental contact provides the most likely explanation for
the considerable geographical variation in the protective efficacy
3 of BCG vaccination (p. ). Recent observations suggest that envi-
Role of macrophages
As mentioned above, cytokine-activated macrophages play a key
role in the destruction of mycobacteria, although the precise
mechanisms involved are not clear. Likely mechanisms involve
the generation of toxic oxygen- and nitrogen-derived products
including superoxide anions, hydrogen peroxide, and nitric oxide
(NO) and peroxynitrites produced by the interaction of NO and
oxygen/reduction products.
It is also likely that the entire granuloma has greater antimycobacterial properties than the isolated activated macrophage, as the
centres of the granulomas are acidic, anoxic and contain high
levels of free fatty acids, all of which inhibit mycobacterial growth.
Once a cavity has formed and the anoxic and acidic contents have
been replaced by air enriched with carbon dioxide, bacterial
growth increases enormously.
Mycobacterial factors
Mycobacteria have evolved several strategies for avoiding the
various host defence mechanisms and a large number of determinants of virulence have been described in M. tuberculosis.12 Some
of these are involved in early events after infection and others are
of more importance at later stages. It is probable that the relative
importance of determinants of virulence varies according to the
lineage or family of the bacillus as they appear, at least in the
mouse, to elicit different patterns of immune responsiveness. Of
prime importance is the ability of mycobacteria to avoid being
killed by phagocytes (Figure 56.11). Within the macrophage, survival of mycobacteria depends principally on their ability to
inhibit phagosome maturation and to block phagosomelysosome fusion.13
Advances in genomic analysis have revealed the molecular
basis of differences between the attenuated BCG vaccine strains
and virulent tubercle bacilli. Several regions of the genome are
missing from BCG and one of these contains three genes associated with virulence, two of which code an immunodominant
antigen ESAT-6 (Early Secretory Antigenic Target, 6 kDa), which
is involved in tissue invasion.14
EPIDEMIOLOGY OF TUBERCULOSIS
As discussed above, not all those who are infected develop overt
tuberculosis, and the interval between infection and disease may
be years or decades. On the basis of skin-testing surveys, the WHO
has estimated that one-third of the worlds human population,
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56.
Tuberculosis
Complement
receptor
Macrophage
2. Resistance to
killing
(a) Tough cell wall
(b) Superoxide dismutase
(c) Free radical scavengers
H+
3. Alterations to vesicles
(a) Failed maturation
(b) Blocked proton pump
(c) Altered fusion pattern
4. Block
apoptosis
6. Increased
T cell
apoptosis
(a) IL-10
(b) IL-6
(c) Fas
between 10 and 15 people every year but the actual number varies
greatly and is affected by many factors including crowding and
ventilation.
Table 56.4 shows the estimated rates of tuberculosis incidence
by WHO region in the year 2004 (Figure 56.12).15 In that year, an
estimated 8.9 million new cases (140 per 100 000 population) of
tuberculosis arose from the infected pool, 95% of them in the
developing nations Around 1.9 million cases occurred in the West
Pacific Region, 2.6 million in Africa and almost 3 million, a third
of all cases, in South-east Asia. Half of all cases of tuberculosis
occur in six Asian countries: Bangladesh, China, India, Indonesia,
Pakistan and the Philippines. Owing to the chronic nature of the
disease and the limited resources for effective diagnosis and treatment in many countries, the prevalence of active disease is much
higher than the incidence of new cases. In 2004, there were an
estimated 14.6 million people with active tuberculosis, of whom
6.1 million had infectious forms of the disease and infected some
100 million people, over 1% of the worlds population. In the
same year, an estimated 1.7 million people, principally young
adults, died of tuberculosis, with 98% of deaths occurring in
the developing nations. This amounts to around 5000 deaths
every day.
LAM
MOLECULAR EPIDEMIOLOGY
OF TUBERCULOSIS
5. Control cell signalling
(a) Activate phosphotyrosine
phosphatase (SHP-1)
(b) Block signalling via IFN receptors
(c) Block class II expression and
antigen presentation
IFN
Receptor
Peptide + Class II
Figure 56.11 Mechanisms of survival of M. tuberculosis in
macrophages. M. tuberculosis avoids the killing mechanisms in
macrophages and blocks apoptosis of macrophages, presumably
because apoptosis also can lead to death of the contained bacteria.
Bad is a pro-apoptotic protein, inactivated when phosphorylated. LAM
has multiple roles, including activation of SHP-1, a phosphotyrosine
phosphatase intimately involved in cell signalling pathways.
Downregulation of Fas, together with increased expression of Fas
ligand, may lead the macrophage to signal apoptosis to Fas-positive
T cells. Short thick lines indicate blocked pathways. IFN, interferon;
IL, interleukin; LAM, lipoarabinomannan; TGF, transforming growth
factor; TNFr2, tumour necrosis factor receptor 2.
10
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Table 56.4 The estimated incidence, prevalence and mortality of tuberculosis, 2004
INCIDENCE
ALL FORMS
SMEAR-POSITIVE
PREVALENCE
MORTALITY
Number
thousands
Number
thousands
WHO region
Number
thousands
(% of global
total)
Number
thousands
Africa
2573 (29)
356
1098
152
3741
518
587
The Americas
363 (4)
41
161
18
466
53
52
Eastern
Mediterranean
645 (7)
122
289
55
1090
206
142
Europe
81
5.9
27
445 (5)
50
199
23
575
65
69
2967 (33)
182
1327
81
4965
304
535
33
Western Pacific
1925 (22)
111
865
50
3765
216
307
18
Total
8918 (100)
140
3939
62
14 602
229
1692
27
South-east Asia
7.8
11
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56.
Tuberculosis
No estimate
024
2449
5099
100299
300 or more
B
Figure 56.12 (A) Estimated TB incidence rates, 2006 (all forms). (B) Estimated HIV prevalence rates in new TB cases, 2006.
12
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antituberculosis agents18 (Table 56.5). There are two types of resistance, initial or primary and secondary or acquired, with quite
different epidemiological significance. Initial resistance is due to
infection by a strain that is already resistant while acquired resistance is the result of selective replication of bacterial mutants
(which occur spontaneously in all bacterial populations) in
patients treated with inadequate or inappropriate drug regimens
or poorly formulated combination drugs and in those in whom
therapy is poorly managed. The contributing factors to acquired
resistance include:
Poor compliance in taking therapy
Irregular supplies of drugs
Addition of single drugs to failing regimens in the absence of
bacteriological control
Unacceptably high cost to the patient
Difficult journeys to the clinic and time off work leading to
irregular intake
Use of time-expired, impure, mishandled or even fake drugs
Use of poorly formulated combination preparations
Prescription of inappropriate drug regimens
Unregulated over-the-counter sales of drugs.
It should be noted that combination preparations of antituberculosis drugs, although ensuring that the patients receive all the
prescribed agents, can lead to drug or multi-drug resistance if taken
irregularly.22 In addition, it is important to obtain combination
preparations from WHO-approved manufacturers as poor formulation can reduce the bioavailability of the component drugs.
By definition, tuberculosis caused by strains resistant to rifampicin and isoniazid, irrespective of other resistances, is termed
multi-drug resistant tuberculosis (MDRTB). Patients with MDRTB
do not respond to standard short-course therapeutic regimens and
must be treated for extended periods with regimens that are more
costly and more likely to cause adverse side-effects. Under ideal
operational conditions, a high proportion of patients with MDRTB
are curable but the cost of managing them can be as much as 100
times that of cases of drug-susceptible disease. As a consequence,
there is a risk that patients will go untreated in resource-poor
regions and pass the infection on to others.
