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Section 8 Bacterial Infections


Chapter 56 John M. Grange and Alimuddin I. Zumla
Tuberculosis
Tuberculosis is among the most widespread and serious of all
human infectious diseases. Owing to widespread poverty, inequity
and conict, suboptimal health services in many countries and
the impact of the HIV/AIDS pandemic, there are more cases of
tuberculosis today than at any previous time in human history
and 95% of all cases, and 98% of deaths due to it, occur in
tropical countries. The World Health Organization (WHO) became
so concerned about the relentless spread of tuberculosis through-
out the world that it declared this disease a Global Emergency in
1993. Tuberculosis has aficted the human race since the dawn
of recorded history and several ancient descriptions of the disease
exist. Many names have been given to this disease and some are
still in use today (Table 56.1). Skeletal changes typical of tuber-
culosis have been seen in Egyptian mummies and in Neolithic
skeletons in Europe and there is compelling evidence that the
disease occurred in the indigenous populations of the American
continent long before the arrival of European explorers and set-
tlers. The WHO has estimated that, unless tuberculosis control is
strengthened, one billion people will be infected with the tubercle
bacillus, 200 million people will develop clinical tuberculosis and
35 million will die from it over the next 20 years. Tuberculosis is
the biggest curable infectious killer of adolescents and young
adults and is responsible for one in four preventable deaths in this
age group world wide. Although the incidence of tuberculosis
declined greatly during the twentieth century in the industrially
developed nations, these nations are now experiencing an upsurge
of this disease. Multi-drug resistant tuberculosis (MDRTB) has
become a major problem in several regions throughout the world
and in some countries extensively resistant forms of the disease
(XDR-TB) have emerged and raise the very serious threat of
untreatable disease.
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
members of which are obligate pathogens of mammals and are
thus distinct from almost all other mycobacteria, of which there
are over 100 ofcially recognized and named species. Other
named species within this complex are M. canetti, a rarely encoun-
tered strain that produces smooth colonies on culture medium,
M. microti, a rare cause of tuberculosis in small mammals but of
very low virulence in humans, M. pinnepedii, the cause of tuber-
culosis in seals and seal handlers and M. caprae, a variant of M.
bovis isolated from goats and, occasionally, humans. Although
differing in several respects, especially in their host ranges, all
species in the Mycobacterium tuberculosis complex are very closely
related, differing in their genomic DNA sequence by less than
0.1% and are therefore really variants of a single species. The vari-
ants have arisen more by devolution than evolution, principally
by the loss of units of DNA termed Regions of Difference (RD)
from a common progenitor type, M. prototuberculosis, which was
probably very similar to M. canetti.
1
Until recently, it was thought that strains of M. tuberculosis were
very similar in their pathogenicity and virulence, but ngerprint-
ing (p. ) has revealed several lineages, superfamilies or clades
(e.g. Haarlem, Beijing, Somali, Indo-Oceanic, Central Asian)
which, certainly in the mouse and probably in humans, differ in
their virulence and growth rate in macrophages, the immune
responses required for overcoming the disease, and the ability of
BCG vaccination to afford protection against them. It has been
postulated that the various lineages have arisen by adaptation to
the local human population, in which they may cause more severe
disease than in genetically less related populations.
2
One lineage,
though, the Beijing (or W/Beijing) lineage, is a cause for concern
as it is spreading worldwide and it appears to be more virulent
than other lineages and less likely to lose some virulence on muta-
tion to multi-drug resistance.
3,4
Tubercle bacilli are aerobic, non-motile, non-sporing, usually
slightly curved rods 24 m in length and 0.30.5 m in diame-
ter. In common with other mycobacteria, they retain arylmethane
dyes on treatment with mineral acids, a property termed acid-
fastness. This property is widely used to detect mycobacteria in
clinical specimens by light microscopy after staining by the Ziehl
Neelsen method (Figure 56.2) or by uorescence microscopy.
Tubercle bacilli grow slowly on conventional solid culture media
and colonies take from 2 to 6 weeks to appear. More rapid auto-
mated culture systems and nucleic acid-based detection systems
are now available (see p. ).
1
2
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56. Tuberculosis
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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 tubercu-
losis 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 intesti-
nal 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 nger-
printing has shown that many cases, particularly among immuno-
suppressed 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
Table 56.1 Historical clinical descriptions of tuberculosis
Description 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
Hydrocephalus (acute or infantile) 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.
A
B
Figure 56.2 (A) ZiehlNeelsen staining of a sputum sample and
(B) a bronchoalveolar lavage washing showing acid-fast bacilli.
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life-long immunity. As a general rule, 25% of persons infected
develop clinically evident primary tuberculosis and a further 2
5% subsequently develop post-primary disease. Little is known of
the early events following initial infection and our limited under-
standing is derived from experimental observations in animals. In
the case of pulmonary infection, the bacilli are initially engulfed
by alveolar macrophages in which they multiply, eventually killing
the cell. Additional blood-borne phagocytic cells, both macro-
phages and polymorphonuclear leucocytes, aggregate around the
focus of infection and form a foreign body granuloma termed the
primary focus or, in the older literature, the Ghon focus. Some bacilli
are transported to the regional lymph nodes (the mediastinal,
paratracheal and, occasionally, the supraclavicular nodes when
the primary focus is in the lung) where secondary lesions develop.
The combination of the primary focus and the local lymphatic
component lymphangitis and lymphadenopathy is termed the
primary complex (Figure 56.5). Bacilli may subsequently enter the
bloodstream and lodge in various organs of the body and cause
the various non-pulmonary forms of primary tuberculosis.
In most cases in which the immune response enables the
primary complex to contain the infection, the lesions become
brotic and may subsequently become calcied but tubercle
bacilli are able to persist within these dormant lesions, and also
possibly in surrounding normal tissue, for years or decades. The
nature of these persisters has generated much speculation. Some
researchers postulate that they are truly dormant until reactivated
by a wake-up call while others suggest that they replicate, albeit
slowly, but are destroyed by immune mechanisms at roughly the
same rate.
In a minority of those infected, overt primary tuberculosis
manifests in a number of ways (Figure 56.6) and local or systemic
spread may occur. Primary foci at the periphery of the lung may
rupture into the pleural cavity, causing a self-limiting pleural effu-
sion or a much more serious empyema. Diseased mediastinal
lymph nodes may rupture into the pericardial cavity, causing
tuberculous pericarditis, or into a bronchus, causing a spreading
endobronchial infection. Enlarged mediastinal lymph nodes may,
particularly in young children, press on the major bronchi, causing
partial or total obstruction and pulmonary collapse, a condition
termed epituberculosis (Figure 56.7). The primary lesion may
progress to tuberculous pneumonia with tissue destruction, espe-
cially when immunity is compromised. Alternatively, it may grad-
ually enlarge to form a circular coin lesion which may progress
to a characteristic post-primary lesion or heal with calcication.
Concentric rings of calcication, resulting from alternating periods
of progression and healing, may be seen. Primary lesions in the
tonsils spread to cervical nodes (Figure 56.8), from which local
and systemic spread may occur.
Haematogenous dissemination following infection leads to
serious, often fatal, non-pulmonary disease, principally involving
the central nervous system, bones and kidneys. Observations in
the pre-antituberculosis therapy era, notably by Wallgren,
6
revealed
a sequence of events, or timetable, of primary tuberculosis, as
shown in Table 56.2. This is only a rough guide and many indi-
vidual variations occur. Young children are very prone to overt
disease following infection but those between the age of 5 years
and the onset of puberty appear to be relatively protected the
safe school age.
Figure 56.3 Primary tuberculous lesion of the skin.
Primary infection
(lung, tonsil, gut or skin)
Lung
Ghons focus
Lymphangitis
Lymphadenitis
= primary complex
Lymph node and/or
lung lesion persists
Resolution
(heals)
Bloodstream
spread
Extensive pulmonary
tuberculosis
Miliary tuberculosis
Organ tuberculosis
Local
spread
Obstruction
of bronchus
Ruptures
into bronchus
Lobar
collapse
TB
bronchopneumonia
Reactivation of
disease due to:
HIV, old age, diabetes,
cytotoxics, steroids,
stress, malnutrition,
malignancies, chronic
liver and renal disease
etc.
Figure 56.4 Natural history and sequelae of tuberculosis infection.
Pathogenesis
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56. Tuberculosis
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Within 38 weeks of initial infection, conversion to dermal
reactivity to tuberculin occurs. Since the introduction of the tuber-
culin skin test by Clemens von Pirquet in the early 1900s, there
has been considerable speculation as to the nature and signi-
cance of positive reactions, particularly their relevance to protec-
tive immunity. It now appears that the dermal induration seen in
a positive reaction is due to tissue oedema resulting from a number
of immune processes, some associated with protection and some
not. Thus a positive test is an indicator of recent or past infection
by a tubercle bacillus or of BCG vaccination but not of the immune
status of the infected person.
Post-primary tuberculosis differs from primary disease in several
important features. It may develop directly from a primary lesion
progressive primary tuberculosis but more often there is a latent
phase of several years or even decades before the disease becomes
apparent. As mentioned above, post-primary tuberculosis may be
the result of either endogenous reactivation of latent foci of infec-
tion or exogenous reinfection. In the case of the lung, post-primary
lesions often develop, for unknown reasons, in the upper regions.
The characteristic feature of post-primary pulmonary tuberculosis
is gross tissue necrosis which, as described below, is attributable
to inappropriate immune responses. As a result, large lesions
containing abundant necrotic tissue develop and, as they radio-
logically resemble tumours, they are termed tuberculomas. The
necrotic tissue has a cheese-like appearance and is thus termed
caseous material, while the process is termed caseous necrosis or
caseation.
The centre of the tuberculoma is anoxic and acidic and is a
hostile environment to tubercle bacilli, so that relatively few viable
bacilli are present. The caseous material is softened and eventually
liqueed by proteases secreted by activated macrophages. The
enlarging tuberculoma may eventually erode into a bronchus so
that the softened caseous material is discharged into the bronchial
tree and a cavity a characteristic feature of post-primary pulmo-
nary tuberculosis is formed. The environment in the cavity is
quite different from that of the closed tuberculoma. Air enriched
with carbon dioxide enters the cavity, neutralizing the acidity and
providing oxygen for the tubercle bacilli which are then able to
replicate freely and huge numbers line the cavity well.
A
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.
Table 56.2 The timetable of primary tuberculosis
Stage Duration Features
1 38 weeks The primary complex develops.
Conversion to tuberculin positivity
occurs
2 About 3 months Life-threatening forms of disease due
to haematogenous dissemination
occur, i.e. tuberculous meningitis
and miliary tuberculosis
3 34 months Tuberculous pleurisy may be the
result of either haematogenous
spread or direct spread from an
enlarging primary focus
4 Up to 3 years This stage lasts until the primary
complex resolves. More slowly
developing extrapulmonary lesions,
particularly in the bones and joints,
may appear
5 Up to 12 years Genitourinary tuberculosis may occur
as a late manifestation of primary
tuberculosis
Adapted from Wallgren and Ustvedt.
6,52
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5
Figure 56.6 (AC) The complications and sequelae of primary pulmonary tuberculous lesions.
Pathogenesis
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56. Tuberculosis
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When bacilli gain access to the bronchi and are expectorated
in the sputum, the patient becomes infectious and is said to have
open tuberculosis. Bacilli escaping from the cavities may infect
other parts of the same and the other lung by endobronchial
spread. A typical radiological appearance of post-primary
pulmonary tuberculosis is of one or more apical cavities and
numerous smaller lesions in the other lung elds (Figure 56.9).
Bacilli in the sputum may also lodge in the larynx, causing tuber-
culous laryngitis, or may be swallowed and cause indurating ulcers
in the intestinal tract and, rarely, anal stulae. In contrast to
primary tuberculosis, the post-primary lesions are usually so
walled off by brosis that lymphatic and haematogenous dis-
semination of disease is unusual. Both cavity formation and the
localization of disease are due to immune processes and, as
described below, are compromised in immunosuppressed
patients.
PATHOLOGY OF TUBERCULOSIS
A wide spectrum of pathological manifestations is seen in tuber-
culosis. The initial host response to infection consists of an
acute inammatory reaction with an inux of polymorphonuclear
neutrophil leucocytes. If this acute inammatory response is
unable to limit the infectious process, a progressive inltration
with macrophages occurs. The macrophages have a pale eosino-
philic cytoplasm and elongated nuclei and as they resemble epi-
thelial cells they are called epithelioid cells. Some macrophages
fuse to form multinucleated Langhans giant cells. A zone of
lymphocytes and broblasts surrounds this compact cellular struc-
ture 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 specic
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 macro-
phages and an inltration of T lymphocytes. The extent and mor-
phological features of the granuloma vary considerably from
person to person so that a wide spectrum of granulomatous reac-
tions is seen in tuberculosis. At one end of this spectrum, charac-
terized by compromised immune responses, there is poor
granuloma formation and extensive areas of tissue necrosis con-
taining 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 inammatory, brin-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 brosis and
Figure 56.7 Progressive primary tuberculosis. Postmortem specimen
of the lungs of a 6-month-old child showing extensive caseous
necrosis, enlarged hilar lymph nodes and numerous tuberculous
lesions throughout the lung elds.
Figure 56.8 Caseating cervical lymph nodes in child with
tuberculosis.
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between mycobacteria, cells of the immune system and their
secreted cytokines. Mild and self-limiting disease is associated
with protective cellular immune responses whereas advanced
disease is associated with immune suppression and inappropriate
cell-mediated hypersensitivity reactions which cause tissue damage
and immunopathology.
HOST IMMUNE RESPONSES TO
M. TUBERCULOSIS
Many factors including host genetics, microbial virulence and dis-
turbances in host immunity (Table 56.3) determine whether infec-
tion by M. tuberculosis is contained or progresses to overt disease,
whether it follows an acute or chronic course and whether lesions
A
B
Figure 56.9 (A) Extensive pulmonary tuberculosis with cavitation.
(B) Postmortem lung showing several cavities and extensive lung
involvement due to tuberculosis.
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
inltrate. (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.
Host Immune Responses to M. Tuberculosis
may eventually calcify. Alternatively, it may soften and enlarge
with individual necrotic foci tending to coalesce, resulting in
large areas of necrotic debris. The surrounding granulomatous
reaction and associated scarring assist in localization of the
infection.
Expression of clinical disease
The variety of clinical presentations of pulmonary tuberculosis
seen in clinical practice reects a complex series of interactions
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56. Tuberculosis
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are localized or widespread.
7
There is a constant battle between
the various immune defence mechanisms of the host and strate-
gies developed by the pathogen for evading these mechanisms.
Although in recent years much light has been shed on what is
clearly a very complex interplay of specic and non-specic
immune phenomena in tuberculosis, the reasons why the immune
system in most people is capable of preventing active disease but
is not capable of clearing the infection are not fully understood.
Many basic questions remain unanswered regarding the host-
organism interactions:
1. What are the mechanisms of protective immunity to M.
tuberculosis?
2. Why do only a small proportion of people who are infected
go on to develop clinical disease?
3. In those who develop disease, why does tuberculosis manifest
as a spectrum of clinical forms?
4. Why can mycobacteria survive for such long periods of time
in host tissues?
5. Why do some patients with apparently normal immune
systems develop disease?
Both non-specic and specic effector mechanisms appear to play
a role in protective immunity to tuberculosis.
Non-specic immune effector mechanisms
When M. tuberculosis bacilli are inhaled they pass through the
upper and lower respiratory tract and reach the alveoli, where
initial infection occurs. The mycobacteria are phagocytosed by
alveolar macrophages, phagocytosis being facilitated by surfactant
apoprotein A. This initial interaction can result in destruction of
the organism or persistence and replication of the organism within
the macrophage.
Protective cell-mediated immunity and
immunopathology in tuberculosis
It is now recognized that killing of mycobacteria in humans is a
manifestation of cell-mediated immunity rather than antibody
production and that helper T lymphocytes are of crucial impor-
tance in the induction of such protective immunity. Although
antibody responses to M. tuberculosis antigens occur, their role in
protective immunity, if any, is unclear. As well as mediating pro-
tective immunity, it has long been recognized that T lymphocytes
may also mediate harmful tissue-destroying hypersensitivity reac-
tions that favour progression of disease. The paradox of a single
type of cell mediating such different immune phenomena was
resolved by the discovery that T helper cells mature along at least
two different pathways to produce populations of Th1 and Th2
lymphocytes. The Th1 and Th2 lymphocyte subsets produce or
induce quite different cytokines termed, respectively, type 1 and
type 2. The former include the interleukins IL-2, IL-12 and
interferon-gamma (IFN) and the latter include IL-4, -5, -6,
-10 and -13.
Studies on animal models and humans show that type 1 cyto-
kines are responsible for the activation of macrophages and gran-
uloma formation. IFN plays a major role in the activation of
macrophages, the principal effector cells in the killing of myco-
bacteria. Macrophage activation also requires vitamin D, which
explains the higher incidence of tuberculosis in those with low
levels of this vitamin, a phenomenon seen particularly in vegetar-
ians a few years after migrating from sunny countries to more
gloomy and dismal environments, such as the UK.
8
Factors con-
tributing to the aggregation of activated macrophages and other
cells into the compact structure termed the granuloma are not
clearly dened but animal models show that cytokines play a
prominent role. In tuberculosis, the type 1 cytokines IL-2 and IFN
and also tumour necrosis factor alpha and beta (TNF and TNF)
are essential for granuloma formation.
By contrast, type 2 cytokines are, directly or indirectly, associ-
ated with impaired granuloma formation. Also, a Th2 response
appears to lead to the gross tissue necrosis that is so characteristic
of tuberculosis, particularly the post-primary type. If mice are pre-
immunized so that they have a mixed response that is mostly Th1
but includes a Th2 component they are more susceptible to the
disease than are non-immunized controls. Although TNF is
essential for granuloma formation, in the presence of even small
amounts of type 2 cytokines it has the opposing property of
causing the tissue damage. An excess of TNF appears to account
for several symptoms of tuberculosis, including fever, lassitude
and the characteristic wasting (consumption or cachexia) and an
older name for TNF is cachectin. Evidence that these symptoms
Table 56.3 Factors affecting susceptibility to tuberculosis
Age Extremes of age: below the age of 5
years, and old age
Geographical origin Asians, Africans, North American Indians
Immune suppression HIV infection
Protein-calorie malnutrition
Steroid therapy
Cytotoxic drugs
Congenital immunodeciencies
Vitamin D deciency
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 HLA-DR allele, NRAMP gene, vitamin D
receptors
Stress Excess corticosteroid production
Environmental factors Exposure to populations of environmental
mycobacteria
Mycobacterial factors Strain variation in virulence
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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may indeed depend on TNF in human tuberculosis has come
from the experimental use of thalidomide, which decreases the
half-life of the mRNA for this cytokine. Patients treated with
thalidomide show rapid symptomatic relief and weight gain.
Thus, depending on the pattern of cytokines generated by the
immune responses in tuberculosis, TNF has the opposing effects
of aiding protective granuloma formation and mediating harmful
immunopathological phenomena.
There is some evidence that other mechanisms contribute to
protective immunity in tuberculosis, including CD8+ cytotoxic T
lymphocytes, / T cells and natural killer (NK) cells. These may
protect by causing programmed cell death, or apoptosis, of infected
macrophages, a process accompanied by metabolic changes that
destroy at least some of the contained bacilli.
Factors determining the nature of the immune
response in tuberculosis
The ndings that the immune responses, protective or harmful,
are determined to a major extent by the Th1 and Th2 responses
raise the question of which factors regulate the patterns of T lym-
phocyte maturation. Although details are far from clear, hormonal
and environmental factors appear to have key roles.
Hormonal factors in tuberculosis
Before the age of 5 years, children are highly susceptible to tuber-
culosis but they tend to develop consolidation and pneumonia,
without cavitation or caseous necrosis. Between the ages of 5 and
10 (i.e. during adrenarche) children appear to be resistant to the
disease in spite of an increasing incidence of tuberculin test posi-
tivity indicative of continuing exposure to infection in this age
group. This interval between the ages of 5 and 10 was known as
the safe school age in nineteenth-century Europe, and the phe-
nomenon is currently observed in high-incidence areas such as
Cape Town, South Africa. Susceptibility returns at puberty, but the
type of disease now resembles that seen in adults, with typical
cavitation and necrosis. These temporal changes suggest an under-
lying endocrinological cause. A reasonable hypothesis, for which
there are supportive animal data, is that the three periods corre-
spond to age-related changes in the ratio of cortisol to the anti-
glucocorticoid hormone, dehydroepiandrosterone (DHEA).
9
In
this context, there is evidence that a preponderance of cortisol,
relative to DHEA, is able to induce a drift of T lymphocyte
maturation towards the Th2 type. Excess cortisol production is a
feature of stress and this may account for the many reports in the
older literature of a link between stress and a higher risk of active
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 efcacy
of BCG vaccination (p. ). Recent observations suggest that envi-
ronmental mycobacteria and related species modify immune
responses by activating Toll-like receptors (TLRs): a group of cell
membrane proteins that bind to certain commonly occurring
microbial components, termed adjuvants.