Owing to limited laboratory resources, the exact global incidence of MDRTB is uncertain. Despite this limitation, the WHO
has undertaken prevalence surveys which showed that acquired
resistance is commoner than primary resistance and that the relative prevalence of both varies enormously from region to region.21
Examples are given in Table 56.5. In most parts of the world,
about 1% of new cases are multidrug-resistant but a number of
hot-spots with a very high prevalence of drug resistance have
been found, including several countries of the former Soviet
Union, China (Henan and Liaoning provinces), Equador and
Israel. By contrast, low prevalences were found in African countries. According to WHO estimates, around 460 000 cases of
MDRTB arise annually, half in new cases and half in previously
treated cases.15
More recently, tuberculosis resistant to almost all known agents
has been described. Cases of MDRTB additionally resistant to
two or more of the six classes of second-line drugs (p. ) are 5
termed extensive or extreme drug resistant tuberculosis (XDRTB).23
On definition is MDRTB (resistance to rifampicin and isoniazid)
plus resistance to any fluoroquinolone, plus to at least one of the
following drugs: kanamycin, amikacin and capreomycin. Although
occurring in many countries, such extreme resistance was highlighted by an outbreak in the Kwazulu-Natal province of South
Africa in which, of 544 patients studied, 221 had MDRTB and of
Table 56.5 Prevalence of combined primary and acquired drug resistance, as percentage of tested isolates, by country or
region, 19961999
Country or region
Multi-drug resistance
Uruguay
4.6
0.4
0.2
Venezuela
4.7
1.9
0.4
Malaysia
5.1
0.6
0.1
Nepal
6.4
1.4
1.4
Botswana
7.7
2.5
2.0
Cuba
8.3
1.5
0.9
South Africa
10.2
3.5
2.5
10.5
3.8
1.1
Guinea
15.9
6.0
1.5
Peru
18.4
7.1
4.3
Mexico
20.6
9.1
7.3
Uganda
22.1
8.1
0.8
Mozambique
23.1
10.0
3.5
24.1
13.4
7.1
Sierra Leone
27.7
8.7
2.6
Estonia
40.8
26.8
15.1
13
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56.
Tuberculosis
Tuberculin reactivity
Tuberculin reactivity is a risk factor for the development of tuberculosis as it is usually indicative of past infection by the tubercle
bacillus, but the relation between such reactivity and risk of
disease is not straightforward. In general, small reactions imply
no increased risk, or even a degree of protection, but large reactions imply increased risk, though considerable regional variations in the risk in relation to reaction size occur.
14
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Diagnosis of Tuberculosis
DIAGNOSIS OF TUBERCULOSIS
The success of tuberculosis control programmes depends critically
on the quality of diagnostic services. Detailed accounts of the
establishment and management of tuberculosis laboratories, the
collection of specimens and subsequent laboratory procedures are
available.29,30
Diagnosis in a community may either be active involving a
deliberate search for cases or passive, relying on patients with
symptoms presenting for treatment. The latter approach requires
much less investment in time and personnel but its success
depends on public education and the availability of user-friendly
facilities.
Diagnosis of tuberculosis is based on a high index of clinical
suspicion (described in relevant sections below), appropriate
clinical and radiological examinations and laboratory investigations. The following investigations help to confirm the diagnosis
and monitor treatment:
1. Bacteriological examinations include detection of acid-fast bacilli
by microscopy and culture of the causative organism from
appropriate clinical specimens such as sputum, bronchial aspirates and brushings, gastric aspirates, pleural, peritoneal and
pericardial fluids, cerebrospinal fluid (CSF), blood, bone
marrow and tissue aspirates or biopsies.
2. Imaging techniques including radiology, ultrasound, computed
axial tomography (CAT) scanning, magnetic resonance imaging (MRI) and radioisotope scans.
3. Molecular techniques utilizing nucleic acid amplification systems the polymerase chain reaction (PCR) and related
techniques.
4. Haematological and biochemical investigations such as haemoglobin levels, erythrocyte sedimentation rate (ESR) and liver
function tests may be required in overall patient management but have limited diagnostic roles.
5. Tuberculin skin tests and other immunological tests including
interferon- assays.
In resource-poor settings, clinical acumen and simple microscopy
are the mainstay of diagnosis and in many cases a trial of therapy
is commenced on clinical suspicion only. One of the most frustrating challenges in tuberculosis management has been the lack
of a specific, sensitive, inexpensive, and rapid point-of-care test for
the diagnosis of tuberculosis. For individual patients, the cost,
complexity and potential toxicity of 6 months of standard
treatment demands certainty in diagnosis. For communities, the
risk of transmission from undetected cases requires widespread
access to diagnostic services and early detection. Unfortunately,
current diagnostic services in most endemic settings fail both the
individual and the community. Patients are commonly diagnosed
after weeks to months of waiting, at substantial cost to themselves,
and at huge cost to society as TB goes unchecked. Many patients
are missed altogether, and contribute to the astonishing number
of annual deaths from tuberculosis worldwide. Some of this failure
Bacteriological identification
Microscopy
In most laboratories, clinical specimens are examined by light
microscopy for acid-fast bacilli after staining by the ZiehlNeelsen
method. Fluorescence microscopy, although requiring more
expensive equipment which must be carefully maintained, is more
sensitive as larger areas of the material on the microscope slide
can be scanned at low-power magnification. Differentiation of
species is not possible on microscopy and reports should only
state whether acid-fast bacilli are or are not seen.
In practice, the great majority of specimens are sputum and
more than one specimen should be examined. Ideally these
include a spot specimen obtained when the patient attends the
15
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56.
Tuberculosis
Culture
Isolation of M. tuberculosis in culture from the clinical specimen
provides a definitive diagnosis. Cultivation, usually on solid
media, is more sensitive than microscopy and increases the diagnostic yield by up to 50%. Its disadvantage is the delay, usually
36 weeks, between receipt of the specimen and the emergence
of visible growth.
A range of media for cultivation of mycobacteria have
been described. The most widely used is the solid egg-based
LwensteinJensen medium but several other egg-based and nonegg-based media are also available. Liquid media such as Kirschner
and Middlebrook broth allow a large inoculum to be used, thereby
enhancing the likelihood of obtaining a positive result. Liquid
media, supplemented with mixtures of antimicrobial agents to
suppress growth of bacteria other than mycobacteria and of fungi,
are used in automated culture systems (e.g. MGIT) that give rela-
tively rapid results, usually 212 days after inoculation. The original automated systems were based on the detection of radioactive
carbon dioxide released during bacterial utilization of a 14C-labelled
substrate. In more recent systems oxygen utilization or CO2 production resulting from bacterial growth is indicated by changes in the
colour of dyes or the unquenching of fluorescent substances.34
Radiological imaging
The advantage of a chest radiograph in the diagnosis of tuberculosis is that of speed, but the equipment is expensive to obtain,
maintain and operate (see also Chapter 26). Experienced radiologists are required in order to interpret the often rather non-specific
radiological signs and the bizarre appearances seen in patients
with HIV disease. Ideally, full-size anteroposterior radiographs
should be obtained but miniature radiography may be useful
under some circumstances, such as for the screening of refugees,
residents of hostels for the homeless and other high-risk populations. Mass miniature radiography is, on grounds of effectiveness
and cost-effectiveness, rarely used for routine screening of the
general population. Fluoroscopy is of very limited diagnostic
value and, as it also poses a serious radiation hazard to the operator, it should be universally abandoned.
Radiology is very sensitive although, exceptionally, the radiograph may appear normal in patients with smear-positive pulmonary tuberculosis. Although radiology is not specific since all the
changes associated with tuberculosis occur in other respiratory
conditions, in most cases the lesions are characteristic enough to
suggest the diagnosis.35 Radiological features vary greatly but those
highly suggestive of post-primary pulmonary tuberculosis are
single or multiple cavities principally in the upper zones, unilateral or bilateral patchy shadows in any part of the lung fields and
calcification. Conditions mimicking tuberculosis include unresolved pneumonias, atypical pneumonia, carcinoma, sarcoidosis,
Kaposis sarcoma and mycetoma.
High-resolution CAT scanning, where available, may help to
distinguish these conditions. Even when CAT scanning is performed the diagnosis may be difficult and bronchoscopy may be
required to obtain lung samples for analyses. Radioisotope scans
may be helpful in detecting extent of disease or relapses, especially
in cryptic areas such as bones and lymph nodes. Magnetic resonance imaging (MRI) with appropriate contrast enhancement is
useful in diagnosis and management of space-occupying lesions
in cerebral tuberculosis.
16
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Diagnosis of Tuberculosis
The principal forms of the test are the Mantoux, Heaf and tine
tests.
Mantoux test
Tuberculin test
This is a standard and widely used diagnostic test but its interpretation is far from straightforward.37 The test is usually positive in patients with tuberculosis although, due to genetic factors,
it is negative in a minority of patients. The dermal response
is suppressed to a varying extent in malnourished persons and
those suffering from advanced tuberculosis, sarcoidosis, chronic
renal failure, cancer and viral infections including HIV, measles,
chickenpox and glandular fever. It is also suppressed in those
receiving anticancer chemotherapy, immunosuppressive drugs
and high doses of corticosteroids. The test does not clearly
distinguish between active tuberculosis, past infection by the
tubercle bacillus and BCG vaccination. In some regions sensitization by environmental mycobacteria induces low levels of
tuberculin cross-reactivity. Misleading negative results may be
due to faulty stor-age of the material or poor technique. The
usual form of tuberculin employed in epidemiological and
diagnostic work is purified protein derivative of tuberculin (PPD),
the strength of which is expressed in international units (IU).
Heaf test
This method employs a spring-loaded gun which drives
six needles into the skin of the dorsal aspect of the forearm
through a drop of undiluted PPD. The method is technically easy
but it is necessary to autoclave the gun between use in order to
avoid transmission of HIV and other viruses. Some guns have
detachable magnetic heads which can be autoclaved separately.
The practice of dipping the head in alcohol and flaming it is
unsafe. The test is read at 4872 h (although a strong reaction will
still be visible at 7 days) and the reaction is scored as shown in
Table 56.6.
Grades III and IV correspond to a Mantoux reaction of 15 mm
or more and are regarded as definite evidence of infection by the
tubercle bacillus. Grade II corresponds to a Mantoux reaction of
1014 mm and indicates probable infection.
Tine test
This is similar in principle to the Heaf test, except that PPD is
dried onto four spikes (tines) on a small, single-use, disposable
unit. The device is pressed firmly onto the skin so that the tines
No reaction
Grade I
Grade II
Grade III
A disc of induration
Grade IV
17
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56.
Tuberculosis
penetrate the skin and held in place for 10 s so that the dried PPD
dissolves in the tissue fluids. Results are more variable than with
the other test methods but it has some advantages when very few
people are tested.
Interferon-g assays
To overcome the problem of specificity encountered with tuberculin testing, the production of interferon-gamma by peripheral
blood lymphocytes when exposed to antigens of M. tuberculosis in
vitro has been utilized for the development of commercially available diagnostic tests. Increased specificity is achieved by selecting
antigens present in M. tuberculosis but not in BCG or environmental mycobacteria. Studies to date indicate that these assays
are of potential value but more extensive evaluations in a range
of populations and settings are required for the confirmation
of their usefulness and benefits and their ability to distinguish
active from latent disease.38
TUBERCULOSIS IN CHILDREN
There are many differences between the pathological, clinical,
radiological and epidemiological features of tuberculosis in children (see also Chapter 23) and adults. Children are usually
infected by the aerogenous route and develop primary pulmonary
complexes as described below. The most usual source is an adult
with tuberculosis in the family. Less frequently they are infected
by drinking milk containing M. bovis, usually with implantation
of the bacilli in the tonsil or intestinal wall. Primary inoculation
lesions due to infection of cuts and abrasions and congenital
tuberculosis resulting from intrauterine infection are rarely
encountered. Guidelines for the management of tuberculosis in
children, including those who are infected with HIV, are available
from the WHO.39
Congenital tuberculosis
This is a very rare condition and the mother always has tuberculosis, although sometimes in a form that is not clinically or radiologically obvious, such as renal tuberculosis.43 There are two main
types resulting from, respectively, transplacental infection and
aspiration or inhalation of infected amniotic fluid.
Transplacental infection causes primary hepatic lesions and
the infant presents with hepatic enlargement, fever and failure to
gain weight. Jaundice is common. Respiratory infection leads to
extensive lung involvement resulting in respiratory distress and
cyanosis and diffuse nodular opacities on chest X-ray. Intrathoracic lymphadenopathy, sometimes extensive enough to cause
respiratory obstruction, and miliary disease are common. The
tuberculin test is often negative but there are numerous
tubercle bacilli in the lungs and/or liver which are usually demonstrable by examination of tracheal or gastric aspirates or fineneedle liver biopsies. Mortality is high, as many as one-half die,
and therapy should be commenced on suspicion of the disease.
Treatment with corticosteroids may be life-saving in seriously ill
children.
Hypersensitivity reactions
Primary tuberculosis in childhood is sometimes associated with
hypersensitivity reactions: phlyctenular conjunctivitis and erythema nodosum (Figure 56.15).
Phlyctenular conjunctivitis is characterized by conjunctival itching
or pain, lacrimation and photophobia, usually in one eye. Small,
grey, translucent nodules are seen near the limbus of the cornea
and the blood vessels in the adjacent conjunctiva are dilated. A
leash of small blood vessels extends to the edge of the conjunctival
18
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Tuberculosis in Children
No
radiograph
Score
Score
1 6
7 or more
Chest
radiograph
Not
diagnostic
? atypical
pneumonia
Diagnostic TB
Wide mediastinium
Miliary shadows
Cavity, etc.
Start TB
treatment
High dose
antibiotic
q.i.d. 7 days
Poor
response
Different
antibiotic
q.i.d. 7 days
Poor
response
Good
response
Not TB
Good
response
Not TB
A
Figure 56.14 (A,B) Paediatric tuberculosis management flow chart.
sac. Occasionally corneal ulceration occurs. More usually, the condition regresses over several days but recurrent attacks may occur.
The condition occurs most frequently in children aged between 5
and 10 years and is much more frequent in girls than in boys. Some
cases have followed BCG vaccination and streptococcal infection.
It usually occurs soon after primary infection but a few cases have
been reported in children with calcified primary complexes.
19
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56.
Tuberculosis
Clinical features
Symptoms related to the lung include cough, mucoid or purulent
sputum, haemoptysis, breathlessness and chest wall pain. More
general and non-specific constitutional symptoms include fever
and sweating (particularly at night), weight loss, general malaise
and anorexia. None of these symptoms are specific for tuberculosis
and some patients, even those with quite extensive disease, may
have no apparent symptoms at all. Physical chest signs may be
absent or limited to fine apical crackles. In more advanced cases
there may be areas of dullness on percussion or localized wheezing.
Clubbing of the finger is rare but is sometimes seen in severe cases
of advanced disease with bronchiectasis. Clinical signs are often less
obvious than would be expected from the radiological picture.
Diagnosis
Diagnosis is usually made by examination of sputum smears by
microscopy and, where facilities are available, bacteriological
culture and radiological examination (Figures 56.1656.20).
Advanced imaging techniques where available are useful in localizing pathology in cryptic sites (Figure 56.2156.23).
Complications
20
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Differential diagnosis
The principal conditions with which pulmonary tuberculosis may
be confused are community acquired unresolved pneumonias,
carcinoma of the lung, Kaposis sarcoma, helminth infections of
the lung (hydatid, schistosomiasis, paragonimiasis), pulmonary
Management
The management of pulmonary tuberculosis involves prescription
of an appropriate antituberculosis drug regimen, management of
21
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56.
Tuberculosis
Clinical features
Diagnosis
complications, supervision of the patient until the course of
therapy has been completed and active contact tracing. Antituber7 culosis therapy is described on pp. .
22
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Disseminated Tuberculosis
Differential diagnosis
Tuberculous pleural effusions must be differentiated from those
secondary to pneumonia, cardiac failure, malignancy, pulmonary
embolism and infarction and amoebiasis.
Management
The basic management is as for pulmonary tuberculosis as
described above. Small effusions usually resolve on antituberculosis therapy but larger ones may require needle aspiration. Corticosteroid treatment prevents recurrence of large effusions and
subsequent constrictive fibrosis which may compromise pulmonary function. Thick empyema fluid may be difficult to aspirate
through a needle and surgical drainage is required. Surgical
removal of the pleura (decortication) may be required to prevent
or relieve gross constrictive scarring.
DISSEMINATED TUBERCULOSIS
This form of tuberculosis was described in the year 1620 by
Sylvius, who wrote: I came moreover constantly upon various
traces of glands small and almost invisible to the eyes, except
occasionally, when they were unnaturally larger and I have seen
them distributed throughout the viscera and flesh of our entire
body.
The clinical and histopathological features of disseminated
tuberculosis are determined by the immune status of the
patient and two main types are recognized miliary and cryptic
disseminated.