10
Activation of TLRs
plays a key role in the maturation and correct functioning of the
various cells that process epitopes and present them to the rele-
vant T cell populations, thereby determining the subsequent
maturation pathways of the T lymphocytes. This raises the pos-
sibility of using bacterial or synthetic adjuvants to modify the
pattern of immune responsiveness in tuberculosis and possibly
other diseases for therapeutic purposes.
11
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 antimyco-
bacterial 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 determi-
nants 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, sur-
vival of mycobacteria depends principally on their ability to
inhibit phagosome maturation and to block phagosome-
lysosome 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 associ-
ated 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,
Epidemiology of Tuberculosis
3
Ch056-X4470.indd 9 7/21/2008 3:45:36 PM
56. Tuberculosis
10
around 2000 million people, are infected by tubercle bacilli. The
percentage of the population infected varies from region to region:
in Western Europe, around 11% are infected, mostly elderly
persons, while in some tropical countries over half may be infected,
including a much higher proportion of younger people.
Infection is spread predominantly by those with open, cavitat-
ing, post-primary pulmonary tuberculosis. Thus those positive on
microscopy are much more likely to be infectious than those who
are negative. Only a small minority of children are infectious. The
number of persons infected by a source case is termed the conta-
gion parameter. On average, an untreated source case infects
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
Pacic 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 treat-
ment 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.
MOLECULAR EPIDEMIOLOGY
OF TUBERCULOSIS
Until about a decade ago, the only bacterial markers available to
study the epidemiology of tuberculosis were drug susceptibility
proles and bacteriophage types. In recent years, a number of
methods have been introduced to ngerprint tubercle bacilli.
16

The most widely used DNA ngerprinting technique is restriction
fragment length polymorphism (RFLP) analysis which relies on
the presence of several copies of insertion sequences (jumping
genes) in the genome of M. tuberculosis. The most commonly used
insertion sequence is IS6110 which is almost specic for M.
tuberculosis and is present in most but not all isolates, with up to
25 copies throughout the chromosome. The mycobacterial DNA
is extracted and then cleaved with restriction endonucleases, and
subsequent electrophoresis and hybridization with labelled
IS6110 DNA probes gives a series of bands, the number and posi-
tion of which distinguishes between different strains.
This technique forms the basis of what is now termed the
molecular epidemiology of tuberculosis and has been used to
determine routes of transmission in a community, to understand
the dynamics and clustering of specic outbreaks of tuberculosis,
to determine to what extent new cases are due to endogenous
reactivation or exogenous reinfection, to study the characteristics
of MDRTB outbreaks in conjunction with the determination of
drug resistance patterns and to detect multiple infections in a
single patient. On a global scale, it has been used to delineate
families or clades of M. tuberculosis that appear to differ in viru-
lence. As mentioned above, the Beijing lineage, which is spreading
globally, appears to be of relatively high virulence.
Although RFLP analysis based on IS6110 is the standard typing
method for M. tuberculosis, it is technically laborious and requires
large quantities of high-quality genomic DNA. Several alternative
typing methods are in use, including spacer oligonucleotide typing,
or spologotyping for short, which, being PCR based, may be con-
1. Blocking uptake mechanism
(a) Via Mannose receptor
(b) Block Ca
2+
signalling by complement receptor
2. Resistance to
killing
(a) Tough cell wall
(b) Superoxide dismutase
(c) Free radical scavengers
6. Increased
T cell
apoptosis
(a) IL-10
(b) IL-6
(c) Fas
LAM
3. Alterations to vesicles
(a) Failed maturation
(b) Blocked proton pump
(c) Altered fusion pattern
5. Control cell signalling
(a) Activate phosphotyrosine
phosphatase (SHP-1)
(b) Block signalling via IFN receptors
(c) Block class II expression and
antigen presentation
4. Block
apoptosis
Complement
receptor
H
+
Receptor
IFN
Macrophage
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.
Ch056-X4470.indd 10 7/21/2008 3:45:37 PM
11
ducted directly on clinical samples. This is based on a structurally
unique part of the mycobacterial genome, of unknown function,
termed the direct repeat (DR) locus and consisting of repetitive 36
base pair (bp) units of DNA separated by non-repetitive 3441 bp
spacer oligonucleotides which can be amplied by PCR employing
just one pair of primers. There are thousands of possible combina-
tions of these oligonucleotides in the M. tuberculosis complex,
providing a highly discriminative typing system.
17
IMPACT OF THE HIV/AIDS EPIDEMIC
Over the last quarter of a century, the epidemiological trends of
tuberculosis have been adversely affected by the HIV/AIDS pan-
demic and infection by HIV is now the most important predispos-
ing factor for the development of active tuberculosis.
18
While, as
described above, a non-immunocompromised person who has
overcome the primary infection has about a 5% chance of devel-
oping post-primary tuberculosis later in life, the chance rises to
50% in an HIV-positive person. The annual risk of a person co-
infected with the tubercle bacillus and HIV developing tuberculo-
sis is around 50 times higher than in an HIV-negative person. The
chance of an HIV-positive person developing tuberculosis after a
primary infection or reinfection is very high, especially in those
with AIDS, in whom the risk approaches 100%. In addition, the
progression from infection to overt disease is very rapid, the time-
scale being telescoped from several years to a few months. These
factors have led to a number of explosive mini-epidemics of
tuberculosis in centres caring for AIDS patients.
At the end of 2006, there were an estimated 39.5 million HIV-
positive persons worldwide; 4.3 million had been newly infected
in that year and 2.9 million died. In 2004, an estimated 741 000
of the 8.9 million new cases of tuberculosis, and 248 000 of the
1.7 million who died of tuberculosis were co-infected with HIV.
Tuberculosis is the single most prevalent cause of death in those
infected with HIV and kills at least 11% and, in some regions,
possibly as many as 50% of AIDS patients.
15,18
At present, the
greatest impact of HIV-related tuberculosis is felt in sub-Saharan
Africa, where 70% of the worlds cases occur and where, in many
regions, 75% of adults and children with tuberculosis are co-
infected with HIV and where the number of cases of tuberculosis
is rising by 4% each year. This dual infection is having a devastat-
ing effect on health services and on societal structure in this region.
In Zambia, for example, one in four pregnant women is infected
with HIV and tuberculosis is now among the top non-obstetric
causes of maternal death in that country.
19
Countries with a high burden of HIV disease often lack facilities
for making signicant impacts on the control of tuberculosis. In
2005, only four of the 25 countries with the highest HIV preva-
lence achieved targets for treatment outcomes under the WHO
DOTS strategy (p. ) for tuberculosis control. In African countries
with a high prevalence of HIV infection, only one in three tuber-
culosis patients receives a full course of antituberculosis therapy.
Until there is a much greater implementation of the effective and
cost-effective DOTS strategy together with key HIV prevention and
treatment measures, it is unlikely that the countries with a high
prevalence of HIV infection will be able to make a signicant
impact on the incidence of HIV-related tuberculosis.
20
A huge potential public health problem is posed by the rapid
spread of HIV infection in Asia where, owing to the huge popula-
tion, most of the worlds cases of tuberculosis occur. Unless the
spread of HIV is checked by public health measures or by the
advent of effective vaccination or therapeutic strategies, the prob-
lems currently facing Africa will be experienced on a much greater
scale in those regions.
IMPACT OF DRUG AND
MULTI-DRUG RESISTANCE
Effective control of tuberculosis is threatened by the emergence of
strains of M. tuberculosis resistant to one or more of the standard
Table 56.4 The estimated incidence, prevalence and mortality of tuberculosis, 2004
INCIDENCE
PREVALENCE MORTALITY ALL FORMS SMEAR-POSITIVE
WHO region Number
thousands
(% of global
total)
Per 100 000
population
Number
thousands
Per 100 000
population
Number
thousands
Per 100 000
population
Number
thousands
Per 100 000
population
Africa 2573 (29) 356 1098 152 3741 518 587 81
The Americas 363 (4) 41 161 18 466 53 52 5.9
Eastern
Mediterranean
645 (7) 122 289 55 1090 206 142 27
Europe 445 (5) 50 199 23 575 65 69 7.8
South-east Asia 2967 (33) 182 1327 81 4965 304 535 33
Western Pacic 1925 (22) 111 865 50 3765 216 307 18
Total 8918 (100) 140 3939 62 14 602 229 1692 27
Data from WHO.
15
Impact of Drug and Multi-drug Resistance
4
Ch056-X4470.indd 11 7/21/2008 3:45:37 PM
56. Tuberculosis
12
No estimate
024
2449
5099
100299
300 or more
A
No estimate
04
519
2049
50 or more
HIV prevalence in new
TB cases, all ages (%)
B
Figure 56.12 (A) Estimated TB incidence rates, 2006 (all forms). (B) Estimated HIV prevalence rates in new TB cases, 2006.
Ch056-X4470.indd 12 7/21/2008 3:45:37 PM
13
antituberculosis agents
18
(Table 56.5). There are two types of resis-
tance, initial or primary and secondary or acquired, with quite
different epidemiological signicance. Initial resistance is due to
infection by a strain that is already resistant while acquired resis-
tance 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
Difcult 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 antitubercu-
losis 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 formu-
lation can reduce the bioavailability of the component drugs.
By denition, tuberculosis caused by strains resistant to rifam-
picin 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 inci-
dence 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 rela-
tive 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 coun-
tries. 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
termed extensive or extreme drug resistant tuberculosis (XDRTB).
23

On denition is MDRTB (resistance to rifampicin and isoniazid)
plus resistance to any uoroquinolone, plus to at least one of the
following drugs: kanamycin, amikacin and capreomycin. Although
occurring in many countries, such extreme resistance was high-
lighted 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 Any form of resistance Poly-resistance (two or more drugs) 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
Central African Republic 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
India (Tamil Nadu State) 24.1 13.4 7.1
Sierra Leone 27.7 8.7 2.6
Estonia 40.8 26.8 15.1
Data from WHO 2004.
21
Impact of Drug and Multi-drug Resistance
5
Ch056-X4470.indd 13 7/21/2008 3:45:38 PM
56. Tuberculosis
14
these 53 (44 HIV positive) had XDRTB. Despite anti TB therapy
including concomitant antiretroviral agents, all except one died
within a few weeks of diagnosis.
FACTORS AFFECTING DYNAMICS OF
TUBERCULOSIS IN POPULATIONS
An epidemic wave of tuberculosis in England began in the six-
teenth century and reached its peak around 1780, at the time of
the Industrial Revolution. Similar peaks were seen in Western
Europe in the early 1800s and in Eastern Europe around 80 years
later. This wave pattern has led some workers to propose that the
disease rapidly rises to epidemic proportions in genetically sus-
ceptible populations and declines as a more resistant population
develops by natural selection. There is, in fact, very little evidence
for such a selection. Although a number of genetic factors affecting
resistance to tuberculosis have been described, these appear much
less important than environmental ones in determining the prev-
alence of the disease in a community.
24
The decline in the inci-
dence of tuberculosis in the industrially developed nations is
more likely to have been due to socioeconomic factors than to
evolutionary selection. In this context, however, the inverse rela-
tionship between the incidence of tuberculosis and the improve-
ment of social conditions is by no means straightforward. While
some workers claim that the decline in the incidence of tubercu-
losis is a natural and predictable consequence of better nutrition
and living and working conditions, others argue that the decline
is the cumulative result of many specic public health measures
introduced only after intense political lobbying.
25
The distinction
is a crucial one as proponents of the rst view claim that tubercu-
losis will decline as socioeconomic conditions improve worldwide
while those holding the second view stress the need for specic
tuberculosis control measures and health advocacy.
RISK FACTORS FOR TUBERCULOSIS
The principal factors predisposing to tuberculosis are listed in
Table 56.3. In recent years, HIV infection has, as described above,
emerged as the most important and widespread risk factor for the
development of active tuberculosis. Other infections such as
measles, whooping cough and chronic malaria and causes of lung
damage, such as exposure to silicon and other industrial dusts, are
also risk factors. Smoking has clearly been shown to be a major
risk factor. An extensive retrospective study in India has shown
that men who smoke are between four and ve times more likely
to develop tuberculosis than non-smokers and that, in that
country, smoking accounts for 200 000 deaths from tuberculosis
each year, many victims being young men (most Indian women
are too sensible to smoke).
26
Other predisposing conditions are those that compromise
immune responsiveness and include malnutrition, alcoholism
and other substance abuse, diabetes, renal failure (particularly if
haemodialysis is required), treatment with immunosuppressive
drugs and steroids (see below), liver failure and cancers, especially
haematological malignancies. Transmission of infection is facili-
tated by overcrowding, poor ventilation and low levels of ultra-
violet light conditions frequently linked to poverty.
Tuberculin reactivity
Tuberculin reactivity is a risk factor for the development of tuber-
culosis 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 reac-
tions imply increased risk, though considerable regional varia-
tions in the risk in relation to reaction size occur.
Immunosuppressive drugs and steroids
Patients receiving post-transplant or other immunosuppressive
therapy are prone to develop tuberculosis which is often insidious
in onset, and miliary or cryptic disseminated forms of the disease
(p. ) are common. Prophylaxis against tuberculosis should be
considered, particularly for tuberculin negative patients who
receive an organ from a tuberculin positive donor. Disease due to
environmental mycobacteria (Chapter 57) is also common in
these patients and poses diagnostic difculties. There is a wide-
spread belief that treatment with steroids predisposes to tubercu-
losis although the evidence for this is weak. Nevertheless, isoniazid
chemoprophylaxis for 1 year is recommended for patients on long-
term steroid therapy with one or more of the following: a history
of inadequately treated tuberculosis, an abnormal chest radio-
graph, a tuberculin reaction of 10 mm or more in diameter and
recent exposure to a tuberculosis patient.
27
Age and sex
As outlined above, children up to the age of 5 years are highly
susceptible to tuberculosis, especially miliary tuberculosis and
tuberculous meningitis, but those between the age of 5 years and
the onset of puberty appear relatively resistant. In developing
countries the great majority of cases occur between the ages of 15
and 59 years. Surveys in several countries show that more males
than females are diagnosed with tuberculosis but it is not clear
whether this is affected by gender-related differences, lifestyle
factors such as smoking or ability to access healthcare. Studies on
the effect of pregnancy on tuberculosis are confusing, with reports
variously claiming no effects, protective effects or a worsening of
the disease.
28
Yet other reports suggest protection during preg-
nancy but an exacerbation after delivery a phenomenon also
observed in leprosy. This subject is in urgent need of investigation
as tuberculosis is a major cause of death of pregnant women in
sub-Saharan Africa, being responsible for more loss of life than
obstetric complications.
16
The added impact of HIV infection on
pregnancy-related mortality due to tuberculosis is also poorly
understood.
CONTACT TRACING AND EXAMINATION
Most tuberculosis is spread within households, although mini-
epidemics occur in schools, prisons, hospitals and other situa-
tions where people at risk are crowded together. Household
contacts of smear-positive patients should be examined: screening
of casual contacts only yields a further 1% of cases and is usually
not justied. Although children with primary tuberculosis are
rarely infectious, household screening will often reveal a sputum-
6
Ch056-X4470.indd 14 7/21/2008 3:45:38 PM
15
positive source case. Procedures for contact tracing vary according
to local facilities and the prevalence of tuberculosis in the com-
munity. Tuberculin testing is useful in young children and, when
indicated, chest radiography.
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 investiga-
tions. The following investigations help to conrm 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 aspi-
rates and brushings, gastric aspirates, pleural, peritoneal and
pericardial uids, cerebrospinal uid (CSF), blood, bone
marrow and tissue aspirates or biopsies.
2. Imaging techniques including radiology, ultrasound, computed
axial tomography (CAT) scanning, magnetic resonance imag-
ing (MRI) and radioisotope scans.
3. Molecular techniques utilizing nucleic acid amplication sys-
tems the polymerase chain reaction (PCR) and related
techniques.
4. Haematological and biochemical investigations such as haemoglo-
bin levels, erythrocyte sedimentation rate (ESR) and liver
function tests may be required in overall patient manage -
ment 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 frus-
trating challenges in tuberculosis management has been the lack
of a specic, 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
could be corrected by better implementation of existing standards
of clinical and laboratory practice. The World Health Organization
(WHO) and its member states have made great gains in the
expansion of the DOTS (Directly Observed Treatment, Short
course) strategy to control tuberculosis, with an important rise in
rates of cure. Improving case detection rates has proven more dif-
cult, in large part because of limitations of existing diagnostic
technologies. As many as 3 million cases of tuberculosis each
year present as sputum smear-negative pulmonary disease and
extra-pulmonary disease, for which sputum smear microscopy is
inadequate.
As an indicator of the difculty of implementing quality
microscopy services, fewer than 45% of predicted incident smear-
positive cases of tuberculosis are currently detected and notied.
Paediatric and multi-drug-resistant (MDRTB) and extensively drug
resistant (XDRTB) cases pose additional diagnostic challenges not
addressed by sputum-smear microscopy. Diagnostics need to be
driven by the reality of health systems infrastructure; well-engi-
neered, simplied tests are needed at the point-of-care, at district
hospital laboratories, and at central laboratories. Different diag-
nostic strategies sputum concentration methods, uorescence
microscopy, improved mycobacterial culture system also need to
be evaluated for their impact on case detection. Diagnostic algo-
rithms, including the use of empiric antibiotic trials to exclude TB,
need to be carefully reassessed and improved. Implementation
research can also assess the potential of integrating health service
at district and health centre levels as a means of overcoming infra-
structural and manpower impediments to operationalizing case
detection services. Key factors to study include transportation, user
fees, hunger, work and gender discrimination, and other barriers
to accessing care. Better clinical diagnostic algorithms and case
denitions are required for diagnosing tuberculosis in HIV-infected
individuals and children. Thus, precisely in the areas of the world
where microscopy has the poorest performance, the need for new
early detection tests is the greatest. Current diagnostics research
priorities are:
To replace or improve microscopy with a simpler, point-of-care
technology to detect smear-positive tuberculosis
To develop a faster alternative to culture to detect smear-
negative tuberculosis
To develop and evaluate tests for rapid antibiotic susceptibility
testing
To develop tests for detecting latent infection at risk for relapse.
Bacteriological identication
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 magnication. 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
Diagnosis of Tuberculosis
Ch056-X4470.indd 15 7/21/2008 3:45:38 PM
56. Tuberculosis
16
clinic, a second one collected by the patient early on the following
morning and a third one taken that day on the patients return to
the clinic. The percentage of additional cases diagnosed by exam-
ination of the third specimen varies from centre to centre, from
0.7% to 7.2% in one multicentre study.
31
Decisions as to whether
to collect and examine the extra specimen should therefore be
made on the basis of locally collected data and on the ability of
the laboratory services to cope with the extra work involved.
31,32
Sputum microscopy has the great advantage of speed, often
enabling a diagnosis to be made at the time of the patients rst
attendance. It is, however, not very sensitive although it detects
those who are the most infectious and thus in need of urgent
management. For a standard examination of ZiehlNeelsen-
stained smears to be positive, there must be at least 5000 acid-fast
bacilli in 1 mL of sputum.
If tuberculosis is suspected but no sputum is produced, phys-
iotherapy and the inhalation of nebulized twice normal (hyper-
tonic) saline may yield sputum suitable for examination. Induction
of sputum should be conducted well away from other patients,
especially those who are immunosuppressed, as mini-epidemics
of tuberculosis have followed such practices on open wards.
Laryngeal swabs provide material suitable for culture but not
for direct microscopy. Swabs should only be taken by staff expe-
rienced in visualizing the vocal cords and, as patients usually
cough violently during the procedure, the operator should wear a
gown and a full face visor. Gastric aspiration after overnight fasting
to harvest any swallowed tubercle bacilli is useful in children who
rarely produce sputum. Aspirated material must be either neutral-
ized immediately or transported to the laboratory without delay.
Where facilities permit, breoptic bronchoscopy is an excellent
means of obtaining bronchial washings and brushings and trans-
bronchial biopsies.
33
Pleural, pericardial and peritoneal uids are obtained by needle
aspiration and CSF by lumbar puncture. For culture, portions of
these uids may be added directly to double-strength liquid media
supplemented with suitable antibiotics to suppress the growth of
microorganisms other than mycobacteria.
In some cases, needle or open biopsies of various organs and
tissues are required. Peritoneal biopsies obtained laparoscopically
are preferable to aspirated peritoneal uid for the diagnosis of
abdominal tuberculosis.
Culture
Isolation of M. tuberculosis in culture from the clinical specimen
provides a denitive diagnosis. Cultivation, usually on solid
media, is more sensitive than microscopy and increases the diag-
nostic 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 non-
egg-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 origi-
nal automated systems were based on the detection of radioactive
carbon dioxide released during bacterial utilization of a
14
C-labelled
substrate. In more recent systems oxygen utilization or CO
2
produc-
tion resulting from bacterial growth is indicated by changes in the
colour of dyes or the unquenching of uorescent substances.
34
Radiological imaging
The advantage of a chest radiograph in the diagnosis of tubercu-
losis is that of speed, but the equipment is expensive to obtain,
maintain and operate (see also Chapter 26). Experienced radiolo-
gists are required in order to interpret the often rather non-specic
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 popula-
tions. 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 oper-
ator, it should be universally abandoned.