Miliary tuberculosis
In cases in which the immune responses are intact, disseminated
disease is characterized by the formation of widespread, multiple,
discrete granulomas macroscopically resembling millet seeds
(Latin: milium, a millet seed), hence the name miliary tuberculosis. Classically, this was a disease of young children but nowadays
it occurs in those of all ages. The symptoms are non-specific and
include fever, malaise and weight loss. Meningeal involvement
may cause headache. On chest X-ray the numerous minute lesions
produce a characteristic snowstorm appearance (Figures 56.25,
56.26). Lesions also occur in the lung (Figure 56.27), spleen
(Figure 56.28) and tubercle bacilli are found in the urine of about
25% of patients with miliary disease. The disease may be acute
and rapidly progressive, and fatal if untreated, but in other cases
it is surprisingly chronic and insidious. Pleural involvement with
small effusions may occur; the meninges are affected in about 10%
of cases; hepatosplenomegaly is detectable in 2030% of cases
and, rarely, papular or macular miliary lesions of the skin are seen
(Figure 56.29).
Acid-fast bacilli are demonstrable in sputum in about half the
cases and in liver biopsies in about a quarter of cases. Probably
the best diagnostic procedure, if facilities are available, is transbronchial biopsy through a fibreoptic bronchoscope. The tuberculin test is usually positive in early cases but becomes negative
as the disease advances.
23
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56.
Tuberculosis
24
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lowed in frequency by the large joints of the lower limb (hip, knee
and ankle) and then the large joints of the upper limb (shoulder,
elbow and wrist). Multiple lesions, often cystic, may occur in disseminated tuberculosis and are easily mistaken for metastatic carcinoma.45
Spinal tuberculosis
Spinal tuberculosis, also termed Potts disease, after Sir Percival
Pott (17131788), a surgeon at St Bartholomews Hospital,
London, is a cause of severe deformity and handicap. Although
any part of the spine may be affected, lesions most often occur at
or near the 10th thoracic vertebra. The disease process usually
begins in an intervertebral disc and subsequently involves the
anterior parts of the adjacent vertebrae (Figure 56.31). Erosion of
the bone by the disease process causes vertebral collapse with
anterior wedging and, in severe cases, the characteristic angular
spinal deformity or gibbus (Figure 56.32). Cold abscesses are
common and may track along fascial planes and emerge at the
skin surface well away from the site of disease. Thus psoas abscesses
secondary to disease in the lumbar vertebrae may emerge in the
thigh below the inguinal ligament. Tuberculosis of the cervical
spine may present as a retropharyngeal abscess.
The usual presenting feature is chronic back pain, often with
stiffness and limitation of movement. An unwillingness to pick
something off the floor is a characteristic sign. Clinical features
may, however, be minimal and non-specific and diagnosis is
often delayed. Neurological signs due to pressure on, or vasculitis
of, the spinal cord occur in about half the cases and paraplegia
develops in severe cases. Clinical examination may reveal
muscular spasm and rigidity, cold abscesses, sinuses and spinal
deformity.
25
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56.
Tuberculosis
in clinical practice tuberculous meningitis, solitary spaceoccupying lesions in the brain or spinal cord and disseminated
miliary lesions.48
Figure 56.33 Tuberculous osteomyelitis. Radionuclide bone scan
shows abnormal, increased tracer uptake in D7. The vertebra has
collapsed, with spinal cord compression resulting in paraplegia. The
excreted activity is seen in the urinary catheter.
Tuberculous meningitis
This is the most common form of CNS tuberculosis and constitutes a medical emergency as diagnostic and therapeutic delays
have very serious consequences; namely, a high mortality and a
high incidence of serious neurological complications in those who
survive. It is most often seen in infants but it may occur at any
age.48 It is usually a manifestation of primary tuberculosis and
there may be radiological evidence of a primary pulmonary
complex. The disease commences with the rupture of a meningeal
or subcortical lesion with liberation of tubercle bacilli into the
CSF and the development of many tubercles on the meninges. The
ensuing meningeal inflammation, particularly at the base of the
brain, leads to the secretion of a thick exudate which may lead to
strangulation of the cranial nerves, especially the optic and auditory nerves, at the base of the brain and to raised intracranial
pressure due to obstruction to the flow of CSF. Raised intracranial
pressure is a major complication of tuberculous meningitis and
some degree of hydrocephalus occurs in 8090% of children with
stage 2 or 3 disease as defined below. An inflammatory endarteritis may lead to thrombosis of the cerebral blood vessels causing
cerebral infarction with convulsions or paralysis.
Clinically, cases are classified into three stages:
Stage 1. The patient is fully conscious and rational with nonspecific symptoms such as general malaise, low-grade
fever, apathy, irritability, personality changes, depression and intermittent headache but with no focal signs
and little or no evidence of meningitis. Symptoms may
be limited or even absent in immunosuppressed
patients, including those who are HIV-positive.
Stage 2. The patient is mentally confused and/or has focal neurological signs such as cranial nerve palsies. Other
26
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Treatment
Standard short-course antituberculosis therapy is effective although
many physicians extend the duration of therapy to 9 or 12 months
to minimize the risk of relapse. Both isoniazid and pyrazinamide
readily cross the bloodbrain barrier but rifampicin does not
penetrate so readily and therefore higher doses, but not exceeding
600 mg daily, should be given. Some authorities recommend
giving pyrazinamide throughout the course of treatment. Ethambutol enters the CSF when the meninges are inflamed but ocular
complications may occur in children. Intrathecal administration
of drugs is not generally recommended. In a major centre in
South Africa, only one relapse was seen in a series of over 200
children with tuberculous meningitis receiving a 6-month course
of daily isoniazid (20 mg/kg), rifampicin (20 mg/kg), ethionamide (20 mg/kg) and pyrazinamide (40 mg/kg).
The use of steroids has been a source of controversy as, although
steroids suppress hypersensitivity reactions and the formation
of basal exudates, some workers claimed that, while they
lowered mortality, they allowed more very seriously disabled children to survive. An extensive review established that the data
were inconclusive,50 and a more recent study in patients over the
age of 14 indicated that, irrespective of severity and HIV status,
treatment with dexamethasone lowered mortality but did not
reduce the incidence of subsequent neurological disability.51 Until
more firm data are available, national guidelines should be
followed.
27
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56.
Tuberculosis
28
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Abdominal Tuberculosis
ABDOMINAL TUBERCULOSIS
Diagnosis
Examination of the urine may reveal a few white cells, red cells
and protein. Care is required in the interpretation of acid-fast
bacilli seen in urine as various environmental mycobacteria occur
as contaminants of the lower urethra and external genitalia. Diagnosis is confirmed by cultivation of tubercle bacilli in urine, for
which purpose up to six specimens, preferably taken in the early
morning, should be examined.
Radiology of the urinary tract (Figure 56.42) is useful for the
detection of urinary obstruction and other forms of gross tissue
damage. Being a late manifestation of primary tuberculosis,
appearances suggestive of pulmonary tuberculosis are only seen
in 5% of cases but patients may give a history of tuberculosis.
Ultrasonography may reveal renal calyceal dilatation and more
overt evidence of obstruction. Between 50% and 75% of males
with genital tuberculosis have radiological abnormalities in the
urinary tract, so the appropriate radiological investigations should
be undertaken.
Diagnosis of tuberculosis of the female genital tract is made by
histological and bacteriological examination of endometrial biopsies and culture of cervical secretions and menstrual blood.
Management
Treatment of all forms of genitourinary tuberculosis is by standard
short-course antituberculosis therapy. Surgical intervention may
29
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56.
Tuberculosis
Management
Treatment is by standard antituberculosis therapy. Subacute
obstruction may be relieved by steroid therapy. Surgery is required
for the rare cases of massive rectal bleeding.
SKIN TUBERCULOSIS
There are several different manifestations of skin tuberculosis
(Figures 56.4656.52) and these have accumulated a large
number of quaint and outmoded names which confuse the
description of the disease. There are four main categories of skin
tuberculosis:
Inoculation into skin injuries, which may be due either to
primary exogenous infection or autoinoculation by contaminated sputum in patients with post-primary pulmonary tuber-
30
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Skin Tuberculosis
31
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56.
Tuberculosis
32
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Figure 56.55 Enlarged posterior auricular lymph node in an HIVpositive adult. M. tuberculosis was isolated from a lymph node aspirate.
33
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56.
Tuberculosis
Tuberculous pericarditis
34
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Ocular tuberculosis
The eye may be involved in disseminated tuberculosis as, for
example, choroidal lesions in miliary tuberculosis or by direct
invasion from surrounding skin in lupus vulgaris (Figure
56.52).66,67 Primary lesions under the eyelids rarely occur in young
children exposed to source cases. The eyelids are swollen, the eye
becomes irritable and the disease may spread to the pre-auricular
lymph nodes. Phlyctenular conjunctivitis, a hypersensitivity reaction sometimes seen in children with primary tuberculosis is
described above (p. ).