Radiology is very sensitive although, exceptionally, the radio-
graph may appear normal in patients with smear-positive pulmo-
nary tuberculosis. Although radiology is not specic 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, unilat-
eral or bilateral patchy shadows in any part of the lung elds and
calcication. Conditions mimicking tuberculosis include unre-
solved 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 per-
formed the diagnosis may be difcult 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 reso-
nance imaging (MRI) with appropriate contrast enhancement is
useful in diagnosis and management of space-occupying lesions
in cerebral tuberculosis.
Molecular methods for diagnosis of tuberculosis
Although isolation of the causative organism in pure culture
remains the gold standard for the diagnosis of tuberculosis, this
is laborious in terms of both time and space. In view of the prob-
lems of sensitivity and speed of the conventional bacteriological
diagnostic systems, much effort has been put into developing
novel methods for the amplication of species-specic nucleic
acid sequences, such as the polymerase chain reaction (PCR) and
related techniques
36
(Figure 56.13). Kits are now available com-
mercially and are proving rapid, sensitive and specic in most
circumstances, with sensitivities approaching 100% and specici-
ties from 85% in non-pulmonary samples to 95% for sputum. The
Ch056-X4470.indd 16 7/21/2008 3:45:38 PM
17
use of such kits has been largely restricted to major reference
centres in the industrially developed nations and major reference
centres in tropical countries but their increasing availability in
user-friendly forms should facilitate their more widespread use.
Haematological and biochemical examination
Haematological and biochemical changes in tuberculosis are non-
specic. Blood examination may reveal a raised lymphocyte count,
a raised ESR, elevated C-reactive protein levels and a mild anaemia.
These changes resolve on effective treatment. Serum albumin
levels are sometimes low and there may be mild abnormalities of
liver function. Elevations in the levels of various enzymes in cere-
brospinal, pleural, pericardial and peritoneal uids have been
described but their diagnostic signicance has not been clearly
established.
Antibodies to a range of antigens of the tubercle bacillus are
detectable in tuberculosis but the rather low sensitivity and spec-
icity of serodiagnostic tests, usually based on the enzyme-linked
immunosorbent assay (ELISA) technique, limits their diagnostic
value.
Tuberculin test
This is a standard and widely used diagnostic test but its inter-
pretation is far from straightforward.
37
The test is usually pos-
itive 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 sensi-
tization 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 puried protein derivative of tuberculin (PPD),
the strength of which is expressed in international units (IU).
The principal forms of the test are the Mantoux, Heaf and tine
tests.
Mantoux test
An intracutaneous injection of 0.1 mL of tuberculin (0.05 mL
in infants) is given on the dorsal aspect of the forearm. After 48
or 72 h, the transverse diameter of any palpable induration,
but not the erythema, is measured. In both epidemiological and
diagnostic work the criteria for a positive reaction are determined
by the national tuberculosis programme, taking into account
the type and concentration of PPD used and the degree of
sensitization by environmental mycobacteria. In the UK and
USA responses of 5 mm or more to 1 IU and of 10 mm or more
to 5 IU are, respectively, regarded as positive. In diagnostic
work, smaller reactions are usually regarded as negative, although
they do not exclude tuberculosis because of the conditions men-
tioned above which suppress the response. Conversely, a positive
reaction, for the reasons discussed above, does not necessarily
indicate active disease. Reactions may be due to prior BCG vacci-
nation but a reaction of 15 mm or more in diameter in a vacci-
nated child is a very likely indication of infection by the tubercle
bacillus.
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 aming 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 denite 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 rmly onto the skin so that the tines
Figure 56.13 Diagnosis of tuberculosis by molecular methods: a
Southern blot of PCR products. M, pGem molecular weight markers;
lanes 110, clinical specimens from patients (lanes 1, 2, 7 and 8 are
positive for mycobacterial DNA); lanes 11 and 12 are positive controls
and lanes 13 and 14 are negative DNA controls.
Table 56.6 The grades of reactions of the Heaf test
Grade 0 No reaction
Grade I At least four discrete papules
Grade II Conuent papules forming a ring
Grade III A disc of induration
Grade IV A disc of induration greater than 10 mm in diameter
or vesiculation of the disc
Diagnosis of Tuberculosis
Ch056-X4470.indd 17 7/21/2008 3:45:39 PM
56. Tuberculosis
18
penetrate the skin and held in place for 10 s so that the dried PPD
dissolves in the tissue uids. 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 specicity encountered with tuber-
culin 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 avail-
able diagnostic tests. Increased specicity is achieved by selecting
antigens present in M. tuberculosis but not in BCG or environ-
mental 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 conrmation
of their usefulness and benets 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 chil-
dren (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
Clinical presentations of tuberculosis in children
Many children with primary tuberculosis have no obvious symp-
toms or signs and may go unnoticed for a while. Thus a high index
of suspicion is essential throughout the tropical countries and
other regions where tuberculosis is common. Bacteriological
investigations are usually regarded as being of limited use for the
diagnosis of pulmonary tuberculosis in children since obtaining
sputum samples is more difcult than in adults. Even when spec-
imens are obtained, acid-fast bacilli are only demonstrable in a
minority of cases, especially in regions where facilities for exten-
sive modern bacteriological investigations are not available. Bac-
teriological investigations are essential for the diagnosis of
non-pulmonary disease, especially tuberculous meningitis. In
view of the diagnostic difculties, clinical algorithms have been
developed,
40
and a ow diagram that has been in use for some
time for diagnosis is shown in Figure 56.14.
Primary pulmonary tuberculosis
Clinical features are usually non-specic and include a failure to
gain weight or loss of weight, a lack of energy, a persistent
cough and/or wheeze and an unexplained fever for more than 1
week. A study in Cape Town, South Africa, of children with a
cough of more than 2 weeks duration showed that a persistent
and non-remitting cough and persistent fatigue of recent origin
were sensitive and specic indicators of pulmonary tuberculosis.
41

Persistent fever and chest pain were also specic indicators but
were present in only a quarter of children with tuberculosis. The
tuberculin test is usually positive and the primary focus and/or
enlarged intrathoracic lymph nodes may be seen on X-ray. It is
not uncommon for children with primary pulmonary tuberculo-
sis to have normal chest X-rays, although a computed tomography
(CT) revealed enlarged mediastinal nodes in 60% of such radio-
logically normal children.
42
Gross enlargement of the intrathoracic lymph nodes or endo-
bronchial spread of the disease causes obstruction of the bronchi
and the children present with cough and wheezing. Partial block-
age of a major bronchus may limit exhalation, resulting in hyper-
ination of the lung and clinically detectable mediastinal shift.
Involvement of paratracheal nodes may cause stridor, sometimes
requiring emergency tracheostomy.
Endobronchial spread of the disease process results in a
range of clinical and radiological changes including pulmonary
collapse, consolidation and hyperination and, in severe cases,
widespread bronchopneumonia, particularly in younger children.
In most cases, the lesions resolve clinically and radiologically
on effective treatment although a few are left with residual
bronchiectasis.
Congenital tuberculosis
This is a very rare condition and the mother always has tubercu-
losis, although sometimes in a form that is not clinically or radio-
logically obvious, such as renal tuberculosis.
43
There are two main
types resulting from, respectively, transplacental infection and
aspiration or inhalation of infected amniotic uid.
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. Intratho-
racic 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 demon-
strable by examination of tracheal or gastric aspirates or ne-
needle 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 ery-
thema 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
Ch056-X4470.indd 18 7/21/2008 3:45:39 PM
19
sac. Occasionally corneal ulceration occurs. More usually, the con-
dition 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 calcied primary complexes.
Erythema nodosum also usually occurs in association with primary
tuberculosis and affects a similar age group as phlyctenular con-
junctivitis. It is more common in girls and in those with fair skin.
It is characterized by erythematous, indurated, painful plaques or
nodules, usually on the lower limbs, and may be accompanied by
fever and joint pain. The ESR is raised and, if the cause is tubercu-
losis, the tuberculin test is strongly positive. Resolution usually
occurs within 2 weeks although the skin may remain discoloured
for several weeks. Treatment, other than that of the underlying
condition, is unnecessary, although corticosteroids may be given if
joint pain is severe. The condition is not unique to tuberculosis as
it also occurs in streptococcal infections, sarcoidosis, leprosy, sys-
temic fungal infections, lymphoproliferative disorders and after
treatment with certain drugs, notably sulphonamides.
Tuberculosis in HIV-infected children
HIV infection is increasingly encountered in children as the risk
of an HIV-positive mother transmitting the virus to her child
during pregnancy or at birth is between 24% and 40%, and even
higher if the mother has AIDS. In sub-Saharan Africa HIV-
A
Score
16
Score
7 or more
Start TB
treatment
Not
diagnostic
No
radiograph
Chest
radiograph
? atypical
pneumonia
Poor
response
Poor
response
Different
antibiotic
q.i.d. 7 days
Diagnostic TB
Wide mediastinium
Miliary shadows
Cavity, etc.
High dose
antibiotic
q.i.d. 7 days
Not TB Not TB
Good
response
Good
response
From score sheet A
B
Figure 56.14 (A,B) Paediatric tuberculosis management ow chart.
Tuberculosis in Children
Figure 56.15 Erythema nodosum due to tuberculosis.
Ch056-X4470.indd 19 7/21/2008 3:45:39 PM
56. Tuberculosis
20
associated tuberculosis in childhood has emerged as a major
public health problem.
44
Such dually infected children are highly
susceptible to tuberculosis and forms such as tuberculous menin-
gitis, miliary tuberculosis and widespread lymphadenopathy are
frequently seen. The diagnosis of tuberculosis in children remains
difcult, even in the best centres. Pulmonary tuberculosis is very
common in the tropics and diagnosis is difcult as both the spe-
cic and the non-specic symptoms of weight loss and fever as
well as clinical and radiological signs are similar to those seen in
several common respiratory illnesses and in HIV-related opportu-
nistic infections such as Pneumocystis carinii pneumonia (PCP).
The tuberculin test is often negative. In the absence of sophisti-
cated diagnostic facilities, therapy is based on clinical suspicion
and many children with tuberculosis will be misdiagnosed and
receive no antituberculosis therapy.
POST-PRIMARY PULMONARY TUBERCULOSIS
This is the most common form of the disease seen worldwide and
although sometimes called adult-type tuberculosis it may occur
in adolescents and children. In many cases, pulmonary cavities
communicate with the bronchial tree so that tubercle bacilli enter
the sputum and the patient becomes infectious.
Clinical features
Symptoms related to the lung include cough, mucoid or purulent
sputum, haemoptysis, breathlessness and chest wall pain. More
general and non-specic constitutional symptoms include fever
and sweating (particularly at night), weight loss, general malaise
and anorexia. None of these symptoms are specic 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 ne apical crackles. In more advanced cases
there may be areas of dullness on percussion or localized wheezing.
Clubbing of the nger 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 local-
izing pathology in cryptic sites (Figure 56.2156.23).
Complications
The complications of post-primary pulmonary tuberculosis include
pleural effusion and empyema, pneumothorax or pyopneumotho-
rax due to formation of a bronchopleural stula, tuberculous
laryngitis and indurated intestinal ulcers due to implantation of
tubercle bacilli in swallowed sputum. Occasionally an empyema
or an intercostal node ruptures into the chest wall to form a cold
abscess. Spread to other organs by the haematogenous or lym-
phatic route is uncommon when patients are relatively immuno-
competent, but it is seen in many patients infected with HIV or
with other conditions compromising their immunity. A late com-
plication is chronic obstructive airways disease and cor pulmonale
secondary to extensive pul monary brosis. Other, much rarer, late
complications include aspergillomas (Figure 56.24) developing in
healed cavities and amyloidosis.
Figure 56.16 Chest X-ray showing right lower lobe consolidation
due to tuberculosis.
Figure 56.17 Chest X-ray with extensive patchy consolidation in
the right lung elds. Sputum examination revealed acid-fast organisms
conrmed on culture to be M. tuberculosis.
Ch056-X4470.indd 20 7/21/2008 3:45:39 PM
21
Figure 56.18 Chest X-ray of an HIV-positive patient with cavitating
tuberculous consolidation in the right middle and left lower lung
elds.
Figure 56.19 Post-primary tuberculosis. Right upper lobe
tuberculous consolidation in a 15-year-old HIV-positive patient.
Figure 56.20 Post-primary tuberculosis. Pleural and pericardial
effusions in a 44-year-old HIV-positive patient. M. tuberculosis was
isolated from pleural uid.
Post-primary Pulmonary Tuberculosis
Figure 56.21 CT of the chest showing tuberculous cavity.
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
brotic lung disease secondary to sarcoidosis or industrial dust
disease and pulmonary infarct. Lung cancers, pulmonary amoe-
biasis and abscesses of unresolved pneumonia, especially when
caused by Staphylococcus aureus or Klebsiella pneumoniae, and cysts
of Paragonimus westermanii may appear as cavitating lesions on
chest X-ray. The absence of acid-fast bacilli on microscopy may
suggest one of these other causes and, in the case of unresolved
pneumonia, the causative organisms may be isolated by the
appropriate bacteriological examinations. A therapeutic trial with
a suitable antibiotic(s) may also differentiate tuberculosis from
atypical pneumonia and pulmonary abscesses. The cachexia and
malaise of advanced tuberculosis resemble that seen in AIDS, dis-
seminated cancer and diabetes mellitus.
Management
The management of pulmonary tuberculosis involves prescription
of an appropriate antituberculosis drug regimen, management of
Ch056-X4470.indd 21 7/21/2008 3:45:39 PM
56. Tuberculosis
22
complications, supervision of the patient until the course of
therapy has been completed and active contact tracing. Antituber-
culosis therapy is described on pp. .
TUBERCULOUS PLEURAL EFFUSION
AND EMPYEMA
Pleural effusions occur in both primary and post-primary tuber-
culosis and are due to spread of the disease process from a lesion
in the periphery of the lung or, occasionally, from an intercostal
node into the pleural space. They are more likely to occur in
immunocompromised patients. Effusions may be small and tran-
sitory and due, in part, to a hypersensitivity reaction to antigens
of the tubercle bacillus. In other cases, particularly in older
patients, an empyema develops.
Clinical features
The main clinical features, in addition to those of the underlying
pulmonary disease, are chest pain accentuated by breathing, a dull
ache over the lower chest and breathlessness on exertion. There is
stony dullness on percussion over the lower chest and dimin-
ished air entry on the affected side and, if the effusion is large, the
mediastinum may be shifted to the opposite side.
Diagnosis
On chest X-ray, a small effusion (about 100 mL) causes a blunting
of the costophrenic angle, while larger ones are denser at the base,
tailing up into the axilla (Figures 56.18 and 56.20). Fluid levels are
seen in cases where there is a bronchopleural stula. The diagnosis
of tuberculosis is made by bacteriological examination of aspirated
pleural uid or by histological examination of pleural biopsies
which may show tuberculous granulomas or the presence of acid-
fast bacilli. For bacteriological culture, some of the pleural uid
may be added to an equal volume of double-strength liquid culture
medium at the bedside. Large effusions should be aspirated slowly
as rapid expansion of the lung may cause coughing, breathlessness
and, occasionally, pulmonary oedema. Mycobacterial DNA can be
detected in pleural uid and biopsy samples by PCR.
Figure 56.22 CT scan of the chest showing pleural effusion.
Figure 56.23 CT scan of the chest showing calcied empyema of
old treated tuberculosis.
Figure 56.24 Chest X-ray showing a fungal (Aspergillus) ball in a
tuberculous cavity.
7
Ch056-X4470.indd 22 7/21/2008 3:45:40 PM
23
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 antitubercu-
losis therapy but larger ones may require needle aspiration. Cor-
ticosteroid treatment prevents recurrence of large effusions and
subsequent constrictive brosis which may compromise pulmo-
nary function. Thick empyema uid may be difcult 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 esh 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 tuberculo-
sis. Classically, this was a disease of young children but nowadays
it occurs in those of all ages. The symptoms are non-specic 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 trans-
bronchial biopsy through a breoptic bronchoscope. The tuber-
culin test is usually positive in early cases but becomes negative
as the disease advances.
Characteristic single or multiple tubercles, greyish-white or
yellowish in colour and 0.53 mm in diameter (Figure 56.30),
may be seen on the choroid of the eye. Although not present
in all cases, this is a very useful diagnostic sign and a very careful
examination by ophthalmoscopy should always be undertaken
Figure 56.25 Chest X-ray: miliary tuberculosis. Note enlarged
paratracheal nodes.
Figure 56.26 Miliary tuberculosis. Chest X-ray of an HIV-positive
patient showing extensive bilateral shadowing.
Disseminated Tuberculosis
Ch056-X4470.indd 23 7/21/2008 3:45:40 PM
56. Tuberculosis
24
in cases of suspected miliary tuberculosis and, indeed, in
anyone with an unexplained fever. The differential diagnosis
includes viral or mycoplasmal pneumonia, histoplasmosis and
coccidioidomycosis.
Miliary tuberculosis responds well to antituberculosis therapy
but corticosteroid therapy may be life-saving in seriously ill
patients.
Cryptic disseminated tuberculosis
This form of tuberculosis is common in HIV-positive adults
and children, particularly in the more profoundly immunosup-
pressed, as well as in others whose immune responses are sup-
pressed, or weakened due to old age. In contrast to miliary
tuberculosis, the widespread lesions show very little cellular inl-
tration but consist of minute necrotic foci teeming with acid-fast
bacilli. The lesions are usually too small to be visible on chest
X-ray which is often deceptively normal, hence the name cryptic
disseminated tuberculosis for this form of the disease. The diag-
nosis is often missed as patients present with non-specic features
such as fever, weight loss and anaemia and the tuberculin test is
almost always negative. Many cases are therefore only detected at
autopsy Patients are usually extremely ill on presentation and,
without therapy, rapidly die. Biopsy of the lung, liver or bone
marrow may provide the diagnosis after staining for acid-fast
mycobacteria, culture for M. tuberculosis or identication of myco-
bacterial DNA by PCR.
BONE AND JOINT TUBERCULOSIS
This is the result of haematogenous dissemination of bacilli from
a primary focus and, in the tropics, it is a common manifestation
of tuberculosis in children. Most cases present 6 months to 3 years
after the initial infection. Any bone or joint may be affected but
the most frequent site is the spine, involved in half the cases, fol-
Figure 56.27 Postmortem lung specimen showing miliary
tuberculosis.
Figure 56.28 Miliary tuberculosis involving the spleen.
Figure 56.29 Grouped erythematous papules on the skin of the
face in miliary tuberculosis.
Figure 56.30 Choroidal tubercules.
Ch056-X4470.indd 24 7/21/2008 3:45:41 PM
25
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 dis-
seminated tuberculosis and are easily mistaken for metastatic car-
cinoma.
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 oor is a characteristic sign. Clinical features
may, however, be minimal and non-specic 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.
On radiological examination lesions may be confused with
those of pyogenic osteomyelitis. Features suggesting tuberculosis
include a relative sparing of the disc space, a fragmentary pattern
of bone destruction and large paraspinous abscesses with dense
rims and, in some cases, calcication within them.
46
Radiological
signs may, however, be minimal and give an underestimate of the
extent of the disease and, where available, CT, MRI or radionuclide
bone scans (Figure 56.33) permit a more accurate assessment of
the extent of the disease. Biopsies or ne-needle aspirates,
conducted by those with adequate experience, may establish the
diagnosis. Histological as well as bacteriological examination is
essential as there may be too few acid-fast bacilli in the biopsy
material for them to be detectable microscopically. The tuberculin
test is usually positive although it may be negative in malnour-
ished or immunosuppressed patients.
The differential diagnosis includes bacterial osteomyelitis and
blood tests for staphylococcal and streptococcal infections and for
typhoid, paratyphoid and brucellosis may help to rule these infec-
tions out. Spinal tuberculosis may resemble tumours and care
should be taken not to confuse the combination of opacities on
chest X-ray and osteolytic lesions of the spine with metastatic lung
cancer.
Surgical intervention is required for patients with marked
spinal deformity and severe neurological signs but most patients
can be managed by standard therapy alone.
47
The most effective
form of surgery for correction of deformity and relief or pre-
vention of paraplegia is radical excision of diseased tissue and
anterior spinal fusion the so-called Hong Kong operation. This,
however, calls for surgical skills and resources that are not widely
available.
Tuberculosis of other bones and joints
Tuberculosis of other bones and joints mimics a wide range of
other conditions, especially the various forms of arthritis, and
diagnosis is not easy. Disseminated lesions in many bones may
mimic metastatic carcinoma. Tuberculosis of the skull usually
Figure 56.31 Spinal tuberculosis. Note involvement of two adjacent
vertebrae and loss of joint space.
Figure 56.32 Potts disease of the spine: spinal tuberculosis in a
child showing a visible, palpable lump (gibbus) over the spine. The
nappy was being used for urinary incontinence caused by spinal cord
involvement.
Bone and Joint Tuberculosis
Ch056-X4470.indd 25 7/21/2008 3:45:42 PM
56. Tuberculosis
26
presents with uctuant abscesses (Figure 56.34), sometimes with
sinus formation, and underlying osteolytic lesions a condition
termed Potts puffy tumour. Osteitis is a rare complication of BCG
vaccination in neonates and young children. Diagnosis may
require bacteriological examination of biopsies of bone or
synovium or of aspirated synovial uid.
Unless prevented by pain, joint mobility should be maintained
during antituberculosis therapy. Arthroplasty or other orthopaedic
procedures may be required if there is residual immobility or
deformity. Poncets disease and hypertrophic osteoarthropathy are
rare conditions affecting bones and joints in patients with tuber-
culosis but are thought to be due to immune reactions rather than
the direct result of bacillary invasion. Poncets disease is a form
of polyarthritis which resolves on treatment of the underlying
disease. Hypertrophic osteoarthropathy, characterized by perios-
teal inammation and subperiosteal new bone formation, occa-
sionally occurs in both humans and animals with pulmonary
tuberculosis although it is more usually associated with lung
cancer.
TUBERCULOSIS OF THE CENTRAL
NERVOUS SYSTEM
Tuberculosis of the central nervous system (CNS) is a serious and
life-threatening condition and three main types are encountered
in clinical practice tuberculous meningitis, solitary space-
occupying lesions in the brain or spinal cord and disseminated
miliary lesions.
48
Tuberculous meningitis
This is the most common form of CNS tuberculosis and consti-
tutes 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 inammation, 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 audi-
tory nerves, at the base of the brain and to raised intracranial
pressure due to obstruction to the ow 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 dened below. An inammatory endarteri-
tis may lead to thrombosis of the cerebral blood vessels causing
cerebral infarction with convulsions or paralysis.
Clinically, cases are classied into three stages:
Stage 1. The patient is fully conscious and rational with non-
specic symptoms such as general malaise, low-grade
fever, apathy, irritability, personality changes, depres-
sion 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 neu-
rological signs such as cranial nerve palsies. Other
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.
Figure 56.34 CT scan of the head showing a brain tuberculoma
exuding its contents through the skull into scalp soft tissues: collar
stud abscess.
Ch056-X4470.indd 26 7/21/2008 3:45:42 PM
27
symptoms include more severe and persistent headache
and vomiting and some degree of photophobia.
Stage 3. The patient is deeply stuporose or comatose and/or has
complete hemiplegia, paraplegia or quadriplegia.
Examination of CSF is essential, although lumbar puncture should
be performed carefully after ruling out raised intracranial pres-
sure, and may reveal lymphocytes, a raised protein level and
decreased glucose level although these parameters may some-
times be normal. In some cases there is a high polymorph count,
which suggests tuberculous meningitis of rapid onset or a non-
acid-fast bacterial infection. A chest X-ray may be helpful as pul-
monary tuberculous lesions are evident in about half the patients.
The diagnosis is conrmed by the microscopical detection of acid-
fast bacilli in centrifuged samples of CSF, although a very thor-
ough search only detects such bacilli in 1030% of cases. Where
a CSF clot of brin is present, acid-fast bacilli may be seen in it.
Culture of CSF is far too slow, even with the use of automated
systems but, where facilities are available, PCR and related nucleic
acid amplication techniques may be useful.
49
If in any doubt as
to the diagnosis, antituberculosis therapy should be commenced
immediately. CT and MRI, where available, are of value in the
investigation of tuberculous meningitis as they detect cryptic
lesions, raised intracranial pressure, hydrocephalus and cerebral
infarctions.
Tuberculomas of the brain and spinal cord
These usually manifest as space-occupying lesions. CT and MRI,
where available, are very helpful as the lesions often have a
characteristic appearance (Figures 56.3456.38).
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. Etham-
butol enters the CSF when the meninges are inamed 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), ethion-
amide (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 chil-
dren 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 rm data are available, national guidelines should be
followed.
Raised intracranial pressure often resolves on treatment with
acetazolamide (100 mg/kg per day) or frusemide (1 mg/kg per
day) given in divided doses at 6- or 8-hourly intervals for 1 month.
Dehydration must be prevented, especially in children who are
vomiting. Children who fail to respond require the insertion of
ventriculoperitoneal shunts.
Small solid lesions in the brain and spinal cord often resolve
with medical treatment alone, but surgery is required for larger
lesions, especially if sight is threatened or, in the case of the spinal
cord, if there is paralysis.
Figure 56.35 Pre-contrast enhanced cranial CT. The parafalcine
ring-enhancing lesion exerts mass effect. Its appearance is non-specic,
in this case being another example of an intracranial abscess due to
M. tuberculosis.
Figure 56.36 Post-contrast enhanced cranial CT (see also
Figure 56.35).
Tuberculosis of the Central Nervous System
Ch056-X4470.indd 27 7/21/2008 3:45:43 PM
56. Tuberculosis
28
URINARY AND GENITAL TRACTS
Tuberculosis of the kidney is a common form of extrapulmonary
tuberculosis and autopsy studies indicate that it is commoner than
expected in AIDS patients. Renal tuberculosis is usually a late mani-
festation of haematogenous spread from a primary focus of tuber-
culosis, presenting 615 years after the initial infection.
52
The
disease, which may be unilateral or bilateral, usually commences in
the renal cortex and progresses towards the medulla (Figures 56.39,
56.40). Lesions may eventually rupture into the renal pelvis with
release of tubercle bacilli into the urine, causing secondary lesions
in the ureters and bladder and, in males, in the epididymis, testis,
seminal vesicles and prostate.
53
Although usually secondary to
tuberculosis of the kidney, some cases of tuberculous epididymitis
appear to be due to direct haematogenous spread from primary foci
Figure 56.37 T1-weighted MRI, pre-contrast. Multiplanar
reformation (coronal, left column, sagittal, right column) is as routine
as conventional axial images. Enhancement patterns mirror those of
CT scan. The patient has cerebral tuberculosis.
Figure 56.38 T1-weighted MRI, post-contrast. (see also
Figure 57.37).
Figure 57.39 Postmortem kidney specimens showing caseating
tuberculous lesions.
Figure 56.40 Non-enhanced CT scan through the lower abdomen.
Large parenchymal deposits of calcication involving both kidneys
as a result of earlier tuberculous infection.
Ch056-X4470.indd 28 7/21/2008 3:45:43 PM
29
of disease. In advanced disease, an entire kidney may be replaced
with caseous material a condition termed cement kidney.
Symptoms, including frequency, dysuria, nocturia, suprapubic
pain and haematuria, resemble those of non-acid-fast bacterial
cystitis.
54,55
In other cases, symptoms are of a vague orthopaedic
nature. Renal colic is uncommon, occurring in less than 10% of
patients and constitutional symptoms are also uncommon. Sec-
ondary infection of the kidney, with renal pain and fever, may
develop or if, as is often the case, diagnosis is delayed, ureteric
obstruction, shrinkage and brosis of the bladder and even renal
failure may develop. About 40% of patients have subclinical
impairment of renal failure indicated by raised serum creatinine
levels and about 10% have mild hypertension, which resolves
on antituberculosis therapy. A male patient may present with a
swollen epididymis or testis or with infertility.
An insidious form of renal tuberculosis termed tuberculous
interstitial nephritis may lead to advanced renal failure without
the usual tissue destruction and anatomical distortion.
56
Renal
biopsies reveal an interstitial granulomatous inltrate with limited
caseation and scanty acid-fast bacilli. Diagnosis is not easy as it is
unusual to nd acid-fast bacilli in the urine. As tuberculosis is
common in the tropics, it should be considered in all cases of
renal failure when there are no other obvious causes.
57
Tuberculosis of the female genital tract is, in contrast to the
disease in males, almost always the direct result of haematogenous
dissemination from the primary focus. Sexually transmitted tuber-
culosis is exceedingly rare. The disease usually commences in the
epithelium of the Fallopian tubes (Figure 56.41) and spreads to
the endometrium or to the peritoneal cavity, causing tuberculous
peritonitis. Presenting features include infertility, pelvic pain and
either excessive menstrual bleeding or amenorrhoea.
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. Diag-
nosis is conrmed 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 biop-
sies 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
be required for relief of ureteric or urethral obstruction, shrunken
bladders or, rarely, for the removal of grossly damaged and non-
functioning kidneys in the presence of symptoms. Ureteric obstruc-
tion may respond to treatment with steroids.
ABDOMINAL TUBERCULOSIS
This is divisible into intestinal and peritoneal disease. The former
is either a primary infection, usually due to drinking milk contain-
ing M. bovis or a manifestation of post-primary disease as a result
of swallowing sputum containing tubercle bacilli. The latter is the
result of lymphatic or haematogenous dissemination from a
primary focus, usually pulmonary, or to spread from an infected
intra-abdominal organ such as the intestine or a Fallopian tube.
Primary intestinal tuberculosis usually involves the ileocaecal
region and results in mucosal hypertrophy which, together with
enlarged lymph nodes, presents as a tender mass in the right iliac
fossa. Complications including malabsorption, intestinal obstruc-
tion, stulae, peritonitis and, rarely, massive rectal bleeding which
may be life-threatening. The stomach and small intestine are the
usual sites of post-primary lesions and ulceration, rather than
hypertrophy, is characteristic, with a risk of intestinal perforation
leading to peritonitis.
The principal groups of patients developing tuberculous perito-
nitis are young women and elderly alcoholic men. It is a common
cause of ascites: in a study in Lesotho it was found to account for
42% of all cases of ascites and there was a mortality rate of 26%
among elderly alcoholic patients.
58
Diagnosis is difcult, especially
in elderly alcoholics, as the symptoms and signs are non-specic.
The doughy abdomen cited in many textbooks as a classical sign
is an uncommon manifestation of advanced disease. Tubercle
bacilli in swallowed bacilli may enter anal ssures and lead to local
granulomatous lesions and stula formation.
Figure 56.41 Hysterosalpingogram showing distortion of Fallopian
tubes due to chronic tuberculous salpingitis.
Abdominal Tuberculosis
Ch056-X4470.indd 29 7/21/2008 3:45:44 PM
56. Tuberculosis
30
Diagnosis of abdominal tuberculosis
Symptoms and signs of abdominal tuberculosis include weight
loss, abdominal pain and tenderness, anorexia, diarrhoea, fever
and night sweats. An abdominal mass may be palpable and ascites
may be detectable. Some patients present with intestinal strictures
causing subacute obstruction, suggesting carcinoma. Chest radio-
graphs show signs of pulmonary tube tuberculosis in about one-
third of patients.
Where available, ultrasonography or CT scanning may demon-
strate ascites, thickened intestinal walls and enlarged mesenteric
lymph nodes.
59
Colonoscopy enables biopsies to be obtained
from the caecal region, which is commonly involved in primary
disease. Diagnosis is made by examination of biopsies obtained
by laparoscopy or endoscopy or by percutaneous aspiration of
abdominal abscesses.
60
Peritoneal biopsies are more likely to yield
positive results than aspirated peritoneal uid and may be obtained
through a 34 cm midline abdominal incision under local anaes-
thetic.
61
Other viscera in the abdominal cavity may be affected
by tuberculosis and tuberculosis lesions in the psoas muscle
(Figure 56.43), para-aortic nodes (Figures 56.44, 56.45) and
spleen (Figure 56.28) are illustrated.
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 contami-
nated sputum in patients with post-primary pulmonary tuber-
Figure 56.42 Renal tuberculosis. Note loss of calyceal architecture
and ureteric obstruction.
Figure 56.43 Abdominal CT scan. Left psoas abscess. Pus aspirate
grew M. tuberculosis.
Figure 56.44 Abdominal CT, post-contrast, at level of splenic hilum.
Ch056-X4470.indd 30 7/21/2008 3:45:44 PM
31
culosis (tuberculosis oricialis cutis). The latter may occur on
or near the mouth, and also on the anus as a result of implan-
tation of tubercle bacilli from swallowed sputum
Lesions resulting from direct extension of disease from under-
lying organs or tissues such as lymph nodes, bones or the
thoracic cage
Lesions resulting from haematogenous dissemination from an
internal organ
A range of skin lesions of uncertain pathogenesis termed
tuberculides.
Primary inoculation tuberculosis is an occupational hazard of
butchers and pathologists and an old name for it is prosectors or
butchers wart.
62
Occasional cases occur in medical laboratory
workers and in children exposed to sources of infection. Warty
lesions develop at the inoculation site and there may be secondary
lesions along the draining lymphatics and regional lymphade-
nopathy. It is, in common with other forms of primary tubercu-
losis, often self-limiting.
Figure 56.45 Hypo-attenuating lesions in the spleen and associated
para-aortic lymph nodes. The main differential lies between lymphoma
and tuberculosis. The cystic change in the lymph nodes on the lower
cuts, with strongly enhancing periphery, favours tuberculosis.
Figure 56.46 Chronic skin lesion on forehead due to M. tuberculosis.
Figure 56.47 Chronic granulomatous skin lesions due to
M. tuberculosis on the nose and around the mouth (lupus
vulgaris).
Figure 56.48 Verrucous plaque, chronic granulomatous reaction
and supercial ulceration of the foot due to skin tuberculosis:
tuberculosis verrucosa cutis.
Skin Tuberculosis
Ch056-X4470.indd 31 7/21/2008 3:45:45 PM
56. Tuberculosis
32
Extension of disease from underlying structures results in sinus
formation. The usual cause is a spread from an underlying tuber-
culous lymph node: a condition termed scrofuloderma.
Lupus vulgaris is a very slowly progressive and chronic form of
skin tuberculosis that usually occurs on the nose, cheeks or neck
and, if untreated, may cause severe disgurement (Figures 56.47,
56.49 and 56.52). It is characterized by red-brown semi-
translucent nodules which may subsequently coalesce and ulcer-
ate. When compressed with a glass slide the nodules often have
an opalescent apple jelly appearance. It is due either to haema-
togenous dissemination of tubercle bacilli from internal organs or
Figure 56.49 Lupus vulgaris of the face. Chronic ulcerating
granulomatous lesion due to M. tuberculosis.
Figure 56.50 Chronic ulcerating lesion with parotid stula due
to parotid gland tuberculosis.
Figure 56.51 Tuberculous mastitis affecting the left breast.
Figure 56.52 Chronic granulomatous skin lesions on the face due
to M. tuberculosis (lupus vulgaris).
Ch056-X4470.indd 32 7/21/2008 3:45:46 PM
33
to secondary spread from scrofuloderma. There is some evidence
to suggest that lupus vulgaris is more likely to be caused by M.
bovis than M. tuberculosis. The skin may be involved in dissemi-
nated tuberculosis, and small skin papules may be seen in cases
of miliary tuberculosis (Figure 56.29).
The tuberculides are uncommon and poorly understood skin
lesions associated with tuberculosis.
63
Two main types have been
described: lichen scrofulosorum and papulonecrotic tuberculide.
The former is characterized by non-necrotic dermal granulomas
with epithelioid and giant cells and the latter by tissue necrosis,
sometimes extensive, due to an obliterative vasculitis. The aetiol-
ogy of the tuberculides is unknown but it has been suggested that
they are due to hypersensitivity reactions to blood-borne whole
tubercle bacilli, bacillary debris or antigens. The rarely encoun-
tered erythema induratum (Bazins disease) and tuberculosis-
associated idiopathic gangrene of the extremities may be due to
similar necrotic hypersensitivity reactions in larger blood vessels.
Lupus vulgaris occasionally develops at the site of a tuberculide,
indicating the presence of viable tubercle bacilli.
SUPERFICIAL LYMPH NODES
Tuberculous lymphadenitis is well documented in early literature
in which it is referred to, for unknown reasons, as scrofula (Figures
56.8, 56.5356.57). The usual site is the neck and two main
types have been described: that due to primary inoculation
of bacilli, usually milk-borne M. bovis, into the pharynx and that
secondary to intrathoracic primary complexes. Lymphadenopathy
also occurs as a component of disseminated tuberculosis in HIV-
positive patients. Lymphadenopathy in children aged 5 years or
below is occasionally caused by other mycobacterial species (see
Chapter 57).
Lymphadenopathy associated with a primary pharyngeal lesion
usually affects the tonsillar and pre-auricular nodes, while the
supraclavicular nodes are involved when the disease is due to an
upward extension of an intrathoracic primary complex. The latter
is more common in females than males. In early disease, affected
nodes are discrete, rubbery in texture and usually painless. Con-
stitutional symptoms occur in less than half the patients. Subse-
quently, the affected glands may undergo necrosis and become
uctuant, and the disease may invade the surrounding tissues and
ultimately the skin with the formation of sinuses. The disease
Figure 56.53 Enlarged tuberculous cervical lymph nodes exuding
caseous material (open tuberculosis).
Figure 56.54 Cervical lymphadenopathy due to tuberculosis in an
HIV-positive Zambian adult.
Figure 56.55 Enlarged posterior auricular lymph node in an HIV-
positive adult. M. tuberculosis was isolated from a lymph node aspirate.
Supercial Lymph Nodes
Ch056-X4470.indd 33 7/21/2008 3:45:46 PM
56. Tuberculosis
34
process may then spread into the surrounding skin a condition
termed scrofuloderma. There are relatively few tubercle bacilli in
the affected lymph nodes: much of the enlargement is due to the
immune response. Microscopy is positive for acid-fast bacilli in
less than half the cases and cultures are positive in only 6070%.
Diagnosis is thus often based on histological examination of biop-
sies or cytological examination of ne-needle aspirates which, in
trained hands, establishes the diagnosis in 80% of cases.
64
The
tuberculin test is usually positive and a chest X-ray often reveals
lesions of pulmonary tuberculosis. Tuberculous lymphadenopa-
thy must be differentiated from other infections, lymphomas and
other neoplasms, sarcoidosis and branchial cysts.
Tuberculous lymphadenopathy responds to standard short-
course therapy. Nodes may undergo enlargement, sometimes
quite extensive and with sinus formation, during the course of
therapy but this is due to hypersensitivity reactions and usually
responds to steroid therapy. Surgical intervention is seldom
indicated.
TUBERCULOSIS AT OTHER SITES
Tuberculous lesions may develop in any site of the body although
muscles are rarely involved, except in widespread disseminated
disease.
Tuberculous pericarditis
This occurs either as a manifestation of disseminated disease or
secondary to the rupture of an involved mediastinal lymph node
into the pericardial sac. Although uncommon, a high incidence
of tuberculous pericarditis occurs, for unknown reasons, in certain
regions such as the Transkei, where it has been termed the Tran-
skei heart.
65
Exudates cause distension of the pericardium, exert-
ing pressure on the heart (cardiac tamponade) which may be
sufcient to cause heart failure and requiring urgent aspiration of
the uid. Clinical ndings include chest pain, fever, breathless-
ness, low blood pressure, a rapid pulse, a raised jugular venous
pressure and a pericardial rub on auscultation. Hepatomegaly and
ascites may be detected in severe cases. An enlarged heart shadow
is visible on chest X-ray and the presence of pericardial uid is
conrmed by ultrasonography. The chest X-ray may also reveal
pulmonary tuberculosis and enlarged mediastinal lymph nodes.
T wave changes may be seen on electrocardiography. Diagnosis is
conrmed by bacteriological examination of the effusion or peri-
cardial biopsies. The case fatality is high (Figure 56.58).
High-dose corticosteroid therapy, such as prednisolone 80 mg
daily for 1 week and then progressively reduced over the ensuing
Figure 56.56 Enlarged cervical and supraclavicular lymph nodes in
an HIV-positive Zambian patient. M. tuberculosis was isolated from
lymph node aspirates. Note the generalized muscle wasting.
Figure 56.57 Supraclavicular lymphadenopathy due to
M. tuberculosis.
Figure 56.58 Section of the heart showing chronic tuberculous
pericarditis. Note the 2 cm thick band of tuberculous caseation.
Ch056-X4470.indd 34 7/21/2008 3:45:47 PM
35
68 weeks reduces the size of the effusion and associated mortal-
ity and also the long-term incidence of constrictive sequelae.
Unless contraindicated, steroid therapy should therefore be given
for this form of tuberculosis. Healing with brosis and calcica-
tion 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.
Tuberculosis of upper respiratory tract
Tuberculous laryngitis is usually due to the implantation of tuber-
cle bacilli from sputum. The principal clinical feature is pain,
which may be severe enough to prevent eating. Speech is often
affected. The disease may occur in the absence of radiological
evidence of pulmonary tuberculosis, especially in older patients,
and may thus be misdiagnosed as cancer. Diagnosis is made by
histological examination of biopsy. Pain responds rapidly to cor-
ticosteroid therapy.
Primary tuberculous lesions occasionally occur in the nose,
pharynx, epiglottis and Eustachian tubes or on the gums. The
presenting feature may be an enlarged cervical lymph node.
Lesions in the Eustachian tube may spread to the middle ear and
mastoid.
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 reac-
tion 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 hypo-
adrenalism or Addisons disease and is the result of haematoge-
nous 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 dark-
skinned patients. Diagnosis of hypoadrenalism is conrmed by
tests of adrenal function and tuberculosis is suggested by the
presence of calcication in the adrenals visible on abdominal
X-rays. Hormonal replacement, in addition to antituberculosis
therapy, is required.
Other manifestations of tuberculosis
Tuberculous breast abscesses may follow rupture of involved
intercostal lymph nodes through the chest wall and present as a
painless mastitis which is easily confused with cancer (Figure
56.51). Tuberculous nodules or abscesses may occur in the thyroid.
Discrete hepatic tuberculous lesions are a very rare cause of hepa-
tomegaly but the liver is frequently involved in disseminated
tuberculosis. The liver is also usually involved in congenital tuber-
culosis due to infection via the umbilical artery.