The optic nerve may be damaged in tuberculous meningitis,
sometimes leading to blindness.
Adrenal gland
Tuberculosis is a well-recognized but uncommon cause of hypoadrenalism or Addisons disease and is the result of haematogenous spread of tubercle bacilli to the adrenal gland.68 The clinical
features of Addisons disease include weakness, weight loss, low
blood pressure, amenorrhoea and gastrointestinal symptoms. A
characteristic hyperpigmentation of the skin, most notably over
the elbows and the lower back, occurs in fair-skinned persons.
Pigmented patches also occur in the mouth, a useful sign in darkskinned patients. Diagnosis of hypoadrenalism is confirmed by
tests of adrenal function and tuberculosis is suggested by the
presence of calcification in the adrenals visible on abdominal
X-rays. Hormonal replacement, in addition to antituberculosis
therapy, is required.
Figure 56.59 Constrictive tuberculous pericarditis: X-ray shows
pericardial calcification.
68 weeks reduces the size of the effusion and associated mortality and also the long-term incidence of constrictive sequelae.
Unless contraindicated, steroid therapy should therefore be given
for this form of tuberculosis. Healing with fibrosis and calcification may result in chronic constriction of the heart, requiring
surgical relief (Figure 56.59). Tuberculous myocardial lesions are
very rare but are a cause of fatal heart block.
35
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56.
Tuberculosis
Clinical manifestations of
HIV-related tuberculosis
Pulmonary tuberculosis occurs in patients with a wide spectrum
of immunodeficiency but, as mentioned above, the risk and clinical manifestations are not entirely dependent on the degree of
depletion of CD4+ lymphocytes. Around 30% of cases of tuberculosis in HIV-positive patients are extrapulmonary. If tuberculosis
occurs in the early stages of HIV infection when immunity is only
slightly compromised, the clinical characteristics are similar to
post-primary tuberculosis occurring in HIV-negative persons. Thus
disease is often localized to the apices of the lungs; there is lung
destruction and cavitation and abundant acid-fast bacilli are seen
on sputum microscopy. HIV-positive patients with more advanced
immunodeficiency present with atypical pulmonary disease characterized by extensive pulmonary infiltrates with limited or no
cavitation, involvement of all parts of the lung especially the lower
lobes, enlargement of the hilar and mediastinal lymph nodes and
few or no acid-fast bacilli seen in sputum smears. Dissemination
of the disease beyond the lung is common.
36
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Table 56.7
Comparison of the clinical and radiological characteristics of post-primary tuberculosis in
non-immunosuppressed and immunosuppressed persons
Characteristic
Non-immunosuppressed
Immunosuppressed
Pulmonary cavitation
Prominent
Diminished or absent
Localization by fibrosis
Marked
Limited
Intrathoracic lymphadenopathy
Uncommon
Common
Pleural effusions
Present
Very common
Miliary disease
Uncommon
Common
Atelectasis
Uncommon
Common
Uncommon
Common
Uncommon
Common
Tuberculin test
Positive
Uncommon
Frequent
Mortality rate
Low
Increased
Extrapulmonary tuberculosis in
HIV-positive adults
Frequent manifestations of extrapulmonary tuberculosis seen in
HIV-infected persons in sub-Saharan Africa include pleural disease,
lymphadenopathy (usually asymmetrical), pericardial disease and
widely disseminated disease. Tuberculosis affecting the CNS, genitourinary tract and bone marrow is, in contrast to the industrialized countries, infrequently reported but this probably reflects
patient selection and differences in the availability of diagnostic
facilities. Patients usually present with non-specific constitutional
symptoms (fever, night sweats and weight loss) and local symptoms and signs related to the site of disease. Lymphadenopathy is
a frequent manifestation of tuberculosis in HIV-infected persons
and can present in a variety of ways. While usually chronic and
cryptic, it may also occasionally be acute and resemble an acute
pyogenic infection. Diagnosis of lymph node tuberculosis can be
made by simple techniques such as staining needle aspirates for
acid-fast bacilli, naked eye inspection of biopsied lymph nodes
for macroscopic caseation and microscopy of smears from the cut
surface of a lymph node. The CSF may be normal or near-normal
in HIV-infected patients with tuberculous meningitis and clinical
features can easily be confused with those of cryptococcal menin-
37
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56.
Tuberculosis
Drug resistance
Although several outbreaks of MDRTB have been reported from
industrialized countries among HIV-infected patients, HIV infection itself does not induce MDRTB, but it fuels the spread of this
dangerous condition by increasing susceptibility to infection and
accelerating transmission between persons, especially in closed
confined spaces such as prisons. Although data collated by the
WHO show that the incidence of MDRTB in sub-Saharan Africa is
low in comparison with India, Eastern Europe, China and Southeast Asia,21 the problems faced by many tuberculosis programmes
in sub-Saharan Africa, including the difficulties in obtaining
second-line antituberculosis drugs, render MDRTB a very real
threat to tuberculosis control in this region.
Quality of healthcare
38
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10
Recurrence rates of tuberculosis (defined as return of clinical features of active tuberculosis, positive sputum smears for acid-fast
bacilli or positive sputum cultures for M. tuberculosis) after completion of antituberculosis therapy are increased in HIV-positive
patients. Recurrence rates have been observed at between 18 and
22 per 100 person-years of observation. It is not known to what
extent endogenous reactivation or exogenous reinfection contributes to the recurrence of tuberculosis in HIV-infected patients in
sub-Saharan Africa but recent evidence suggests that the latter
commonly occurs. Information on this issue would be of value in
determining strategies, such as isoniazid prophylaxis, to prevent
recurrence of tuberculosis. Patients who relapse with smearpositive pulmonary tuberculosis are treated with the WHOrecommended retreatment regimen shown below in Table 56.9.
Preventive therapy is described on p. .
Table 56.8 Reports of the prevalence of bovine tuberculosis and use of the test and slaughter policy in countries within
the WHO regions
Region
Not reported
No data
Africa
55
25
18
Asia
36
16
34
12
12
39
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56.
Tuberculosis
TREATMENT OF TUBERCULOSIS
The introduction of rifampicin in the late 1960s made it possible
to develop highly effective short-course therapeutic regimens
which, when used within the WHO DOTS strategy, form the basis
of the modern management of tuberculosis.
11
40
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Treatment of Tuberculosis
Table 56.9 The WHO-recommended short-course antituberculosis drug regimens in four categories of patients81
Treatment
category
Initial phasea
Preferred
2 HRZE
Continuation
phase
4 HR
Or
4 (HR)3
Optional
2 (HRZE)3
Or
2 HRZE
II
Preferred
2 HRZES/1 HRZE
5 HRE
Optional
2 (HRZES)3/1 (HRZE)3
III
4 (HR)3
Or
6 HE
5 (HRE)3
Preferred
Preferred
2 HRZES/1 HRZE
5 HRE
Optional
2 (HRZES)3/1 (HRZE)3
2 HRZE
5 (HRE)3
4 HR
4 (HR)3
Optional
2 (HRZE)3
Or
2 HRZE
IV
4 (HR)3
Or
6 HE
Specially designed
standardized or
individualized regimens
a
The subscripted figure 3 indicates thrice weekly intermittent dosing.
H, isoniazid; R, rifampicin; Z, pyrazinamide; E, ethambutol; S, streptomycin.
are also of use. These drugs are generally more toxic, more
expensive and less active than the first-line drugs and treatment
is often prolonged and therefore costly.
Isoniazid
This has a powerful bactericidal activity against replicating tubercle bacilli but little or no activity against near-dormant bacilli. It
is cheap and cross-resistance with other drugs does not occur.
Effective concentrations of the drug are obtained in all tissues and
the CSF. Isoniazid is converted to an inactive form by the process
of acetylation which is under genetic control, with some people
being rapid acetylators and others slow acetylators. About 50% of
Caucasians and Africans and 8090% of Chinese and Japanese are
41
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56.
Tuberculosis
Ethambutol
Figure 56.64 Extensive skin reaction due to isoniazid.
Pyrazinamide
Pyrazinamide is only active in acidic environments and is therefore principally effective against intracellular tubercle bacilli and
those in acidic, anoxic inflammatory lesions. It freely enters the
CSF, where levels achieved are similar to those in the plasma.
Resistance is uncommon.