TUBERCULOSIS IN HIV-INFECTED PERSONS
Infection with HIV is the highest risk factor for reactivation of
tuberculosis. In 2005, approximately 14 million people were
thought to be dually infected with the two organisms. The stron-
gest association between HIV and tuberculosis has been recorded
in sub-Saharan Africa where, in many regions, around two-thirds
of children and adults with tuberculosis are co-infected with HIV.
Many new and recurrent cases of HIV-related tuberculosis are the
result of recent infection.
69
Effects of tuberculosis on HIV
In addition to the course of tuberculosis being adversely affected
by HIV disease, active tuberculosis accelerates progression of HIV
disease. The exact mechanisms are not clear but, in common with
Figure 56.59 Constrictive tuberculous pericarditis: X-ray shows
pericardial calcication.
Tuberculosis in HIV-Infected Persons
8
Ch056-X4470.indd 35 7/21/2008 3:45:48 PM
56. Tuberculosis
36
HIV infection, tuberculosis leads to a lowering of the CD4+ T cell
count and to a marked increase in the viral load in HIV-infected
patients.
70
Increased IL-2, IL-6 and TNF (type 2 cytokines) gener-
ated by infection with M. tuberculosis may be responsible for these
increases in HIV burden.
Pathology of tuberculosis in HIV infection
Autopsy studies in Africa show that between one-third and one-
half of those dying of an AIDS-dening condition had active
tuberculosis, many showing brous and calcied lesions of tuber-
culosis adjacent to recent active lesions containing viable tubercle
bacilli. These new lesions may be due to endogenous reactivation
of primary complex lesions but DNA ngerprinting indicates that
many are due to exogenous reinfection. In HIV-infected patients
a range of histological features related to the extent of immuno-
suppression are seen.
71
For practical purposes, there are three iden-
tiable histological stages of cellular immune responses which
correlate well with the stage of HIV disease granulomatous
response, hyporeactive response and anergic response. The suscep-
tibility to, and clinical characteristics of, tuberculosis show only a
partial correlation with the CD4+ lymphocyte counts as qualita-
tive as well as quantitative defects of these cells compromise
protective immune functions such as macrophage maturation
and granuloma formation.
Patients showing a granulomatous response have relatively
intact cellular immune responses, a relatively high CD4+ lympho-
cyte count and develop typical, well-formed granulomas contain-
ing abundant epithelioid cells and Langhans giant cells, clusters
of CD4+ T cells and low numbers of acid-fast bacilli. Macrophages
show abundant cytoplasm and markers of maturation.
With progressive immunosuppression and decline of CD4+ T
cell counts, there is a hyporeactive response with loss of Langhans
giant cells and, subsequently, of epithelioid cells. The proportion
of macrophages with abundant cytoplasm is also decreased.
Intracellular killing of mycobacteria is compromised and there-
fore the number of acid-fast bacilli increase (Figure 56.60). The
caseous centres enlarge centrifugally and lesions coalesce. A
mixture of suppurative and caseous necrosis is seen.
Finally, in the late stages of AIDS, disseminated anergic tuber-
culosis develops and is often only detected at autopsy. While no
relative decrease in the number of macrophages in the tuberculous
lesion is seen, they show little or no maturation. Epithelioid cells
are scanty, Langhans giant cells are absent, there are few CD4+ T
cells in the lesions and granuloma formation is not seen (Figures
56.10A and B). Caseous necrosis is replaced by suppuration, coag-
ulative necrosis and large amounts of apoptotic debris. Large
numbers of mycobacteria are present within macrophages and in
the necrotic areas.
Clinical manifestations of
HIV-related tuberculosis
Pulmonary tuberculosis occurs in patients with a wide spectrum
of immunodeciency but, as mentioned above, the risk and clin-
ical manifestations are not entirely dependent on the degree of
depletion of CD4+ lymphocytes. Around 30% of cases of tuber-
culosis 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
immunodeciency present with atypical pulmonary disease char-
acterized by extensive pulmonary inltrates 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.
Diagnosis of pulmonary tuberculosis in
HIV-positive adults
As the proportion of patients with smear-negative pulmonary
tuberculosis is greater in those co-infected with HIV than in those
who are not, the diagnosis of tuberculosis in an HIV-positive
patient with a chronic cough, night sweats, weight loss but nega-
tive sputum smears for acid-fast bacilli is a challenge for the clini-
cian. In studies in HIV-positive African patients with respiratory
illness and negative sputum smears, bronchoscopy with bron-
choalveolar lavage or induction of sputum demonstrated that
about one-third had tuberculosis. Another third had other respira-
tory diseases including Pneumocystis carinii pneumonia (PCP),
bacterial pneumonia due to a wide range of pathogens, Kaposis
sarcoma, nocardiosis and fungal infections. Even where facilities
exist for more extensive investigations (e.g. bronchoscopy with
bronchoalveolar lavage and biopsy, sputum culture and molecu-
lar methods) the bacteriological conrmation of tuberculosis
may be difcult. In most developing country health centres,
the diagnosis of pulmonary tuberculosis is based on simple
techniques only: sputum smear microscopy and, possibly, chest
radiography.
There is a large range and variety of radiological appearances.
72

In those with relatively intact immunity, the appearances are those
Figure 56.60 Lung histopathology of an AIDS patient who died of
tuberculosis. Note the vast number of acid-fast tubercle bacilli in the
alveolar necrotic exudate.
Ch056-X4470.indd 36 7/21/2008 3:45:48 PM
37
of typical pulmonary tuberculosis but in the more profoundly
immunosuppressed atypical appearances are common, including
vague, spreading opacities suggestive of pneumonia, predomi-
nantly lower lobe disease, pleural effusions, air-uid levels, wide-
spread pulmonary mottling and intrathoracic lymphadenopathy.
On the other hand, there is signicantly less cavitating disease and
atelectasis. Radiological features may change rapidly in appear-
ance. Classical miliary lesions are seen in a minority of HIV-
positive patients with disseminated disease, as in most cases the
formation of these granulomatous lesions is suppressed. The
X-rays may therefore appear deceptively normal. The atypical
clinical and radiological features seen in the more profoundly
immunosuppressed patients are summarized in Table 56.7.
Further details on the clinical aspects of HIV-related tuberculosis
are available from the WHO.
73
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, gen-
itourinary tract and bone marrow is, in contrast to the industrial-
ized countries, infrequently reported but this probably reects
patient selection and differences in the availability of diagnostic
facilities. Patients usually present with non-specic constitutional
symptoms (fever, night sweats and weight loss) and local symp-
toms 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-
gitis (a common HIV-related infection), making the diagnosis very
difcult. Empirical treatment may have to be given on clinical
suspicion alone.
Management considerations in HIV-positive persons
There are several specic management issues which arise in the
treatment of HIV-infected persons with tuberculosis. These patients
overall tend to have:
Increased morbidity rates
Increased mortality rates
Increased number of drug side-effects
Serious interactions between antiretroviral drugs and antituber-
culosis drugs
Immune reconstitution inammatory syndrome (IRIS)
Increased recurrence rates after completion of treatment.
Increased morbidity rates
Clinical response to antituberculosis treatment, clearing of chest
X-ray abnormalities and sputum conversion rates occur at
the same rates during treatment in both HIV-positive and HIV-
negative patients with tuberculosis. On the other hand, HIV-
positive patients on treatment for tuberculosis often have other
opportunistic infections and tumours and thus commonly suffer
from recurrent fever, chest infections, recurrent diarrhoea, oral
candidiasis, bacteraemia, cryptococcosis and Kaposis sarcoma.
These other conditions require appropriate drug treatment, ren-
dering the care more expensive than is the case with HIV-negative
patients. Delays in the diagnosis and treatment of tuberculosis
compromise the chances of individual cure in HIV-positive
patients. Untreated tuberculosis in HIV-infected persons acceler-
ates the decline in immunocompetence and the progression to
severe immunodeciency.
Increased mortality rates
HIV-positive patients not receiving antiretroviral therapy have a
much higher mortality during and after antituberculosis treatment
compared with HIV-negative patients. In sub-Saharan Africa,
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 brosis Marked Limited
Intrathoracic lymphadenopathy Uncommon Common
Pleural effusions Present Very common
Miliary disease Uncommon Common
Atelectasis Uncommon Common
Lymphatic and haematogenous dissemination Uncommon Common
Adverse drug reactions Uncommon Common
Tuberculin test Positive Small reaction or negative
Relapse following therapy Uncommon Frequent
Mortality rate Low Increased
Tuberculosis in HIV-Infected Persons
Ch056-X4470.indd 37 7/21/2008 3:45:49 PM
56. Tuberculosis
38
approximately 30% of HIV-positive smear-positive tuberculosis
patients die within 12 months of commencing treatment, and
about 25% of those who survive die during the subsequent 12
months. The introduction of effective antiretroviral treatment has
dramatically reduced mortality rates in HIV-infected patients in
the USA and in Europe and efforts are being made by the United
Nations to make such treatment available to all HIV-infected
patients throughout the world by the end of 2010; thus the number
of patients receiving therapy in the developing nations rose from
400 000 in December 2003 to 1 million in June 2005. Antiretro-
viral treatment reduces the incidence of tuberculosis by around
80% in those receiving it but the incidence remains higher than
in those who are HIV negative, suggesting that protective immu-
nity is only partly restored.
74
Since opportunistic infections are a cause of mortality in HIV-
positive persons with tuberculosis, interventions with prophylac-
tic antimicrobial agents may be useful. Studies in several African
countries show that co-trimoxazole given daily during the 6
months of treatment for tuberculosis causes a signicant reduc-
tion of mortality.
75
As co-trimoxazole prophylaxis is a safe and
effective way of reducing mortality, it is recommended for all
adults undergoing treatment for tuberculosis in regions with a
high prevalence of HIV disease, irrespective of their HIV status.
Increased drug side-effects
Adverse drug reactions appear to be infrequent in HIV-positive
patients given standard short-course regimens although they occur
more frequently than in HIV-negative patients. Adverse cutaneous
reactions were frequently seen in HIV-positive patients, particu-
larly children, who were given regimens including thiacetazone
and included cases of StevensJohnson syndrome (Figure 56.61)
and toxic epidermal necrolysis which were frequently fatal. For
this reason, thiacetazone has been abandoned in favour of
ethambutol.
Interactions between antiretroviral drugs and
antituberculosis drugs
Serious interactions between antiretroviral and antituberculosis
drugs can occur (see pp. -). Protease inhibitors and non-
nucleoside reverse transcriptase inhibitors interfere with the
metabolism of rifampicin, the most potent of the antituberculosis
drugs. Rifampicin is a potent liver cytochrome p450 inducer and
thus may enhance the metabolism of protease inhibitors and non-
nucleoside reverse transcriptase inhibitors, causing serum levels to
be decreased to sub-therapeutic levels.
Immune reconstitution inammatory syndrome (IRIS)
The introduction of antiretroviral therapy (ART) produces a rapid
suppression of HIV replication (about 90% in 12 weeks), which
is associated with an, at least partial, reconstitution of the immune
system. The typical recovery of CD4 cells following ART is bipha-
sic. The initial rise is rapid and mainly due to the redistribution
of memory CD4 cells from lymphoid tissue. Thereafter, a slow
increase in CD4 cells, mainly due to naive CD4 cell regeneration,
is observed. Moreover, IRIS is an adverse consequence of immune
reconstitution due to ART-induced immune hyperactivation due
to viral suppression, and an increase in the diversity of T cells and
an accompanying uninhibited production of Th1 cytokines.
Tuberculosis, other mycobacterial infections and cryptococcal
disease account for about 60% of cases of IRIS.
76
Patients may
develop ascites, lymphadenopathy and fever, as well as increases
in the size of cerebral lesions and pleural effusions.
77
Patients who
develop IRIS are more likely to have an initial CD4 count less than
100 cells/mm
3
and a rapid rise in this count after starting antiret-
roviral therapy. Clinicians treating tuberculosis in HIV-positive
patients receiving antiretroviral therapy need to be aware of this
phenomenon.
Drug resistance
Although several outbreaks of MDRTB have been reported from
industrialized countries among HIV-infected patients, HIV infec-
tion 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
conned 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 South-
east Asia,
21
the problems faced by many tuberculosis programmes
in sub-Saharan Africa, including the dif culties in obtaining
second-line antituberculosis drugs, render MDRTB a very real
threat to tuberculosis control in this region.
Quality of healthcare
The capacity and quality of healthcare provided by the local health
service and the health status of the staff (clinical ofcers, clini-
cians, nurses, technical personnel) available to care for patients
inuence the outcome of tuberculosis treatment. The advent of Figure 56.61 StevensJohnson syndrome due to thiacetazone.
9
Ch056-X4470.indd 38 7/21/2008 3:45:49 PM
39
HIV with large increases in tuberculosis cases has threatened to
overwhelm National Tuberculosis Control Programmes in sub-
Saharan Africa. The health staff in many African countries have
the same HIV-seroprevalence rates as the general adult popula-
tion, and in some urban areas this approaches 30% or more. High
absentee rates from work due to illness or attending funerals, and
high death rates of the healthcare staff due to AIDS, threaten the
capacity of many developing countries to deliver good and effec-
tive healthcare, including tuberculosis control.
Recurrence after treatment
Recurrence rates of tuberculosis (dened as return of clinical fea-
tures of active tuberculosis, positive sputum smears for acid-fast
bacilli or positive sputum cultures for M. tuberculosis) after com-
pletion 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 contrib-
utes 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 smear-
positive pulmonary tuberculosis are treated with the WHO-
recommended retreatment regimen shown below in Table 56.9.
Preventive therapy is described on p. .
HUMAN TUBERCULOSIS OF BOVINE ORIGIN
This is a neglected area of interest. Human tuberculosis due to M.
bovis was a major problem in the industrially developed countries
before the completion of bovine tuberculosis eradication pro-
grammes in the middle of the twentieth century but is now very
uncommon. Tuberculosis is known to occur in cattle in many
tropical countries, although little has been done to survey the
extent of the problem and even less to control it.
78
The number
of tropical countries reporting bovine tuberculosis in 1998 and
the number that have adopted the test and slaughter control strat-
egy are shown in Table 56.8.
Owing to a lack of laboratory facilities, the prevalence of
human tuberculosis due to M. bovis in most tropical countries is
likewise unknown. One reason for the lack of concern is that early
reports indicated that, even in rural communities where cattle
disease was common, transmission to humans was rare. In addi-
tion, it has been generally but rather dogmatically assumed that
M. bovis is less virulent than M. tuberculosis in humans and is rarely
transmitted from person to person. All these assumptions have
been seriously questioned by surveys undertaken by the WHO and
human tuberculosis due to M. bovis has been found in many
regions where it has been actively sought.
79
Thus further surveys
are required to determine the magnitude of the problem in both
cattle and humans and to determine the cost-effectiveness of
eradication programmes.
The clinical presentation of tuberculosis due to M. bovis depends
on the route of infection. Oral infection acquired by drinking milk
from diseased cattle usually leads to cervical (Figures 56.62, 56.63)
or mesenteric lymphadenopathy and other forms of non-
pulmonary disease. Aerogenous infection from cattle or humans
leads to pulmonary tuberculosis indistinguishable from that
caused by M. tuberculosis. The treatment is as for disease due to M.
tuberculosis, although as M. bovis is naturally resistant to pyrazin-
amide this agent may be omitted.
Infection by HIV increases the risk of human disease following
infection by M. bovis and a number of examples of human-to-
human transmission of disease have been reported. Thus HIV
infection could exacerbate the risk of human disease following
infection from cattle as well as human sources and this is therefore
another incentive to consider the institution of bovine tuberculo-
sis eradication programmes.
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 Number of countries reporting Number of countries with
test and slaughter policy
Enzootic or
high prevalence
Sporadic or
low prevalence
Not reported No data
Africa 55 8 25 18 7
Asia 36 1 16 9 7
Latin America and Caribbean 34 8 12 2 12
Data from Cosivi et al.
78
Figure 56.62 Lymphadenopathy (tonsillar node) with sinus
formation in tuberculosis due to M. bovis.
Human Tuberculosis of Bovine Origin
10
Ch056-X4470.indd 39 7/21/2008 3:45:49 PM
56. Tuberculosis
40
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.
Antituberculosis drug therapy
The three aims of antituberculosis therapy are to cure the patient,
to render the patient rapidly non-infectious and to prevent the
emergence of drug resistance.
From the point of view of therapy, the tubercle bacilli may be
thought of as being in three different compartments: those rep-
licating rapidly on the walls of the cavities, those replicating less
rapidly in anoxic and acidic solid lesions and those in a dormant
or near dormant state within dense lesions or macrophages.
80
It
is important to kill all bacilli as the immune responses cannot be
relied on to deal with any remaining viable bacilli.
Effective cure of the patient is ensured by using combinations
of agents that, together, are able to kill bacilli in all three compart-
ments. In those with open or infectious pulmonary tuberculosis,
the great majority of bacilli are freely replicating in the cavity walls
and are rapidly killed by isoniazid, thereby speedily rendering the
patient non-infectious. Isoniazid is much less active against slowly
replicating bacilli in closed, acidic lesions but rifampicin and
pyrazinamide are effective against this population. There are two
phases in the drug treatment of tuberculosis:
1. An initial or intensive phase in which, in most modern regimens,
four antituberculosis drugs (rifampicin, isoniazid, pyrazin-
amide and ethambutol) are given for 2 months. This intensive
treatment greatly reduces the mycobacterial load and renders
the patient non-infectious.
2. A continuation phase which is less intense, usually consisting of
rifampicin and isoniazid given for a further 4 months.
If the patient regularly receives at least two drugs to which the
bacilli are susceptible, the chance of the emergence of drug resis-
tance is very small. In view of the increasing prevalence of resis-
tance to one or two drugs, four drugs are now routinely given in
the intensive phase of treatment. The best drug for the destruction
of near-dormant persisting bacilli is rifampicin, which is therefore
also given during the continuation phase. Although isoniazid has
little activity against near-dormant bacilli, it is included in the
continuation phase to destroy any rifampicin-resistant mutants
that commence active replication.
Modern short-course regimens have the added advantages of
low toxicity and low cost. In most regimens, all the drugs are given
orally. As four drugs are used in the intensive phase, resistance to
one of the drugs used does not render the regimen ineffective.
Combination tablets containing two, three or four of the rst-line
drugs are available and ensure that the prescribed drugs are all
taken. The WHO recommends that only those combination tablets
that have been shown in human studies to yield bactericidal levels
of the constituent drugs should be used.
Drugs and regimens
The selection of the drug regimen depends on the nature
and extent of the disease. The WHO divides patients into four
groups, with regimens suitable for each, as shown in Table 56.9.
Ideally, drugs are administered daily, but for ease of supervision
they may be given thrice weekly during the continuation phase
or, in some cases, throughout. Alternative drug regimens are
still in use in some regions but should be abandoned in favour
of the highly effective, and cost-effective, WHO-recommended
regimens.
81
Supervision of therapy is considered essential for the cure of
the patient, the prevention of relapse and of the emergence of drug
resistance. Thus, directly observed therapy (DOT) is strongly advo-
cated by the WHO. DOT should not be confused with DOTS,
which is a 5-point strategy for the control of tuberculosis discussed
on p. .
Short-course therapy is suitable for all forms of tuberculosis
although in the case of tuberculous meningitis, some physicians
extend the duration of therapy to 9 or 12 months to minimize the
risk of relapse.
Drugs used in antituberculosis therapy
As referred to above, the rst-line antituberculosis drugs used in
the WHO-recommended short-course regimens are isoniazid,
rifampicin, pyrazinamide and ethambutol. Other drugs are avail-
able for the treatment of relapsed or drug-resistant disease
or when adverse drug reactions require a change in the regimen.
Six classes of these are recognized, namely: aminoglycosides,
uoroquinolones, polypeptides, thioamides, cycloserine and
p-aminosalicylic acid.
23
As discussed above, MDRTB strains
additionally resistant to three or more of these six classes
are termed XDRTB (extensive or extreme drug resistant
tuberculosis).
Limited evidence indicates that the newer macrolides, the anti-
leprosy drug clofazimine and combinations of aminopenicillins
and -lactamase inhibitors, such as amoxicillin with sulbactam,
Figure 56.63 Chronic skin tuberculosis due to M. tuberculosis
(secondary to tracking and sinus formation from lymph node
involvement).
11
Ch056-X4470.indd 40 7/21/2008 3:45:50 PM
Treatment of Tuberculosis
41
are also of use. These drugs are generally more toxic, more
expensive and less active than the rst-line drugs and treatment
is often prolonged and therefore costly.