Despite early reports of hepatotoxicity, pyrazinamide is usually
well tolerated and skin rashes occur rarely (Figure 56.66). Although
moderate elevations of serum transaminases occur early in treatment, severe hepatotoxicity is uncommon except in patients with
pre-existing liver disease. Its principal metabolite, pyrazinoic acid,
inhibits renal excretion of uric acid, occasionally resulting in gout
requiring treatment with allopurinol. An unrelated arthralgia,
notably of the shoulders and responsive to analgesics, also occurs.
42
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Treatment of Tuberculosis
Fluoroquinolones
Second-line drugs
These are indicated in cases of drug resistance and, very occasionally, when the use of a first-line drug is prevented by adverse drug
reactions. In general, they are less effective, more toxic and more
expensive than the first-line drugs. As mentioned above, there are
six classes of second-line drugs, namely: aminoglycosides, thioamides, fluoroquinolones, polypeptides, p-aminosalicylic acid
and cycloserine.23 In addition, a few experimental agents are being
evaluated.82
Thiacetazone is no longer included as, although once widely
used, the WHO strongly recommends that it should be abandoned on account of its poor activity, widespread resistance to it
and the high risk of severe and sometimes fatal skin reactions,
including exfoliative dermatitis and StevensJohnson syndrome,
particularly in those who are infected with HIV.
Aminoglycosides
Streptomycin was the first effective antituberculosis drug but is
no longer a first-line drug as it has the disadvantage that it is
not absorbed from the intestine and must therefore be given
by intramuscular injection. This raises the associated danger of
transmission of HIV and other viruses by contaminated needles.
The principal side-effects involve the vestibular apparatus of the
inner ear and manifest as unsteadiness and vertigo. This complication is more likely in older patients and the damage may be
permanent if the drug is not stopped immediately when the symptoms commence. Deafness occasionally occurs and, if an aminoglycoside is given during pregnancy, it can lead to impaired
hearing in the child. A further uncommon complication is anaphylaxis. Other aminoglycosides active against tubercle bacilli are
kanamycin and amikacin which, in common with streptomycin,
must be given by intramuscular injection and are ototoxic and
nephrotoxic.
p-Aminosalicylic acid
This was one of the early antituberculosis drugs but is now rarely
used as it has only bacteristatic activity, commonly causes gastrointestinal upsets and is of limited availability.
Cycloserine
This is a bacteriostatic drug which has unpleasant side-effects
including headache, dizziness and psychiatric complications. It is
usually the last drug of choice.
Immunotherapy
The use of adjunct immunotherapy to treat tuberculosis is a
subject of growing interest. Administration of exoogenous IFN or
43
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56.
Tuberculosis
IL-2 and other agents might augment host cell mediated immune
(CMI) responses in active TB, improve or accelerate clearance of
tubercle bacilli, and improve clinical outcomes. A substantial
body of evidence indicates that the response to therapy in drugsensitive disease may be accelerated, and treatment potentially
shortened, by antigranuloma strategies targeted at eliminating
dormancy. Immunomodulators such as: corticosteroids, HSP65DNA, TGF inhibitors, HE2000, IL-4 inhibitors, intravenous
immunoglobulin, rHuIFN, Eternacept therapeutic vaccines, and
other drugs and biologics have the potential to shorten treatment,
by modulating the host response and helping the immune system
eliminate persistent organisms. Strategies studied to date in mouse
models have been found to reduce the Th2 inhibitory effect on
the protective Th1 response, either by inhibiting IL-4 production,
or by downregulating the Th2 response. In animal models, impressive treatment shortening times have been observed, and further
human testing under appropriate study designs is warranted. In
addition to the treatment shortening described above, immunomodulation might improve treatment outcomes using immunomodulators as adjunctive therapies to existing regimens in all
groups of patients, including those with MDRTB and XDRTB.
Agents under investigation include cytokines such as IFN and a
heat-killed preparation of an environmental mycobacterium, M.
vaccae. Although clinical trials of single doses of the latter as an
adjunct to standard drug therapy yielded variable results,87 repeated
doses improved the cure rate of those with MDRTB, even when
they received very inappropriate drug therapy.88 Further studies are
therefore required, especially in regions where extreme drug resistance is encountered.
Adverse reactions
ISONIAZID
Common
Rare
Vertigo, convulsions, optic neuritis and atrophy, psychiatric disturbance, haemolytic anaemia, aplastic anaemia,
dermal reactions including pellagra, purpura and lupoid syndrome, gynaecomastia, hyperglycaemia, arthralgia
RIFAMPICIN
Common
Rare
Dyspnoea, hypotension with or without shock, Addisonian crisis, haemolytic anaemia, acute renal failure,
thrombocytopenia with or without purpura, transient leucopenia or eosinophilia, menstrual disturbances, muscular
weakness, pseudomembranous colitis
PYRAZINAMIDE
Common
Uncommon
Rare
44
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Treatment of Tuberculosis
Adverse reactions
ETHAMBUTOL
Uncommon
Rare
Hepatitis, cutaneous hypersensitivity including pruritis and urticaria, photosensitive lichenoid eruptions, paraesthesia
of the extremities, interstitial nephritis
STREPTOMYCIN
Uncommon
Rare
Renal damage, aplastic anaemia, agranulocytosis, peripheral neuropathy, optic neuritis with scotoma, severe
bleeding due to antagonism of Factor V, neuromuscular blockade in patients receiving muscle relaxants or with
myaesthenia gravis
OTHER AMINOGLYCOSIDES
Uncommon
Rare
THIACETAZONE
Common
Uncommona
Rare
Agranulocytosis
P-AMINOSALICYLIC ACID
Common
Gastrointestinal upsets
Uncommon
Rare
ETHIONAMIDE/PROTHIONAMIDE
Common
Uncommon
Rare
Uncommon
Loss of hearing, vertigo, tinnitus, electrolyte disturbances including hypokalaemia, leucopenia or leucocytosis
Rare
CLOFAZIMINE
Common
Discolouration of skin and body fluids, nausea, vomiting, abdominal pain, diarrhoea
Uncommon
Rare
Intestinal obstruction
CYCLOSERINE
Common (especially
exceeding 500 mg)
Drowsiness, sleep disturbance, headache, tremor, vertigo, confusion, irritability, aggression and other personality
changes, psychosis (sometimes with suicidal tendencies)
Uncommon
Rare
OFLOXACIN
Uncommon
Rare
Restlessness, convulsions, psychiatric disturbances including psychotic reactions and hallucinations, oedema of face,
tongue and epiglottis, disturbance of taste and smell, anaphylactoid reactions
45
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56.
Tuberculosis
Table 56.11 Interactions between antituberculosis drugs and other therapeutic agents
Drugs whose effects are opposed by rifampicin
Antiretroviral agents
Azathioprine
Corticosteroids
Ciclosporin
Diazepam
Digoxin
Haloperidol
Imidazoles
Opioids
Oral contraceptives
Phenytoin
Propranolol
Quinidine
Tolbutamide
Theophylline
Warfarin
Trimethoprimsulfamethoxazole (cotrimoxazole)
Enflurane
Phenytoin
Insulin
Carbamazepine
Prednisolone
Cimetidine
Aminophylline
Theophylline
Months of
therapy
Antiretroviral therapy
Rifampicin
16
Isoniazid
16
Pyrazinamide
12
Triple non-nucleoside
reverse transcriptase
inhibitors (NRTI)
Ethambutol
12
Rifabutin
16
Isoniazid
16
Pyrazinamide
12
Ethambutol
12
Nelfinavir, indinavir,
amprenavir, efavirenz or
nevirapine
46
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Treatment of Tuberculosis
Day 2
Isoniazid
Least/first
50 mg
300 mg 300 mg
75 mg
Rifampicin
1g
Day 3
Pyrazinamide
250 mg
Full dose
Ethambutol
Streptomycin Greatest/last
Pregnancy
The standard 6-month regimens may be safely used during pregnancy. Streptomycin, other aminoglycosides, capreomycin and
viomycin should be avoided as they may damage the inner ear of
the fetus, leading to impairment of hearing. Ethionamide and
prothionamide should also be avoided as they have been shown
to be teratogenic. Pyridoxine 10 mg daily prevents damage of fetal
nerves by isoniazid. Vitamin K should be given to newborn infants
of mothers receiving rifampicin to lower the risk of haemorrhagic
complications.
47
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56.
Tuberculosis
Dosage
There are no absolute guidelines but the following have been
recommended. When the patient is not seriously ill and when the
risk of sequelae due to fibrous scarring is low, 10 mg of prednisolone twice daily for 46 weeks, followed by a reduction of the
daily dose by 5 mg each week, is usually adequate.
For more serious conditions, including tuberculous meningitis
and pericarditis, 30 mg of prednisolone twice daily for 4 weeks
should be administered, or longer if indicated, followed by a
tailing off as above. Pleural effusions usually respond to 20 mg
twice daily for 2 weeks.
The dose in children, depending on severity, is 13 mg/kg. It
is important to note that rifampicin leads to a more rapid metabolism of steroids and the dose of steroids should therefore be
increased by one-half for up to 4 weeks in patients receiving
rifampicin.
The use of steroids in the treatment of severe drug reactions is
described on p. .
13
Preventive therapy
Few aspects of tuberculosis control have generated more controversy than treatment of latent infection in order to prevent the
emergence of active tuberculosis. Such so-called preventive therapy
is distinct from chemoprophylaxis which is given to uninfected
persons at a high risk of being infected and developing the disease,
such as a young child exposed to a source case in the home. In
some countries, such as the USA, where tuberculosis is very
uncommon in most states and where BCG vaccination is no
longer used, preventive therapy is given to tuberculin reactors. In
such circumstances, isoniazid monotherapy, usually for 1 year, is
given on the assumption that very few viable bacilli are present
and the chance of mutation to isoniazid resistance is therefore
very small. Such therapy has been shown, under these circumstances, to be effective and, as the chance of reinfection is very
low, protection is long-lasting. The major problems encountered
in the use of isoniazid monotherapy are those of ensuring compliance and the occurrence of hepatic complications. On account of
the latter, some authorities recommend that only those under 35
years of age should receive chemoprophylaxis.96 Another problem
is the high incidence of multi-drug resistant tuberculosis in some
regions, against which isoniazid monotherapy would afford no
protection. It is understandable that healthcare staff are anxious
about the risk to their health if reliance is placed on chemoprophylaxis rather than BCG vaccination.
48
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Treatment of Tuberculosis
In general, in view of problems of compliance and organization, preventive therapy has not played a major role in tuberculosis control.97 The advent of the HIV/AIDS pandemic has led to
a reappraisal of preventive therapy, as the chance of a dually
infected person developing overt tuberculosis is very high. Several
placebo-controlled studies of isoniazid monotherapy in patients
co-infected with M. tuberculosis and HIV have shown that preventive therapy is effective. Unfortunately, however, the preventive
effect of isoniazid is short-lived in HIV-positive persons and
rapidly declines after completion of the course of therapy. Indeed,
in one study no protection was apparent after 18 months. Thus,
repeated courses of preventive therapy or even lifetime medication
may be required. The preventive effect is greatest in those who are
tuberculin-positive and who have a relatively high lymphocyte
count. For this reason, and on account of the difficulty of diagnosing infection by M. tuberculosis in tuberculin-negative persons, the
WHO recommends that preventive therapy should be restricted
to HIV-positive persons who are tuberculin-positive.
Isoniazid monotherapy for 9 months is suitable for preventive
therapy in HIV-positive persons: continuation of therapy to 12
months adds very little. Shorter prophylactic regimens, such as
rifampicin with pyrazinamide for 2 months, have been evaluated
but rejected on the basis of an unacceptable level of adverse
effects.
It is important to ensure that HIV-positive persons receiving
preventive therapy do not have active tuberculosis or there is a
strong risk of masking the disease and encouraging the emergence
of drug resistance. It is also necessary to supervise the therapy
and this adds another burden to stretched tuberculosis control
services.
Policies for the use of preventive therapy vary from country
to country. National guidelines should be consulted for indications for chemoprophylaxis and for the recommended drug regimens. Preventive therapy is, however, unlikely to have a major
impact on tuberculosis control because of the difficulties of
implementation.
Surgical treatment
In general, surgery plays a minor role in the treatment of pulmonary tuberculosis, although resection of lesions caused by multidrug resistant tubercle bacilli in those with persistently positive
sputum achieves high cure rates with acceptable morbidity.98
Other indications include life-threatening haemoptysis, mycetomas forming in old tuberculous cavities, empyema and respiratory
distress due to grossly enlarged mediastinal lymph nodes. Surgery
has also been used in cases of localized pulmonary disease due to
environmental mycobacteria but the availability of more effective
therapeutic regimens is reducing the need for surgical resection.
Surgical treatment for extrapulmonary disease is discussed
under the appropriate headings.
culosis. Indeed, an ideal window of opportunity to control tuberculosis before the advent of HIV disease was missed. Instead, the
global tuberculosis problem became so serious that, in 1993, the
WHO took the unprecedented step of declaring this disease a
global emergency.
This declaration led to an intensifying of interest in tuberculosis by the WHO, culminating in the formulation of the Global
Plan to Stop Tuberculosis (GPSTB) in 1998. The commitment to
stop tuberculosis has been linked to the Advocacy Forum for
Massive Effort Against Diseases of Poverty, sponsored by the WHO
and UNAIDS and launched in October 2000 in the Swiss city of
Winterthur with the aim of conquering tuberculosis, HIV disease
and malaria the three infectious diseases that pose the greatest
threat to human health and life and are responsible for 1 in 10 of
all human deaths.99 Tuberculosis is certainly a disease that affects
the poor and is a major cause of poverty as it has a devastating
economic impact on a household in a developing country.100 On
average, a family loses 30% of its income if a money-earner develops tuberculosis, and 15 years of income if that person dies of the
disease. Accordingly, tuberculosis control as a way of alleviating
poverty is a key aim of the Millennium Development Goals which
set the target of halving, by application of the WHO DOTS strategy
and other innovations, the prevalence of tuberculosis, and deaths
due to it, by the year 2015.101
Two important related initiatives of the WHO are The Global
Alliance for TB Drug Development and The Global TB Drug
Facility (GDF).102 The former is an alliance of governments, nongovernmental organizations, pharmaceutical companies and
funding agencies committed to the development of new costeffective antituberculosis drugs that will improve and simplify the
treatment of tuberculosis, including drug-resistant forms. As a
direct result of this commitment, several promising new drugs
and regimens are currently being developed and evaluated.82
The GDF was launched in March 2001 to increase access to
high-quality antituberculosis drugs. By 2004, the GDF had supplied effective drug regimens to almost 2 million patients in 49
countries and had brought down the cost of treating a patient to
under US$10 dollars.
The GPSTB has grown into an extensive network of numerous
governmental, non-governmental and academic organizations
with a secretariat based at the WHO headquarters in Geneva. Full
details are available on the GPSTB website (www.stoptb.org). The
GPSTB programme is based on the WHO DOTS strategy, a 5-point
control strategy formally introduced in 1994 and described
below.103 Originally DOTS was an acronym of Directly Observed
Therapy, Short Course but it is now the brand name for the
overall strategy. In addition GPSTB aims to ensure that countries
are able to establish effective tuberculosis control programmes
and it disseminates up-to-date news, knowledge and information
through various media, including the internet. In addition, it
hosts a very valuable e-mail forum for the interchange of ideas
and opinions between workers in the field.
The strategic objectives of the GPSTB are to expand the DOTS
programme so that all those with tuberculosis will be effectively
diagnosed and treated, to address the challenges of HIV-related
tuberculosis and multi-drug resistance, to improve disease control
by developing and evaluating new diagnostic tests, drugs and vaccines, and to strengthen global partnerships so that the control
strategies can be effectively utilized.
49
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56.
Tuberculosis
Diagnosis
This is usually based on sputum microscopy. As case holding is
of key importance, the number of times that a patient has to
attend a clinic should be kept to a minimum. A commonly
adopted policy is to examine a sputum sample produced by the
patient on his or her first visit, an early morning specimen brought
to the clinic the following day and a third specimen collected on
that visit. As mentioned above (p. ) there are differing opinions
on the value of the third specimen.