Isoniazid
This has a powerful bactericidal activity against replicating tuber-
cle 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
rapid acetylators. The elimination half-lives in slow and rapid
acetylators are, respectively, 24 and 0.51.5 h. Acetylation status
does not affect the efcacy of standard short-course antitubercu-
losis therapy but adverse side-effects and interactions with other
drugs are more pronounced in slow acetylators. The rate of acety-
lation is reduced in renal failure. Adverse side-effects of isoniazid
are uncommon and are mostly neurological, including restless-
ness, insomnia, muscle twitching and difculty in starting mictu-
rition. Dermatological side-effects have been observed in
HIV-positive patients (Figure 56.64). More serious but rare side-
effects include peripheral neuropathy, optic neuritis, encepha-
lopathy and psychiatric disorders including anxiety states,
confusion, depression and paranoia. The risk of neurological
side-effects is greatly reduced by giving pyridoxine (vitamin B
6
)
Table 56.9 The WHO-recommended short-course antituberculosis drug regimens in four categories of patients
81
Treatment
category
Denition of treatment category Initial phase
a
Continuation
phase
I New smear-positive pulmonary TB; new smear-negative pulmonary
TB with extensive parenchymal involvement; concomitant HIV
disease or severe forms of extrapulmonary TB
Preferred
2 HRZE 4 HR
Or
4 (HR)
3
Optional
2 (HRZE)
3
Or
2 HRZE
4 (HR)
3
Or
6 HE
II Previously treated sputum smear-positive pulmonary TB:
relapse;
treatment after default
Preferred
2 HRZES/1 HRZE 5 HRE
Optional
2 (HRZES)
3
/1 (HRZE)
3
5 (HRE)
3
Treatment failure of category I in settings with:
adequate programme performance;
representative DRS data showing high rates of MDRTB and/or
capacity for DST if cases and
availability of category IV regimens
Specially designed standardized or individualized
regimens
In settings where representative DRS data show low rates of
MDRTB or individualized DST shows drug-susceptible disease or in
settings of
poor programme performance
absence of representative DRS data
insufcient resources to implement category IV treatment
Preferred
2 HRZES/1 HRZE 5 HRE
Optional
2 (HRZES)
3
/1 (HRZE)
3
5 (HRE)
3
III New smear-negative pulmonary TB (other than Category I); less
severe forms of extrapulmonary TB
Preferred
2 HRZE 4 HR
4 (HR)
3
Optional
2 (HRZE)
3
Or
2 HRZE
4 (HR)
3
Or
6 HE
IV Chronic (still sputum-positive after supervised re-treatment);
proven or likely MDRTB cases
Specially designed
standardized or
individualized regimens
a
The subscripted gure 3 indicates thrice weekly intermittent dosing.
H, isoniazid; R, rifampicin; Z, pyrazinamide; E, ethambutol; S, streptomycin.
Ch056-X4470.indd 41 7/21/2008 3:45:50 PM
56. Tuberculosis
42
10 mg/day and this has become standard practice in many
countries. Some national programmes recommend the routine
prescription of pyridoxine to patients with liver disease, renal
failure requiring dialysis, pregnant women, alcoholics, HIV-posi-
tive patients, the malnourished and the elderly.
Rifampicin (rifampin in the USA)
This, a member of the rifamycin group of antibiotics, is readily
absorbed from the gastrointestinal tract and effective concentra-
tions are obtained in all tissues, with moderate levels in the CSF.
Cross-resistance to other classes of antituberculosis drugs does not
occur. It is red coloured and patients should be warned that it
imparts this colour to urine, tears and sweat.
Adverse reactions include mild and usually self-limiting
skin rashes, erythema multiforme (Figure 56.65) and itchiness
of the skin. Gastrointestinal upsets occur in some patients
and are reduced by giving it with food. Impairment of liver func-
tion may be seen in patients with pre-existing liver disease
and a history of alcoholism and, if possible, assay of serum
bilirubin and other liver function tests should be done monthly
on such patients. Another adverse effect is the so-called u
syndrome, characterized by fever, chills and headache, aching
bones and, in some cases, a mild thrombocytopenic purpura.
For unknown reasons, the u syndrome is more frequent in
those on intermittent treatment than in those given rifampicin
daily.
Much rarer, but serious, adverse events usually associated with
intermittent dosing include respiratory shock syndrome, throm-
bocytopenic purpura, haemorrhages, haemolytic anaemia and
renal failure. Rifampicin must be stopped immediately if one of
these serious adverse reactions develops and must never be given
again. Corticosteroid therapy may be required for the respiratory
shock syndrome.
Ethambutol
This has bactericidal activity in the early, intensive, phase of
treatment and is reported to enhance the activity of other antitu-
berculosis agents by increasing mycobacterial cell wall permeabil-
ity. Resistance is uncommon. It is concentrated in the alveolar
macrophages. It does not diffuse through healthy meninges but
CSF levels of 2540% of the plasma concentration, with consi-
derable variation between patients, are achieved in tuberculous
meningitis.
The most important side-effect is optic neuritis, which may
become irreversible and lead to blindness. This rarely occurs if no
more than 25 mg/kg is given daily for no longer than 2 months.
National codes of practice for detection and prevention of ocular
toxicity should be followed. Patients should be instructed to stop
therapy and to seek medical advice if they notice any change in
visual acuity, peripheral vision or colour perception. Ethambutol
should not be given to young children and others unable to
comply with this advice. Other adverse effects include peripheral
neuritis, joint pain due, in some cases, to hyperuricaemia, rashes
and, rarely, thrombocytopenia and jaundice.
Pyrazinamide
Pyrazinamide is only active in acidic environments and is there-
fore principally effective against intracellular tubercle bacilli and
those in acidic, anoxic inammatory 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 treat-
ment, 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.
Figure 56.64 Extensive skin reaction due to isoniazid.
Figure 56.65 Erythema multiforme skin reaction due to rifampicin.
Ch056-X4470.indd 42 7/21/2008 3:45:51 PM
Treatment of Tuberculosis
43
Other side-effects include anorexia, nausea and photosensitiza-
tion of the skin.
Second-line drugs
These are indicated in cases of drug resistance and, very occasion-
ally, when the use of a rst-line drug is prevented by adverse drug
reactions. In general, they are less effective, more toxic and more
expensive than the rst-line drugs. As mentioned above, there are
six classes of second-line drugs, namely: aminoglycosides, thio-
amides, uoroquinolones, 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 aban-
doned 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 rst effective antituberculosis drug but is
no longer a rst-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 complica-
tion is more likely in older patients and the damage may be
permanent if the drug is not stopped immediately when the symp-
toms commence. Deafness occasionally occurs and, if an amino-
glycoside is given during pregnancy, it can lead to impaired
hearing in the child. A further uncommon complication is ana-
phylaxis. 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.
Thioamides ethionamide and prothionamide
These are bacteriostatic drugs structurally related to isoniazid,
although no cross-resistance occurs. Their use is restricted by a
high incidence of gastric irritation, although this undesirable
effect is reduced by commencing with a low dose and gradually
increasing to the full dose and by taking the drugs at bedtime.
Fluoroquinolones
Clinical trials on several uoroquinolones including ooxacin,
ciprooxacin, ooxacin, levooxacin and moxioxacin have been
or are currently being evaluated in clinical trials.
83
Although not currently recommended as rst-line drugs for the
treatment of drug-susceptible tuberculosis (although preliminary
reports suggest that they could reduce the length of standard
therapy) these agents are included in regimens for MDRTB. Further
studies to compare the efcacy of the various uoroquinolones
and to establish their optimum use are required.
Polypeptides capreomycin and viomycin
In common with the aminoglycosides, they must be given by
intramuscular injection and are ototoxic and nephrotoxic. They
show partial cross-resistance with the aminoglycosides. Viomycin
is no longer obtainable in many countries.
p-Aminosalicylic acid
This was one of the early antituberculosis drugs but is now rarely
used as it has only bacteristatic activity, commonly causes gastro-
intestinal 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.
Other (including experimental) agents
After three decades of neglect, there is now a Gates Foundation-
funded Global Alliance for TB Drug Development, which has
considerable interest and activity in the development of new anti-
tuberculosis drugs. Among the rifamycins, rifabutin is used as an
alternative to rifampicin in HIV-positive patients receiving antiret-
roviral therapy (p. ). There is anecdotal evidence for efcacy of
the antileprosy drug clofazimine and of amidopenicillins in com-
bination with -lactamase inhibitors, such as amoxicillin with
sulbactam. Groups of novel agents being evaluated in pre-clinical
and clinical studies include diarylquinolones, nitroimidazoles,
quinazolines and ethambutol analogues.
82
More detailed accounts
of the antituberculosis drugs are available in other texts.
8486
Immunotherapy
The use of adjunct immunotherapy to treat tuberculosis is a
subject of growing interest. Administration of exoogenous IFN or
Figure 56.66 Reaction to antituberculosis drugs: Target lesions due
to pyrazinamide.
12
Ch056-X4470.indd 43 7/21/2008 3:45:51 PM
56. Tuberculosis
44
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 drug-
sensitive disease may be accelerated, and treatment potentially
shortened, by antigranuloma strategies targeted at eliminating
dormancy. Immunomodulators such as: corticosteroids, HSP-
65DNA, 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, impres-
sive treatment shortening times have been observed, and further
human testing under appropriate study designs is warranted. In
addition to the treatment shortening described above, immuno-
modulation might improve treatment outcomes using immuno-
modulators 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 resis-
tance is encountered.
Adverse drug reactions and interactions
Adverse reactions are discussed in the descriptions of the indi-
vidual drugs above and summarized in Table 56.10.
Drug interactions require careful attention, notably in HIV-
positive patients, in whom such interactions may be accentuated
and who may be taking a number of drugs, such as antiretroviral
combinations and/or antibiotics for the treatment or prevention
of opportunistic infections, with which antituberculosis agents are
likely to interact.
89
Care must therefore be taken in prescribing
concurrent antituberculosis therapy and, in cases where drug
interactions are known, changes to therapy may be required.
The principal interactions between the antituberculosis agents
and other drugs are listed in Table 56.11. Most drug interactions
encountered in antituberculosis therapy are associated with the
rifamycins (rifampicin, rifabutin and rifapentine), which induce
hepatic cytochrome enzymes, notably cytochrome p450 isoen-
zyme 3A4 (CYP3A4), involved in the metabolism of many drugs.
Rifabutin is less enzyme-inducing than rifampicin. Cytochrome
induction by antituberculosis agents affects some antiretroviral
agents, notably the protease inhibitors such as saquinavir, indina-
vir, nelnavir and ritonavir, and thus could result in signicantly
reduced levels and promote the development of viral resistance.
Conversely, co-administration of ritonavir or indinavir with rifa-
mycins inhibits their metabolism and dose adjustments may be
required. Thus the concomitant administration of antituberculosis
drugs and antiretroviral agents poses serious problems, as described
below.
It is important to note that rifamycins enhance the metabolism
of oral contraceptives and alternative means of contraception
should therefore be used during therapy. Rifamycins also reduce
the therapeutic levels of azoles such as ketoconazole and ucon-
azole. In patients taking dapsone prophylaxis for PCP, there are
seven- to 10-fold reductions in dapsone levels.
Absorption of rifampicin is signicantly reduced by the co-
administration of antacids such as aluminium hydroxide, sodium
hydroxide and magnesium trisilicate due to an increased gastric
pH. Aluminium may also form chelates with rifampicin which are
less soluble and less well absorbed.
Isoniazid delays the metabolism of warfarin, carbamazepine
and phenytoin and, conversely, reduces the plasma levels of the
azoles by enhancing their metabolism.
Table 56.10 Adverse reactions (side-effects) of the antituberculosis agents
Agent Adverse reactions
ISONIAZID
Common Anorexia, nausea, vomiting, fever, skin rashes, peripheral neuropathy
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 Orange-red discolouration of urine, anorexia, nausea, vomiting, diarrhoea, skin rashes
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 Anorexia, fever, nausea, vomiting
Uncommon Hepatitis, nausea and vomiting, urticaria, skin rash, nausea, arthralgia
Rare Sideroblastic anaemia, photosensitization, gout, dysuria, aggravation of peptic ulcer
Ch056-X4470.indd 44 7/21/2008 3:45:51 PM
Treatment of Tuberculosis
45
Agent Adverse reactions
ETHAMBUTOL
Uncommon Optic neuritis, arthralgia
Rare Hepatitis, cutaneous hypersensitivity including pruritis and urticaria, photosensitive lichenoid eruptions, paraesthesia
of the extremities, interstitial nephritis
STREPTOMYCIN
Uncommon Vertigo, ataxia, deafness, tinnitus, cutaneous hypersensitivity
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 Cutaneous hypersensitivity, vertigo, deafness
Rare Renal damage, hypoglycaemia, hypokalaemia
THIACETAZONE
Common Gastrointestinal upsets, cutaneous hypersensitivity, vertigo, conjunctivitis
Uncommon
a
Hepatitis, erythema multiforme, exfoliative dermatitis, StevensJohnson syndrome, haemolytic anaemia
Rare Agranulocytosis
P-AMINOSALICYLIC ACID
Common Gastrointestinal upsets
Uncommon Cutaneous hypersensitivity, hepatitis, hypokalaemia
Rare Acute renal failure, haemolytic anaemia, thrombocytopenia, hypothyroidism
ETHIONAMIDE/PROTHIONAMIDE
Common Gastrointestinal upsets, salivation, metallic taste
Uncommon Cutaneous hypersensitivity, hepatitis
Rare Alopecia, convulsions, deafness, diplopia, gynaecomastia, hypotension, impotence, psychiatric disturbance,
menstrual irregularity, hypoglycaemia, peripheral neuropathy
CAPREOMYCIN AND VIOMYCIN
Common Eosinophilia (with capreomycin), pain and induration at injection site
Uncommon Loss of hearing, vertigo, tinnitus, electrolyte disturbances including hypokalaemia, leucopenia or leucocytosis
Rare Renal impairment, hepatitis, thrombocytopenia
CLOFAZIMINE
Common Discolouration of skin and body uids, nausea, vomiting, abdominal pain, diarrhoea
Uncommon Dryness of skin, ichthyosis, photosensitivity
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 Convulsions, cutaneous hypersensitivity, hepatitis, megaloblastic anaemia
Rare Congestive heart failure
OFLOXACIN
Uncommon Gastrointestinal upsets, headache, dizziness, insomnia, cutaneous hypersensitivity reactions
Rare Restlessness, convulsions, psychiatric disturbances including psychotic reactions and hallucinations, oedema of face,
tongue and epiglottis, disturbance of taste and smell, anaphylactoid reactions
a
Severe thiacetazone-induced skin reactions are common in HIV-positive persons.
Table 56.10 continued
Ch056-X4470.indd 45 7/21/2008 3:45:51 PM
56. Tuberculosis
46
Treatment of tuberculosis in patients receiving
antiretroviral agents
Although patients with HIV-related tuberculosis can be prescribed
concomitant therapy such as antiretroviral agents, careful manage-
ment is required. The subject of antiretroviral therapy is a rapidly
changing one as new agents and regimens are constantly being
introduced. Drug interactions are therefore being reported with
increased frequency and the literature on the subject rapidly
becomes out of date.
Detailed discussion on interactions between antituberculosis
drugs and antiretroviral agents and the management of co-infected
patients is beyond the scope of this book. The clinician is therefore
advised to seek specialist help or refer to current guidelines issued
by the Centres for Disease Control, Atlanta, Georgia, or the WHO
(Table 56.12). The WHO recommendations published in 2006
emphasize that the priority is to treat tuberculosis: antiretroviral
agents should be deferred for 28 weeks in those with CD4 counts
of <200/mm
3
and in those whose CD4 counts are unknown; for
8 weeks in those with CD4 counts of 200350/mm
3
, while those
with counts of >350/mm
3
should be evaluated after 8 weeks
and, unless their condition is deteriorating, antiretroviral agents
can be withheld until completion of short-course antituberculosis
therapy.
76
Hypersensitivity reactions to antituberculosis
drugs and their management
These are uncommon in the rst week of treatment and are mostly
seen in the second to fourth weeks. The reactions are graded as
follows:
Mild: itching of the skin only
Moderate: fever and a rash which may be mistaken for measles
or scarlet fever. Blistering may be seen
Severe: in addition to fever and rash there may be hypotension,
generalized swelling of lymph nodes, enlargement of liver
and spleen, swelling round the eyes and swelling of the
mucous membranes of the mouth and lips. StevensJohnson
syndrome (a generalized and severe exfoliative rash and ulcer-
ation of the mucous membranes of the mouth, genitals and
eyes) may occur, particularly in HIV-positive persons receiving
thiacetazone.
Mild itching is often transitory and relieved by antihistamines but
if the moderate or severe signs and symptoms listed above develop,
antituberculosis therapy must be stopped immediately. If the
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
Drug potentiating the effects of rifampicin Trimethoprimsulfamethoxazole (cotrimoxazole)
Drug whose effects are opposed by isoniazid Enurane
Drugs whose effects are potentiated by isoniazid Phenytoin Carbamazepine
Drug potentiating the effects of isoniazid Insulin
Drugs opposing the effects of isoniazid Antacids (inhibit absorption) Prednisolone
Drugs whose effects are potentiated by streptomycin Neuromuscular blocking agents
Drug potentiating the effects of quinolones Cimetidine
Drugs whose effects are potentiated by quinolones Aminophylline Theophylline
Drugs opposing the effects of quinolones Antacids, iron preparations, sucralfate, didanosine (all inhibit
absorption)
Table 56.12 Antituberculosis drug regimens with
concomitant antiretroviral regimens
Antituberculosis
regimen
Months of
therapy
Antiretroviral therapy
Rifampicin 16 Triple non-nucleoside
reverse transcriptase
inhibitors (NRTI)
Isoniazid 16
Pyrazinamide 12
Ethambutol 12
Rifabutin 16 Nelnavir, indinavir,
amprenavir, efavirenz or
nevirapine
Isoniazid 16
Pyrazinamide 12
Ethambutol 12
Ch056-X4470.indd 46 7/21/2008 3:45:52 PM
Treatment of Tuberculosis
47
patient is seriously ill, corticosteroids should be administered.
If the patient is able to swallow, prednisolone 15 mg three
times a day is given until improvement occurs and the dose is
then reduced gradually every 2 days according to the patients
response. If the patient is unable to swallow, a suitable regimen
consists of hydrocortisone 200 mg i.v. or i.m. followed by dexa-
methasone 4 mg i.v. or i.m. until the patient can swallow, when
it is replaced by prednisolone 15 mg three times a day. When
clinical improvement occurs, the oral dose is reduced as above.
Intravenous uid replacement is required if the patient is unable
to swallow.
When the hypersensitivity reaction has subsided, antitubercu-
losis therapy should be recommenced with other drugs. Alterna-
tively, challenge doses of the rst-line drugs may be given in order
to determine which drug was responsible. The challenges should
commence with the drug least likely to have caused the reaction
and with the doses shown in Table 56.13. The patient must remain
under close observation during administration of challenge
doses.
Desensitization may be carried out if the patient is hypersensi-
tive to isoniazid or rifampicin. Desensitization to other drugs is
rarely required and must never be attempted outside specialist
centres. Desensitization to any antituberculosis agent must never
be attempted in HIV-positive patients. The usual method is to give
the patient one-tenth of the standard dose of the drug and to
increase this by one-tenth each day until the standard dose is
reached. As with challenge testing, the patient must remain under
close observation during the procedure. During desensitization
the patient should be given two antituberculosis drugs that he or
she has not received before.
Special treatment situations
Renal insufciency
Rifampicin, isoniazid, pyrazinamide, ethionamide and prothion-
amide are either fully metabolized or eliminated in the bile and
may be used safely at the normal doses in patients with renal
impairment. Isoniazid carries an increased risk of neurological
toxicity, including peripheral neuropathy and encephalopathy, in
patients with impaired renal function but this is preventable in
most cases by giving pyridoxine. Ethambutol is mainly eliminated
by the kidney but may be used in reduced doses in patients with
impaired renal function. As streptomycin and other aminoglyco-
sides are eliminated entirely by the kidney and are nephrotoxic
their use should be avoided whenever possible. Careful monitor-
ing of drug levels in patients, especially those on dialysis, is
required for successful therapy and the avoidance of adverse drug
reactions.
90
Impaired liver function
Patients with impaired liver function may be treated safely with
isoniazid, ethambutol and, if required, streptomycin. It is usually
advised that pyrazinamide should be avoided although there is
no clear evidence that it is any more toxic in patients with impaired
hepatic function. Rifampicin should be used with caution: doses
should be reduced in patients with bilirubin concentrations
exceeding 50 mmol/L . Liver function should be regularly moni-
tored, where possible, in alcoholics, the elderly, malnourished
children and children under 2 years of age.
If jaundice develops during antituberculosis therapy, treatment
should be stopped until the jaundice resolves. In many cases
resumption of treatment does not cause a recurrence of the jaun-
dice. Patients who are seriously ill with tuberculosis may be
treated with streptomycin and ethambutol even in the presence
of jaundice.
Pregnancy
The standard 6-month regimens may be safely used during preg-
nancy. 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.
Management of patients with drug- and
multi-drug resistant organisms
Patients with organisms resistant to one of the rst-line drugs
usually respond to modern short-course therapy. Resistance to
isoniazid and rifampicin (multi-drug resistance) is much more
serious as patients with such resistance do not respond to standard
regimens. Indeed, there is a risk that such treatment will result in
the development of resistance to the other agents in the regimen,
usually pyrazinamide and ethambutol.
Treatment of MDRTB is based on the second-line drugs, which
are more toxic, more costly and less effective than the rst-line
drugs. Therapy must often be continued for much longer than
standard regimens for at least 12 months after the sputum
becomes bacteriologically negative.
91
With increasing therapeutic
experience, the prognosis of patients with MDRTB is improving;
in one study of patients with disease resistant to a median of six
drugs, 85% of patients had a favourable outcome,
92
and high
levels of cure can be achieved in resource-limited settings.