The efficiency and accuracy of sputum microscopy critically
depend on the skill and dedication of the microscopist. As microscopical examination of sputum smears is tedious work, it is
important to give laboratory staff a variety of examinations to
undertake and no member of staff should examine more than 20
sputum smears each day. Quality control, training and attention
to job satisfaction are important factors to be attended to in the
management of microscopy services. The organization and practice of microscopy and other aspects of the tuberculosis laboratory
are discussed in detail elsewhere.29,30
14
Supply of drugs
The WHO DOTS strategy
In the expanded DOTS framework for effective tuberculosis control
published in 2002,103 the five elements of the DOTS strategy are
defined as:
Sustained political commitment to increase human and financial resources and to make tuberculosis control a nationwide
activity integral to national health systems
Access to quality-assured tuberculosis sputum microscopy for
case detection among people presenting with, or found through
surveys to have, symptoms of tuberculosis (most importantly,
prolonged cough). Special attention is necessary for case detection among HIV-infected people and other high-risk groups,
such as people in institutions
Standardized short-course therapy for all cases of tuberculosis
under proper case-management conditions, including direct
observation of therapy. Proper case-management conditions
imply technically sound and socially supportive treatment
services
Uninterrupted supply of quality-assured drugs with reliable
procurement and distribution systems
Recording and reporting system enabling outcome assessment
of each and every patient and assessment of the overall programme performance.
Case finding
This may be active, involving a deliberate enquiry of symptoms,
usually a history of a cough of more than 3 weeks duration,
sometimes by means of door-to-door surveys. Passive case finding
relies on patients with symptoms presenting at a clinic. The efficiency of the latter approach critically depends on public health
education, the proximity of the clinic from the patients homes
and the reputation of the clinic in the region. In some regions,
poor people prefer attending private practitioners even though
they can ill afford them, as the state-sponsored centres have a poor
reputation for caring and competence.
It is essential that a regular supply of good-quality drugs is maintained and that these are available to the patients at no cost to
them. Intermittent supplies of drugs are a major cause of treatment failure, the emergence of drug resistance and a loss of public
confidence in the treatment services. Combination preparations,
containing two or more antituberculosis drugs, must only be purchased from manufacturers approved by the WHO, as poorly
formulated preparations may not allow adequate levels of the
drugs to be absorbed, with a risk of treatment failure and the
development of drug resistance.
Supervision of therapy
As a result of the effectiveness of modern short-course therapy,
and the rapid loss of infectiousness, patients with no complicating
factors can be treated as out-patients and pursue normal occupational and social activities. As hospitalization is thus the exception
rather than the rule in many regions, the question of supervision
of therapy must be addressed. This, of the five points of the WHO,
DOTS strategy, is the one that calls for particular care and attention in its planning and application.105,106 While non-compliance
with therapy is one of the major reasons for the global failure to
control tuberculosis, dogmatic assertions on the need for every
dose to be taken in the presence of a qualified health worker may
well add to the problems. In some countries, patients accept a
restrictive discipline of attending regularly for their medicine but
in others this may prove counterproductive. Good results have
been obtained by the use of volunteer supervisors chosen from
the local community as this encourages a relationship between
equals concordance rather than compliance with authority.
Various incentives may enhance adherence to therapy. In one successful programme, patients pay a nominal fee at the commencement of therapy which is reimbursed, with interest, on successful
completion of therapy.107 Supervision strategies must be userfriendly, and must respect the dignity and human rights of the
patient. In this respect, it is important to organize services on the
basis of local attitudes and related factors and not on dogma.108110
50
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DOTS-plus
A necessary addition to the DOTS strategy is the effort to detect
and treat multi-drug resistant tuberculosis (MDRTB) which can be
cured in the majority of cases, even in relatively poor nations, if
the required facilities for diagnosis and supervised treatment are
available. To achieve effective control, the so-called DOTS-Plus
strategy is required,112, and the GPSTB has established a green
light committee to assess and facilitate pilot projects and publishes guidelines for establishing such pilot projects.93,113
Projects being evaluated include those based on empirical treatment regimens and the more costly but more effective ones based
on individualized treatment regimens according to drug susceptibility patterns determined in the laboratory. DOTS-Plus strategies
are in a state of evolution, and up-to-date WHO publications
should be consulted for developments and guidelines. It is important that DOTS-Plus programmes are only introduced in regions
where optimal DOTS strategies are already in place. The establishment of a DOTS-Plus programme at the expense of a DOTS programme can have a detrimental effect on overall tuberculosis
control.
North America
1935
020 years
80
Chicago, USA
1937
3 months
75
Great Britain
1950
1415 years
78
Puerto Rico
1949
118 years
31
South India
1950
All ages
31
Georgia, USA
1950
5 years
14
Illinois, USA
1948
Young adults
South India
1968
All ages
Malawi
1978
All ages
No protection at 7.5-year follow-up but some protection at 15-year follow-up in those vaccinated in infancy.
51
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56.
Tuberculosis
Vaccination strategies
These vary from region to region, and are influenced by the prevalence of tuberculosis and information on the efficacy of the
vaccine in a given region. The WHO recommends that BCG should
be given to all neonates in high-prevalence regions and communities. In view of the risk of BCG-related complications, there has
been debate as to whether the vaccine should be used in regions
where there is a high incidence of HIV infection. Although there
is a small increase in the incidence of adverse effects of BCG in
children born to HIV-infected women, almost all are mild and in
regions with a high incidence of tuberculosis the benefits of vaccination greatly outweigh any disadvantages. The WHO recommends that BCG vaccination of infants likely to be exposed to HIV
should be based on the risk of tuberculosis. If the risk is high,
neonatal vaccination should be given according to the Expanded
Programme on Immunization schedule but, if the risk is low,
children suspected of being infected with HIV should not receive
BCG. In addition, no individuals with symptomatic HIV disease
should be vaccinated with BCG.117
52
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References
Ongoing research
To improve the treatment outcomes of tuberculosis, research led
by a number of international organizations and academic institutions is now leading to the discovery of new drug compounds,
immunotherapeutics, immune markers of disease, diagnostics and
vaccines. The revised Global TB control Plan of the WHO Stop TB
Partnership, announced in March 2006, has six elements, the sixth
of which is enabling and promoting research for new tools and programme performance.119 Current UNDP/UNICEF/World Bank/WHO
Special Programme in Research and Training, Scientific Working
Group recommendations120,121 for priority research into tuberculosis are grouped into several areas:
1. Improved diagnostics tuberculosis122
2. Improved clinical management of tuberculosis in HIV-positive
and HIV-negative individuals
3. Social, economic and behavioural research and the global
tuberculosis agenda
4. Immunopathogenesis and vaccine studies
5. Operational and implementation research
CONCLUSIONS
There can be no doubt that tuberculosis ranks among the leading
causes of morbidity and mortality in the tropics. This is a tragedy
as the therapy for tuberculosis is among the most effective and
cost-effective of all treatments for life-threatening conditions. The
incidence of the disease declined rapidly in the industrially developed countries during the late nineteenth and twentieth centuries
and this led to the false assumption that it would do likewise in
other parts of the world. Too much emphasis was, however, placed
on the concept of the development of population immunity a
very dubious proposition and not enough on the very many
public health innovations, often introduced only after intense
advocacy, that contributed to the decline of tuberculosis in the
industrially developed countries. Tuberculosis is a disease of
poverty, and the fact that it is both preventable and treatable, and
that it has been reduced to a shadow of its former self in many
resource-rich countries, attests to the fact that a rectification of the
gross inequities and injustices that deny the poor ready access to
treatment will play a crucial role in the eventual conquest of this
affliction.
Despite the threats of HIV and extreme drug resistance, there
are grounds for optimism as encouraging changes are underway.
In the era of globalization, it has become abundantly clear that
global health is a local issue and that, in the face of infectious
disease, no one is safe until all are safe. It is also clear that the
epidemic of new tuberculosis, fuelled by HIV and multi-drug
resistance, could have the most catastrophic social and economic
impacts from which no part of the globe will be immune. Urgent
action is required, not just to implement the WHO DOTS strategy
worldwide but to develop novel therapeutic agents and vaccines
for the prevention of both tuberculosis and HIV disease. The goal
of halving the incidence and prevalence of, and deaths due to,
tuberculosis by the year 2015 is not unrealistic, although it calls
for a massive response to the public health challenges in countries
with a high burden of HIV disease and a serious resolution by the
global community to make poverty history.
ACKNOWLEDGEMENTS
We would like to thank the following for use of their illustrations:
Professor Sebastian Lucas (Pathology), Dr Jonathan Richenberg
(Radiology) and Dr Peter Mwaba (Clinical).
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Pratt RJ, Grange JM, Williams G. Tuberculosis: A Foundation for Nursing and
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Raviglione MC. Reichman and Hershfields Tuberculosis. A Comprehensive, International
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