93
Strict
supervision of therapy is essential to prevent emergence of extreme
Table 56.13 Sequence of reintroduction and challenge
doses for restarting therapy
CHALLENGE DOSE
Agent Likelihood of the
drug causing the
reaction and
sequence of
reintroduction
Day 1 Day 2 Day 3
Isoniazid Least/rst 50 mg 300 mg 300 mg
Rifampicin 75 mg 300 mg Full dose
Pyrazinamide 250 mg 1 g Full dose
Ethambutol 100 mg 500 mg Full dose
Streptomycin Greatest/last 125 mg 500 mg Full dose
Ch056-X4470.indd 47 7/21/2008 3:45:52 PM
56. Tuberculosis
48
drug resistance. Guidelines for the management of MDRTB are
available from the WHO.
94
In view of the growing problem of MDRTB in several regions,
the DOTS-plus strategy has been advocated.
94
In principle, all
possible steps should be taken to link the tuberculosis control
programmes in which MDRTB is encountered with a reference
laboratory where drug susceptibility testing can be carried out. The
alternative is to develop empirical regimens for the treatment of
MDRTB based on a knowledge of the patterns of drug resistance
in a given region.
In the absence of good-quality laboratory services, treatment
should be based on drugs which the patient has not received
before. Unfortunately it is often far from easy to ascertain which
drugs a patient has previously received. The golden rule of empir-
ical therapy is that a single drug must never be given to a patient
whose therapy is failing. This is a certain way of generating further
drug resistance.
The difculties in the management of MDRTB cannot be over-
emphasized. Practical advice has been published by the WHO
and, whenever possible, expert advice should be obtained. Inad-
equate therapy will be of no benet to the patient and will only
exacerbate the growing problem of resistance and has, as described
above, led to the emergence of extensively drug resistant tubercu-
losis (XDRTB) in some regions and to the very real danger of
disease untreatable by conventional means.
The role of corticosteroids in tuberculosis
Corticosteroids play no part in the treatment of uncomplicated
pulmonary tuberculosis. Although some studies indicate that they
relieve symptoms, they may well suppress protective immune
responses. In some forms of extrapulmonary tuberculosis, their
use may prevent sequelae due to scarring and may be life-saving.
95

They should never be administered unless the patient is receiving
supervised antituberculosis therapy. Their use is discussed under
the various headings of extrapulmonary tuberculosis above and is
briey summarized here:
Hypersensitivity reactions to drugs, particularly if they are life-
threatening
Life-threatening tuberculosis. Some physicians consider that ste-
roids reduce mortality in those very seriously ill with tubercu-
losis and, although not based on rm evidence, nothing is to
be lost by giving steroids to such patients. There are limited
reports of clinical benets of steroid therapy in HIV-positive
patients with serious progressive tuberculosis, even though
such therapy is likely to further reduce immune function
Pleural, pericardial and peritoneal tuberculosis. Corticosteroids
reduce the effusion, and enhance its clearance and subsequent
restrictive scarring
Tuberculous meningitis. Corticosteroids increase survival but
their ability to reduce long-term adverse sequelae in this con-
dition remains controversial. National guidelines should be
followed
Genitourinary tuberculosis. Corticosteroids relieve ureteric
obstruction and prevent further obstructive scarring and shrink-
age of the bladder
Lymph node tuberculosis. Corticosteroids are indicated when
massive enlargement of a lymph node causes respiratory dis-
tress. The use of steroids in cases with non-life-threatening
enlargement of lymph nodes due to hypersensitivity reactions
during therapy is controversial, although skin necrosis, sinus
formation and scarring may be prevented in cases of extensive
enlargement
Other indications. Steroid therapy is indicated in destructive
ocular lesions to preserve sight, in laryngeal lesions to amelio-
rate pain, for hormone replacement therapy in Addisons
disease and, extremely rarely, in life-threatening generalized
hypersensitivity reactions to tuberculin.
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 brous scarring is low, 10 mg of predniso-
lone 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 metab-
olism 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. .
Preventive therapy
Few aspects of tuberculosis control have generated more contro-
versy 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 circum-
stances, 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 compli-
ance 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 chemopro-
phylaxis rather than BCG vaccination.
13
Ch056-X4470.indd 48 7/21/2008 3:45:52 PM
Treatment of Tuberculosis
49
In general, in view of problems of compliance and organiza-
tion, preventive therapy has not played a major role in tubercu-
losis 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 preven-
tive 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 difculty of diagnos-
ing 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 indica-
tions for chemoprophylaxis and for the recommended drug regi-
mens. Preventive therapy is, however, unlikely to have a major
impact on tuberculosis control because of the difculties of
implementation.
Surgical treatment
In general, surgery plays a minor role in the treatment of pulmo-
nary tuberculosis, although resection of lesions caused by multi-
drug resistant tubercle bacilli in those with persistently positive
sputum achieves high cure rates with acceptable morbidity.
98

Other indications include life-threatening haemoptysis, myceto-
mas 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.
Tuberculosis control programmes
Following the introduction of short-course therapy in the early
1970s, a huge amount of effort was devoted to establishing
optimum drug regimens, but few concerted operational efforts
were made to apply this work to the global eradication of tuber-
culosis. Indeed, an ideal window of opportunity to control tuber-
culosis 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 tuberculo-
sis 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 devel-
ops 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, non-
governmental organizations, pharmaceutical companies and
funding agencies committed to the development of new cost-
effective 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 sup-
plied 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 eld.
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 vac-
cines, and to strengthen global partnerships so that the control
strategies can be effectively utilized.
Ch056-X4470.indd 49 7/21/2008 3:45:52 PM
56. Tuberculosis
50
In January 2006, the GPSTB published its ambitious, yet
realistic, global plan for control of tuberculosis between 2006
and 2015.
104
The aim of the plan, in common with that of
the Millennium Development Goals, is to halve the prevalence
of, and deaths due to, tuberculosis from the 1990 baseline by
the year 2015. This will require the successful treatment of
50 million patients, including 800 000 with MDRTB or XDRTB
and three million co-infected with HIV who will also receive
antiretroviral therapy under the UNAIDS plan for universal
access. The estimated cost will be US$50 billion dollars and will
therefore require an enormous and sustained advocacy effort
but it has the potential to save at least 14 million lives. Other
key elements of the plan are to develop and deploy, by 2015, new
and effective vaccines and also therapeutic regimens that will
reduce the treatment time to 12 months, be suitable for the cure
of MDRTB and XDRTB and be compatible with antiretroviral
therapy. It is noted in the plan that a particular effort will be
required in the African and Eastern European WHO regions due,
respectively, to the high incidence of HIV infection and MDRTB
and XDRTB.
The WHO DOTS strategy
In the expanded DOTS framework for effective tuberculosis control
published in 2002,
103
the ve elements of the DOTS strategy are
dened as:
Sustained political commitment to increase human and nan-
cial 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 detec-
tion 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 pro-
gramme performance.
Case nding
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 nding
relies on patients with symptoms presenting at a clinic. The ef-
ciency 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.
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 rst 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 efciency and accuracy of sputum microscopy critically
depend on the skill and dedication of the microscopist. As micro-
scopical 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 prac-
tice of microscopy and other aspects of the tuberculosis laboratory
are discussed in detail elsewhere.
29,30
Supply of drugs
It is essential that a regular supply of good-quality drugs is main-
tained and that these are available to the patients at no cost to
them. Intermittent supplies of drugs are a major cause of treat-
ment failure, the emergence of drug resistance and a loss of public
condence in the treatment services. Combination preparations,
containing two or more antituberculosis drugs, must only be pur-
chased 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 occupa-
tional 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 ve points of the WHO,
DOTS strategy, is the one that calls for particular care and atten-
tion 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 qualied 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 suc-
cessful programme, patients pay a nominal fee at the commence-
ment of therapy which is reimbursed, with interest, on successful
completion of therapy.
107
Supervision strategies must be user-
friendly, 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

14
Ch056-X4470.indd 50 7/21/2008 3:45:52 PM
51
Tuberculosis, especially HIV-related tuberculosis, carries a denite
stigma which may hinder treatment-seeking and adherence, and
should be addressed in health education activities.
111
Monitoring of tuberculosis control services
This is essential to ascertain whether the above strategies are effec-
tive and cost-effective in a given circumstance. For this purpose,
record-keeping is essential and patients reaching the end of therapy
should be followed up to detect early bacteriological relapse due
to inadequate supervision of therapy.
When adopted and applied, the DOTS strategy is able to make
a signicant impact on tuberculosis and in 2005 about 45% of all
tuberculosis patients received treatment under this strategy.
Between 2002 and 2003 the global incidence of new cases of
tuberculosis rose by 1% but, as a result of improved case nding
and treatment, the prevalence declined by 5% and deaths dropped
by 2.5% overall and 3.5% among those not infected with HIV.
15
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 pub-
lishes guidelines for establishing such pilot projects.
93,113
Projects being evaluated include those based on empirical treat-
ment regimens and the more costly but more effective ones based
on individualized treatment regimens according to drug suscepti-
bility 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 impor-
tant that DOTS-Plus programmes are only introduced in regions
where optimal DOTS strategies are already in place. The establish-
ment of a DOTS-Plus programme at the expense of a DOTS pro-
gramme can have a detrimental effect on overall tuberculosis
control.
Global strategies for control of tuberculosis
and HIV
The WHO DOTS strategy is the best way of controlling tubercu-
losis in regions with a high prevalence of HIV infection. Effective
antituberculosis therapy is a highly effective and cost-effective way
of prolonging life and improving the quality of life in those with
HIV-related tuberculosis. In view of the particular stigma associ-
ated with HIV infection and the ways that this differs from region
to region, operations research is essential to ensure that tubercu-
losis is diagnosed promptly and that therapy is completed. It is,
however, becoming apparent that DOTS alone is insufcient to
control tuberculosis in areas with a high prevalence of HIV infec-
tion and that additional strategies are required. To this end the
GPSTB established a TB/HIV Working Group in 2001 to coordi-
nate activities aimed at reducing the burden of tuberculosis in
those infected with HIV and the burden of HIV-related problems
in those with tuberculosis. There is increased collaboration
between WHO groups involved in tuberculosis and HIV and a key
aim is to make antiretroviral agents more widely available.
114
BACILLE CALMETTEGURIN VACCINATION
The only vaccine currently available for the prevention of tuber-
culosis is Bacille CalmetteGurin (BCG), named after Albert
Calmette and Camille Gurin, the French investigators who devel-
oped the vaccine from a strain of M. bovis early in the twentieth
century. This live attenuated vaccine was intended for oral admin-
istration in neonates to mimic protection conferred by milk-borne
M. bovis infection but without the risk of disease. Following a
tragedy at the German city of Lbeck in 1930, when children were
accidentally vaccinated with a virulent strain of M. tuberculosis with
the death of over 70, the vaccine was prepared in central facilities
and freeze-dried for intradermal use.
The mode of action of BCG vaccination is poorly understood.
It prevents disseminated forms of primary tuberculosis, such as
tuberculous meningitis, in children but it has only a small impact
on post-primary, infectious, pulmonary tuberculosis. It is there-
fore of limited value in global control strategies. A major problem
in its use is that, as shown in Table 56.14, its efcacy has been
Table 56.14 Protection afforded by BCG vaccination in nine major trials
Country Year of commencement of trial Age range at time of vaccination Protection afforded (%)
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 0
South India
a
1968 All ages 0
Malawi 1978 All ages 0
a
No protection at 7.5-year follow-up but some protection at 15-year follow-up in those vaccinated in infancy.
Bacille CalmetteGurin Vaccination
Ch056-X4470.indd 51 7/21/2008 3:45:52 PM
56. Tuberculosis
52
found to vary from region to region, from around 80% to no
protection at all.
115
Indeed, in some studies, it appears to have a
small adverse effect by rendering vaccinated subjects more suscep-
tible to active tuberculosis. This variation in efcacy has been
attributed to prior exposure to various mycobacterial species in
the environment, which has three postulated effects. First, such
exposure may induce a good level of protective immunity that
BCG vaccination cannot further enhance. Second, it may induce
immune responses that prevent the replication of BCG in the
tissues that appears essential for inducing protection and, third, it
may induce inappropriate tissue-destroying immune reactions
that BCG vaccination is unable to overcome and may even boost.
These three explanations are not mutually exclusive. Whatever the
explanation, neonatal BCG vaccination affords some degree of
protection in infants and small children against disseminated
forms of the disease even in regions where no protection is seen
in older children and adults. For this reason neonatal BCG remains
a part of the vaccination programme in many countries.
Many questions remain over the use of BCG vaccine. There is
very little information on the relative efcacy of the numerous
daughter strains in the human population, the added benets of
revaccination and the duration of conferred protective immunity.
Also, there is indirect evidence that the level of protection afforded
by BCG varies according to the lineage of M. tuberculosis (e.g.
W/Beijing) causing the disease. Tuberculin reactivity following
vaccination is not a correlate of protective immunity and a dimi-
nution or loss of such reactivity is not a reliable indication of loss
of protection.
BCG is given by intradermal injection or, in neonates, percu-
taneously by means of multi-puncture devices. Vaccine for intra-
dermal use is usually supplied in 10-dose ampoules which are
reconstituted with 1 mL of distilled water and 0.1 mL (0.05 mL in
neonates) is administered. Complications have followed the acci-
dental administration of the entire contents of the 10-dose
ampoule by deep cutaneous or intramuscular injection and by the
intradermal injection of vaccine prepared for percutaneous use,
which contains many more bacilli than the preparations for intra-
dermal use. Vaccines should be used within 4 h of reconstitution
and must be protected from sunlight.
BCG vaccination causes a small papule to develop within a
week or so and in some cases a shallow ulcer forms but usually
heals within 612 weeks. At least 3 weeks should elapse between
BCG vaccination and administration of yellow fever, measles,
rubella, mumps and smallpox vaccines and no vaccination should
be given in the same arm for 4 months.
Complications of BCG vaccination
If properly given, complications are very uncommon. Local adverse
reactions usually occur at a rate of 0.10.5/1000 vaccinations and
serious, disseminated complications occur at a rate of less than
one in a million vaccinations.
116
Local complications include
necrotic lesions due to excessive delayed hypersensitivity reac-
tions, subcutaneous abscesses, lymphadenopathy (mostly axil-
lary) and keloid formation. Hypersensitivity reactions usually
occur within a few days of vaccination and are more frequent in
revaccinated subjects and in those who are tuberculin-positive.
Local abscesses usually appear between 1 and 5 months after vac-
cination or even later. Lymphadenopathy occurs in the drainage
area of the vaccinated site, usually the axilla, although cervical
lymphadenopathy may occur if the vaccine is given in the upper
deltoid region. Some degree of transient lymphadenopathy is not
uncommon after percutaneous vaccination of neonates. The risk
of keloid scarring is reduced by giving the injection in the skin
overlying the insertion of the deltoid muscle. Injections higher up
the arm are much more likely to lead to keloid scaring.
Osteitis is a rare complication of neonatal BCG vaccination. A
relatively high incidence in Scandinavia ceased when the BCG
daughter strain was changed. Disseminated disease (BCG-osis)
is a very rare complication of BCG vaccination and the mortality
rate is high. Some cases have occurred in HIV-positive persons
and others in children with various forms of severe congenital
immunodeciency.
Local hypersensitivity reactions resolve spontaneously and,
although topical steroids are often prescribed, there is no rm
evidence that they are effective. Local abscesses may resolve after
aspiration but if the abscess recurs isoniazid, 6 mg/kg body weight
daily to a maximum of 300 mg, or erythromycin, 250 mg four
times daily, each for 1 month, is usually curative. Local lymphad-
enitis usually resolves spontaneously; antimicrobial therapy has
little effect and surgery should only be used if the nodes are grossly
enlarged or if there is suppuration and sinus formation. More
serious disease, such as osteitis and disseminated infection,
requires treatment with standard antituberculosis therapy,
although pyrazinamide may be omitted as BCG, in common with
M. bovis, is naturally resistant to this agent.
Vaccination strategies
These vary from region to region, and are inuenced by the prev-
alence of tuberculosis and information on the efcacy of the
vaccine in a given region. The WHO recommends that BCG should
be given to all neonates in high-prevalence regions and communi-
ties. 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 benets of vac-
cination greatly outweigh any disadvantages. The WHO recom-
mends 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
Development of new vaccines
Since no infectious disease has ever been eradicated with drug
treatment alone, the current tools available for tuberculosis control
will be insufcient to achieve total eradication of this disease
worldwide. A new vaccine, especially one that would prevent post-
primary, transmissible, disease and a non-viable one that could
be given safely to those infected with HIV would be of very great
Ch056-X4470.indd 52 7/21/2008 3:45:53 PM
53
benet. The development of novel vaccines is currently the subject
of extensive research activity.
118
The complete sequencing of the
genome of M. tuberculosis has facilitated the identication of
several antigens that have the potential to confer protective immu-
nity and a number of delivery systems are under investigation.
Attention will also have to be given to the ability of novel vaccines
to overcome or reverse inappropriate immune responses so that
they are not susceptible to the environmental factors that lead to
the geographical variations in efcacy of BCG. Several approaches
to TB vaccine development have been made:
2526
1. Improved BCG: e.g. over-expression of protective antigens
(AGs), or reconstitution of deleted genes
2. Attenuated Mycobacterium tuberculosis: targeted inactivation
(knock-out) of metabolic or virulence genes
3. Adjuvanted Protein Subunit Vaccines (also peptides or DNA
vaccines)
a. hypothesis driven selection: e.g. secreted AGs
b. empirical selection: e.g. T/B cell recognition and/or MHC
binding, combination of AGs
4. Other approaches: live-vectored AGs, e.g. vaccinia (MVP), ade-
novirus, Salmonella, etc or non-protein AGs, e.g. -TCR or
CD1-binding molecules; conjugates, etc.
As of 2006, there are promising indications of improvements in
BCG efcacy; at least ve vaccine candidates are in phase I/phase
2 clinical trials (rBCG30; rBCG: D ureC-llo+; MVA-85A; Ag85B-
ESAT-6; Mtb72f); and several more candidates are in pre-clinical
development. Many current vaccine candidates are based on mod-
ications to BCG, yet our understanding of the immunobiology
underlying BCGs ineffectiveness remains incomplete. The under-
standing of the distinction between protective immune responses
and immunopathology, though improving, remains blurred.
36

Although some candidate vaccines have reached the stage of
clinical trials, extensive and time-consuming studies, with close
attention to safety and ethical issues, will be required to deter -
mine the degree and duration of the protective effect. As efforts
to nd effective vaccines continue, existing WHO recommenda-
tions for the diagnosis, management and control of tuberculosis
must be rigorously applied and extended worldwide.
Ongoing research
To improve the treatment outcomes of tuberculosis, research led
by a number of international organizations and academic institu-
tions 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 pro-
gramme performance.
119
Current UNDP/UNICEF/World Bank/WHO
Special Programme in Research and Training, Scientic Working
Group recommendations
120,121
for priority research into tubercu-
losis are grouped into several areas:
1. Improved diagnostics tuberculosis
122
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
6. Improved programme performance and capacity building
7. Epidemiological research in national TB programmes
8. Cross-cutting issues.
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 devel-
oped 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 rectication 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
afiction.
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).
REFERENCES
1. Gutierrez MC, Brise S, Brosch R, et al. Ancient origin and gene mosaicism of
the progenitor of Mycobacterium tuberculosis. PLoS 2005; 1(1):e5.
2. Gagneux S, DeRiemer K, Tran Van, et al. Variable host-pathogen
compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci 2006;
103:28692873.
References
Ch056-X4470.indd 53 7/21/2008 3:45:53 PM
56. Tuberculosis
54
3. Kremer K, Glynn JR, Lillebaek T, et al. Denition of the Beijing/W lineage of
Mycobacterium tuberculosis on the basis of genetic markers. J Clin Microbiol
2004; 42:40404049.
4. Toungoussova OS, Caugant DA, Sandven P, et al. Impact of drug resistance
on tness of Mycobacterium tuberculosis strains of the W-Beijing genotype.
FEMS Immunol Med Microbiol 2004; 42:281290.
5. Glynn JR, Crampin AC, Yates MD, et al. The importance of recent infection
with Mycobacterium tuberculosis in an area with high HIV prevalence: a long-
term molecular epidemiological study in northern Malawi. J Infect Dis 2005;
192:480487.
6. Wallgren A. The time table of tuberculosis. Tubercle 1948; 29:245251.
7. Rook GAW, Zumla A. Advances in the immunopathogenesis of pulmonary
tuberculosis. Curr Opin Pulm Med 2001; 7:116123.
8. Wilkinson RJ, Llewelyn M, Toossi Z, et al. Inuence of vitamin D
deciency and vitamin D receptor polymorphisms on tuberculosis among
Gujarati Asians in west London: a case-control study. Lancet 2000; 355:
618621.
9. Hernandez-Pando R, de la Luz Streber M, Orozco H, et al. Emergent
immunoregulatory properties of combined glucocorticoid and anti-
glucocorticoid steroids in a model of tuberculosis. QJM 1998; 91:
755766.
10. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune
response. Nature Immunol 2004; 5:987995.
11. Means TK, Jones BW, Schromm AB, et al. Differential effects of a Toll-like
receptor antagonist on Mycobacterium tuberculosis-induced macrophage
responses. J Immunol 2001; 166:40744082.
12. Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants
of virulence. Clin Microbiol Rev 2003; 16:463496.
13. Deretic V, Singh S, Master S, et al. Mycobacterium tuberculosis inhibition of
phagolysosome biogenesis and autophagy as a host defence mechanism. Cell
Microbiol 2006; 8:719727.
14. Pym AS, Brodin P, Majlessi L, et al. Recombinant BCG exporting ESAT-6
confers enhanced protection against tuberculosis. Nature Med 2003; 9:
533539.
15. WHO. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO
Report. Geneva: World Health Organization; 2006: WHO/HTM/
TB/2006.34962.
16. Van Soolingen D. Molecular epidemiology of tuberculosis and other
mycobacterial infections: main methodologies and achievements. J Int Med
2001; 249:126.
17. Groenen PM, Bunchoten D, van Soolingen D, et al. Nature of DNA
polymorphism in the direct repeat cluster of Mycobacterium tuberculosis and its
use as an epidemiological tool. Mol Microbiol 1993; 10:10571065.
18. UNAIDS/Stop TB Partnership. Information pack on TB/HIV. Geneva: World
Health Organization; 2006.
19. Ahmed Y, Mwaba P, Chintu C, et al. A study of maternal mortality at
University Teaching Hospital, Lusaka, Zambia: the emergence of tuberculosis
as a major non-obstetric cause of maternal death. Int J Tuberc Lung Dis 1999;
3:675681.
20. WHO. Progress Report on the Global Plan to Stop Tuberculosis. Geneva: World
Health Organization; 2004: WHO/HTM/STB/2004.29.
21. WHO. Anti-Tuberculosis Drug Resistance in the World. Report No. 3. Geneva:
World Health Organization; 2004: WHO/HTM/2004.343.
22. Mitchison DA. How drug resistance emerges as a result of poor compliance
during short course chemotherapy of tuberculosis. Int J Tuberc Lung Dis 1998;
2:1015.
23. Centers for Disease Control. Emergence of Mycobacterium tuberculosis with
extensive resistance to second-line drugs worldwide, 20002004. MMWR
2006; 55:301305.
24. Davies RPO, Tocque K, Bellis MA, et al. Historical declines in tuberculosis in
England and Wales: improving social conditions or natural selection? Int
J Tuberc Lung Dis 1999; 3:10511054.
25. Grange JM, Gandy M, Farmer P, et al. Historical declines in tuberculosis
nature, nurture and the biosocial model. Int J Tuberc Lung Dis 2001; 3:
208212.
26. Gajalakshmi V, Peto R, Kanaka TS, et al. Smoking and mortality from
tuberculosis and other diseases in India: retrospective study of 43 000 adult
male deaths and 35000 controls. Lancet 2003; 362:507515.
27. American Thoracic Society, Centers for Disease Control. Treatment of
tuberculosis and tuberculosis infection in adults and children. Am J Respir
Crit Care Med 1994; 149:13591374.
28. Grange JM, Ustianowski A, Zumla A. Tuberculosis and pregnancy. In: Diwan
V, Thorson A, Winkvist A, eds. Gender and Tuberculosis. Gteborg: Nordic
School of Public Health; 1998:7788.
29. Collins CH, Grange JM, Yates MD. Tuberculosis Bacteriology: Organization and
Practice. 2nd edn. London: Butterworth-Heinemann; 1997.
30. International Union Against Tuberculosis and Lung Disease. Management
of Tuberculosis: A Guide for Low Income Countries. 5th edn. Paris: IUATLD;
2000.
31. Rieder HL, Chiang CY, Rusen ID. A method to determine the utility of the
third diagnostic and the second follow-up sputum smear examinations
to diagnose tuberculosis cases and failures. Int J Tuberc Lung Dis 2005; 9:384
391.
32. Leonard MK, Osterholt D, Kourbatova EV, et al. How many sputum
specimens are necessary to diagnose pulmonary tuberculosis? Am J Infect
Control 2005; 33:5861.
33. Saglam L, Akgun M, Aktas E. Usefulness of induced sputum and breoptic
bronchoscopy specimens in the diagnosis of pulmonary tuberculosis. J Int
Med Res 2005; 33:260265.
34. Olu Osoba A. Microbiology of tuberculosis. In: Madkour M, ed. Tuberculosis.
Berlin: Springer; 2003:115132.
35. Andreu J, Caceres J, Pallisa E, et al. Radiological manifestations of pulmonary
tuberculosis. Eur J Radiol 2004; 51:139149.
36. Shamputa IC, Rigouts L, Portaels F. Molecular genetic methods for diagnosis
and antibiotic resistance detection of mycobacteria from clinical specimens.
APMIS 2004; 112:728752.
37. Fitzgerald JM, Menzies D. Interpretation of the tuberculin skin test. In: Davies
PDO, ed. Clinical Tuberculosis. 3rd edn. London: Arnold; 2003:323336.
38. Dheda K, Udwadia ZF, Huggett JF, et al. Utility of the antigen-specic
interferon-gamma assay for the management of tuberculosis. Curr Opin Pulm
Med 2005; 11:195202.
39. WHO. Guidance for national tuberculosis programmes on the management
of tuberculosis in children. Geneva: World Health Organization; 2006:
WHO/HTM/TB/2006.371.
40. Fourie PB, Becker PJ, Festenstein F, et al. Procedures for developing a simple
scoring method based on unsophisticated criteria for screening children for
tuberculosis. Int J Tuberc Lung Dis 1998; 2:116123.
41. Marais BJ, Gie RP, Obihara CC, et al. Well dened symptoms are of value in
the diagnosis of childhood pulmonary tuberculosis. Arch Dis Child 2005;
90:11621165.
42. Delacourt C, Mani TM, Bonnerot V, et al. Computed tomography with
normal chest radiograph in tuberculous infection. Arch Dis Child 1993;
69:430432.
43. Smith KC. Congenital tuberculosis: a rare manifestation of a common
infection. Curr Opin Infect Dis 2002;15:269274.
44. Marais BJ, Donald PR, Gie RP, et al. Diversity of disease in childhood
pulmonary tuberculosis. Ann Trop Paediatr 2005; 25:7986.
45. Ormerod LP, Grundy M, Rathman MA. Multiple tuberculous bone lesions
resembling metastatic disease. Tubercle 1989; 70:305307.
46. Joseffer SS, Cooper PR. Modern imaging of spinal tuberculosis. J Neurosurg
Spine 2005; 2:145150.
47. Nene A, Bhojraj S. Results of nonsurgical treatment of thoracic spinal
tuberculosis in adults. Spine J 2005; 5:7984.
48. Thwaites G, Chan TT, Mai NT, et al. Tuberculous meningitis. J Neurol
Neurosurg Psychiatry 2000; 68:289299.
49. Johansen IS, Lundgren B, Tabak F, et al. Improved sensitivity of nucleic acid
amplication for rapid diagnosis of tuberculous meningitis. J Clin Microbiol
2004; 42:30363040.
50. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis.
Cochrane Database Syst Rev 2000; CD002244.
Ch056-X4470.indd 54 7/21/2008 3:45:53 PM
55
51. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the
treatment of tuberculous meningitis in adolescents and adults. N Engl J Med
2004; 351:17411751.
52. Ustvedt HJ. The relationship between renal tuberculosis and primary
infection. Tubercle 1947; 28:2225.
53. Petersen L, Mommsen S, Pallisgaard G. Male genitourinary tuberculosis:
report of 12 cases and review of the literature. Scand J Urol Nephrol 1993;
27:425428.
54. Eastwood JB, Corbishley CM, Grange JM. Tuberculosis and the kidney. J Am
Soc Nephrol 2001; 12:13071314.
55. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other
mycobacterial infections. In: Davidson AMA, Cameron JS, Grunfeld J-P, et al.,
eds. Oxford Textbook of Nephrology. 4th edn. Oxford: Oxford University Press;
2004;7.3.
56. Morgan SH, Eastwood JB, Baker LRI. Tuberculous interstitial nephritis: the tip
of an iceberg. Tubercle 1991; 71:56.
57. Eastwood JB, Zaidi M, Maxwell JD, et al. Tuberculosis as primary renal
diagnosis in end-stage uraemia. J Nephrol 1994; 7:290293.
58. Menzies RI, Alsen H, Fitzgerald JM, et al. Tuberculous peritonitis in Lesotho.
Tubercle 1986; 67:4754.
59. TshibwabwaTumba E, Mwaba P, Bogle-Taylor J, et al. Four year study of
abdominal ultrasound in 900 Central African adults with AIDS referred for
diagnostic imaging. Abdominal Imaging 2000; 25:290296.
60. Akgun Y. Intestinal and peritoneal tuberculosis. Changing trends over 10
years and a review of 80 patients. Canadian Journal of Surgery 2005; 48:
131136.
61. Falkner MJ, Reeve PA, Locket S. The diagnosis of tuberculous ascites in a rural
African community. Tubercle 1985; 66:5559.
62. Grange JM, Noble WC, Yates MD, et al. Inoculation mycobacterioses. Clin Exp
Dermatol 1988; 13:211220.
63. Morrison JGL, Fourie ED. The papulonecrotic tuberculide from Arthus
reaction to lupus vulgaris. Br J Dermatol 1974; 91:273277.
64. Lau SK, Wei WI, Hsu C, et al. Efcacy of ne needle aspiration in the diagnosis
of tuberculous cervical lymphadenopathy. J Laryngol Otol 1990; 104:2427.
65. Strang JI. Tuberculous pericarditis in Transkei. Clin Cardiol 1984; 7:667670.
66. Dinning WJ, Marston S. Cutaneous and ocular tuberculosis: a review. J R Soc
Med 1985; 78:576581.
67. Rosen PH, Spalton DJ, Graham EM. Intraocular tuberculosis. Eye 1990;
4:486492.
68. Alevritis EM, Sarubbi FA, Jordan RM, et al. Infectious causes of adrenal
insufciency. South Med J 2003; 96:888890.
69. Glynn JR, Crampin AC, Yates MD, et al. The importance of recent infection
with Mycobacterium tuberculosis in an area with high HIV prevalence: a long-
term molecular epidemiological study in Northern Malawi. J Infect Dis 2005;
192:480487.
70. Schon T, Wolday D, Elias D, et al. Kinetics of sedimentation rate, viral load
and TNF-alpha in relation to HIV co-infection in tuberculosis. Trans R Soc
Trop Med Hyg 2006; 100:483488.
71. Lucas SB, Peacock CS, Hounnou A, et al. Disease in children infected with
HIV in Abidjan, Cote-dIvoire. BMJ 1996; 312:335338.
72. Tshibwabwa-Tumba E, Mwinga A, Pobee JOM, et al. Radiological features of
pulmonary tuberculosis in 963 HIV-infected adults at three Central African
hospitals. Clin Radiol 1997; 52:837841.
73. WHO. TB/HIV. A Clinical Manual. 2nd edn. Geneva: World Health
Organization; 2004.
74. Lawn SD, Bekker LG, Wood R. How effectively does HAART restore immune
responses to Mycobacterium tuberculosis? Implications for tuberculosis control.
AIDS 2005; 19:11131124.
75. Grimwade K, Sturm AW, Nunn AJ, et al. Effectiveness of cotrimoxazole
prophylaxis on mortality in adults with tuberculosis in rural South Africa.
AIDS 2005; 19:163168.
76. WHO HIV/AIDS Programme. Antiretroviral therapy for HIV infection in
adults and adolescents in resource-limited settings: towards universal access.
Recommendations for a public health approach. 2006 Revision. Geneva:
World Health Organization; 2006.
77. WHO Global Tuberculosis Programme and UNAIDS. Policy Statement on
Preventive Therapy against Tuberculosis in People Living with HIV. Geneva: WHO,
1998.
78. Cosivi O, Grange JM, Daborn CJ, et al. Zoonotic tuberculosis due to
Mycobacterium bovis in developing countries. Emerg Infect Dis 1998; 4:5970.
79. Kazwala RR, Daborn CJ, Sharp JM, et al. Isolation of Mycobacterium bovis
from human cases of cervical adenitis in Tanzania: a cause for concern?
Int J Tuberc Lung Dis 2001; 5:8791.
80. Mitchison DA. The role of individual drugs in the chemotherapy of
tuberculosis. Int J Tuberc Lung Disease 2000; 4:796806.
81. WHO. Treatment of Tuberculosis: Guidelines for National Programmes. 3rd edn.
Geneva: WHO; 2003: WHO/CDS/TB2003.313.
82. Onyebujoh P, Zumla A, Ribiero I, et al. Treatment of tuberculosis: present
status and future prospects. Bull WHO 2005; 83:857865.
83. Ziganshina LE, Vizel AA, Squire SB. Fluoroquinolones for treating
tuberculosis. Cochrane Database Syst Rev 2005; 3:CD004795.
84. Grange JM, Zumla A. Antituberculosis agents. In: Cohen J, Powderly WG, eds.
Infectious Diseases. London: Elsevier Health Sciences. 2nd edn. Section 7.
2003; 18511867.
85. Grange JM. Antimycobacterial agents. In: Finch RG, Greenwood D, Norrby
SR, et al., eds. Antibiotic and Chemotherapy. 8th edn. Edinburgh: Churchill
Livingstone; 2003:426440.
86. Peloquin CA. Clinical pharmacology of antituberculosis drugs. In: Davies
PDO, ed. Clinical Tuberculosis. 3rd edn. London: Arnold; 2003:171190.
87. Johnson JL, Kamya RM, Okwera AM, et al. Randomised controlled trial of
Mycobacterium vaccae immunotherapy in non-immunodeciency virus-
infected Ugandan adults with newly diagnosed pulmonary tuberculosis.
J Infect Dis 2000; 181:13041312.
88. Stanford JL, Stanford CA, Grange JM, et al. Does immunotherapy with heat-
killed Mycobacterium vaccae offer hope for multi-drug-resistant pulmonary
tuberculosis? Respir Med 2001; 95:444447.
89. Yew WW. Clinically signicant interactions with drugs used in the treatment
of tuberculosis. Drug Saf 2002; 25:111133.
90. Launay-Vacher V, Izzedine H, Deray G. Pharmacokinetic considerations in the
treatment of tuberculosis in patients with renal failure. Clin Pharmacokinet
2005; 44:221235.
91. Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome analysis of 205
patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med
2004; 169:11031109.
92. Nathanson E, Lambregts-van-Weezenbeek C, Rich ML, et al. Multidrug-
resistant tuberculosis management in resource-limited settings. Emerg Infect
Dis 2006; 12:13891397.
93. WHO. Guidelines for the Programmatic Management of Drug-Resistant
Tuberculosis. Geneva: World Health Organization; 2006: WHO/HTM/
TB/2006.361.
94. Farmer P, Kim JY. Community based approaches to the control of
multidrug resistant tuberculosis: introducing DOTS-plus. BMJ 1998;
317:671674.
95. Alzeer AH, FitzGerald JM. Corticosteroids and tuberculosis: risks and use as
adjunct therapy. Tubercle Lung Dis 1993; 74:611.
96. Israel HL. Chemoprophylaxis for tuberculosis. Respir Med 1993; 87:8183.
97. Blumberg HM, Leonard MK, Jasmer RM. Update on the treatment of
tuberculosis and latent tuberculosis infection. J Am Med Assoc 2005;
293:27762784. (Erratum in J Am Med Assoc 2005; 294:182; dosage error in
text).
98. Shiraishi Y, Nakajima Y, Katsuragi N, et al. Resectional surgery combined
with chemotherapy remains the treatment of choice for multidrug-resistant
tuberculosis. J Thorac Cardiovasc Surg 2004; 128:523528.
99. The Winterthur Health Forum. Massive Effort Advocacy Forum Report. Massive
Effort Against Diseases of Poverty. Geneva: World Health Organization; 2000.
Online. Available: www.winterthurhealthforum.org
100. Grange JM, Zumla A. Tuberculosis and the poverty-disease cycle. J R Soc Med
1999; 92:105107.
101. UN Millennium Project. Investing in Development: A Practical Plan to Achieve
the Development Goals. New York: UNDP; 2005.
References
Ch056-X4470.indd 55 7/21/2008 3:45:53 PM
56. Tuberculosis
56
102. Global Drug Facility. Sustaining the Gains. National Self Sufciency for TB Drug
Access. A Global Drug Facility Strategy. Geneva: World Health Organization;
2005.
103. WHO. An Expanded DOTS Framework for Effective Tuberculosis Control. Geneva:
World Health Organization; 2002.
104. Stop TB Partnership and the WHO. The Global Plan to Stop TB: 20062015.
Geneva: World Health Organization; 2006: WHO/HTM/STB/2006.35.
105. Farmer P. Social scientists and the new tuberculosis. Soc Sci Med 1997;
44:347358.
106. Ogden JA. Compliance versus adherence: just a matter of language? The
politics and poetics of public health. In: Porter JDH, Grange JM, eds.
Tuberculosis an Interdisciplinary Perspective. London: Imperial College Press;
1999:213234.
107. Chowdhury AMR, Chowdhury SA, Islam MN, et al. Control of tuberculosis
through community health workers in Bangladesh. Lancet 1997; 350:
160172.
108. Williams G. Patient holding. In: Davies PDO, ed. Clinical Tuberculosis. 3rd
edn. London: Arnold; 2003:427435.
109. Volmink J, Garner P. Directly observed therapy for treating tuberculosis.
Cochrane Database Syst Rev 2003; 1:CD003343. DOI: 10.1002/14651858.
CD003343.
110. Edington ME, Sekante CS, Goldstein SJ. Patients beliefs: do they affect
tuberculosis control? A study of a rural district of South Africa. Int J Tuberc
Lung Dis 2002; 6:10751082.
111. Grange JM. The stigma of tuberculosis. In: Pratt RJ, Grange JM, Williams G,
eds. Tuberculosis: A Foundation for Nursing and Healthcare Practice. London:
Arnold; 2005:189195.
112. Farmer P, Kim JY. Community based approaches to the control of multidrug-
resistant tuberculosis: introducing DOTS plus. BMJ 1998; 317:671674.
113. WHO. Guidelines for Establishing DOTS plus Pilot Projects for the Management of
Multi-Drug Resistant Tuberculosis. Geneva: World Health Organization; 2000.
114. UNAIDS. The Three Ones in Action: Where we are and Where we go from Here.
Geneva: UNAIDS; 2005.
115. Fine PEM. Variation in protection by BCG: implications of and for
heterologous immunity. Lancet 1995; 346:13391345.
116. Lotte A, Wasz-Hckert O, Poisson N, et al. BCG complications. Adv Tuberc Res
1984; 21:107193.
117. WHO. HIV and routine childhood immunization. Wkly Epidemiol Rec 1987;
62:297299.
118. Mustafa AS. Progress towards the development of new anti-tuberculosis
vaccines. In: Smithe LT, ed. Focus on Tuberculosis Research. Hauppauge: Nova
Science; 2005:4776.
119. Stop TB Partnership. Global Plan to Stop TB. STOP TB Partnership; 2005.
Online. Available: http://www.stoptb.org/gpstb/assets/wgstrategicplans/
DEWGfull210905.pdf 14 Nov 2005.
120. Scientic Working Group on Tuberculosis. WHO/TDR Report. Geneva: World
Health Organization; 2005: TDR/SWG/06.
121. WHO. TB/HIV Research Priorities in Resource-Limited Settings. Scientic working
group on Tuberculosis. Report of an expert consultation, 1415 February.
Geneva: World Health Organization; 2005: WHO/HTM/TB/2005.355, WHO/
HIV/2005.03.
122. Perkins M, Rosicgno G, Zumla A. Progress towards improved
tuberculosis diagnostics in developing countries. Lancet 2006; 367:
942943.
GENERAL READING
Cole ST, Eisenach KD, McMurray DN, et al., eds. Tuberculosis and the Tubercle
Bacillus. Oxford: Blackwell; 2004.
Crofton J, Horne N, Miller F. Clinical Tuberculosis. 2nd edn. London: Macmillan;
1999.
Davies PDO, ed. Clinical Tuberculosis. 3rd edn. London: Arnold; 2003.
Davies PDO, Ormerod LP. Case Presentations in Clinical Tuberculosis. London:
Arnold; 1999.
Donald PR, Fourie PB, Grange JM. Tuberculosis in Childhood. Pretoria: van Schaik;
1999.
Gandy M, Zumla A. Return of the White Plague. Global Poverty and the New
Tuberculosis. London and New York: Verso Press; 2003.
International Union against Tuberculosis and Lung Disease. Management of
Tuberculosis: A Guide for Low Income Countries. 5th edn. Paris: IUATLD;
2000.
Madkour M, ed. Tuberculosis. Berlin: Springer; 2003.
Porter JDH, Grange JM, eds. Tuberculosis an Interdisciplinary Perspective. London:
Imperial College Press; 1999.
Pratt RJ, Grange JM, Williams G. Tuberculosis: A Foundation for Nursing and
Healthcare Practice. London: Arnold; 2005.
Raviglione MC. Reichman and Hershelds Tuberculosis. A Comprehensive, International
Approach. 3rd edn. New York: Informa care; 2007.
Schlossberg D. Tuberculosis and Nontuberculosis Mycobacterial Infections. 5th edn.
Maidenhead: McGraw-Hill; 2006.
Schluger N. Tuberculosis. Clinics in Chest Medicine. Philadelphia: Saunders;
2005.
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