Section 8

Bacterial Infections

Chapter 56
Tuberculosis

John M. Grange and Alimuddin I. Zumla

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 throughout 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 tuberculosis 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 settlers. 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 encountered 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 tuberculosis 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 variants 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 ngerprinting (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 mutation 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 diameter. In common with other mycobacteria, they retain arylmethane dyes on treatment with mineral acids, a property termed acidfastness. 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 automated culture systems and nucleic acid-based detection systems are now available (see p. ).

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56.

Tuberculosis

Table 56.1 Historical clinical descriptions of tuberculosis Description

Consumption Pthisis Tabes pulmonalis Tissic Hectic fever Asthenia Galloping consumption Scrofula Struma Kings evil Hydrocephalus (acute or infantile) Potts disease Tuberculous chancre Scrofuloderma Lupus vulgaris

Clinical type of tuberculosis

Pulmonary Pulmonary Pulmonary Pulmonary Pulmonary Pulmonary Pulmonary Cervical lymphadenitis Cervical lymphadenitis Cervical lymphadenitis Tuberculous meningitis Spinal/vertebral tuberculosis Skin Skin Skin A

Figure 56.1 Professor Robert Koch, discoverer of Mycobacterium tuberculosis.

B Figure 56.2 (A) ZiehlNeelsen staining of a sputum sample and (B) a bronchoalveolar lavage washing showing acid-fast bacilli.

PATHOGENESIS
Infection of humans with M. tuberculosis occurs by inhalation, ingestion or traumatic inoculation. Intrauterine infection resulting in congenital tuberculosis is extremely rare. In most cases infection is by inhalation of small droplets of cough spray containing a few bacilli. These particles, around 5 m in diameter, lodge in the alveolae or small airways, mostly in the lower regions of the lung. The usual sources of such infectious

particles are other human beings with open pulmonary tuberculosis but those working with cattle may be infected by M. bovis in the cough spray of diseased animals. A less frequent mode of infection is consumption of milk or food contaminated by M. bovis, in which case the bacilli often lodge in the tonsil or intestinal wall. Rarely, tubercle bacilli enter the skin through cuts and abrasions (Figure 56.3) and primary skin tuberculosis was an occupational hazard of butchers, anatomists and pathologists. Traditionally, tuberculosis has been divided into two forms, primary and post-primary. In the past it was usually assumed that post-primary tuberculosis was always the result of endogenous reactivation of latent or dormant primary lesions but DNA ngerprinting has shown that many cases, particularly among immunosuppressed persons, are due to exogenous reinfection.5 The natural history of infection with M. tuberculosis and its sequelae are shown diagrammatically in Figure 56.4. Most people infected by tubercle bacilli do not develop symptoms and the primary infection may go unnoticed. In most cases, effective immune responses lead to containment of the disease process and

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Pathogenesis

Primary infection (lung, tonsil, gut or skin)

Lung Ghons focus Lymphangitis Lymphadenitis = primary complex Lymph node and/or lung lesion persists Resolution (heals)

Figure 56.3 Primary tuberculous lesion of the skin.

Bloodstream spread

Local spread

Reactivation of disease due to: HIV, old age, diabetes, cytotoxics, steroids, stress, malnutrition, malignancies, chronic liver and renal disease etc.

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 understanding 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 macrophages 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 effusion 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

Obstruction of bronchus

Ruptures into bronchus

Extensive pulmonary tuberculosis Miliary tuberculosis Organ tuberculosis

Lobar collapse

TB bronchopneumonia

Figure 56.4 Natural history and sequelae of tuberculosis infection.

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, especially when immunity is compromised. Alternatively, it may gradually 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 individual 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.

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56.

Tuberculosis

Table 56.2 The timetable of primary tuberculosis Stage

1

Duration
38 weeks

Features
The primary complex develops. Conversion to tuberculin positivity occurs Life-threatening forms of disease due to haematogenous dissemination occur, i.e. tuberculous meningitis and miliary tuberculosis Tuberculous pleurisy may be the result of either haematogenous spread or direct spread from an enlarging primary focus This stage lasts until the primary complex resolves. More slowly developing extrapulmonary lesions, particularly in the bones and joints, may appear Genitourinary tuberculosis may occur as a late manifestation of primary tuberculosis

About 3 months

34 months

4 A

Up to 3 years

Up to 12 years

Adapted from Wallgren and Ustvedt.6,52

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.

Within 38 weeks of initial infection, conversion to dermal reactivity to tuberculin occurs. Since the introduction of the tuberculin skin test by Clemens von Pirquet in the early 1900s, there has been considerable speculation as to the nature and signicance of positive reactions, particularly their relevance to protective 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 infection 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 radiologically 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 pulmonary 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.

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Pathogenesis

Figure 56.6 (AC) The complications and sequelae of primary pulmonary tuberculous lesions.

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Tuberculosis

numerous smaller lesions in the other lung elds (Figure 56.9). Bacilli in the sputum may also lodge in the larynx, causing tuberculous 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 dissemination 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 tuberculosis. 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 eosinophilic cytoplasm and elongated nuclei and as they resemble epithelial cells they are called epithelioid cells. Some macrophages fuse to form multinucleated Langhans giant cells. A zone of lymphocytes and broblasts surrounds this compact cellular structure which is termed the tubercle as it resembles a small potato tuber (Figure 56.10A). The tubercle is an example of a granuloma, a characteristic feature of chronic infections. Within 2 weeks, caseous necrosis is seen in the centres of the granulomas but this is also seen in other chronic infections, including deep-seated fungal infections (e.g. Histoplasma capsulatum) and thus a 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 macrophages and an inltration of T lymphocytes. The extent and morphological features of the granuloma vary considerably from person to person so that a wide spectrum of granulomatous reactions is seen in tuberculosis. At one end of this spectrum, characterized by compromised immune responses, there is poor granuloma formation and extensive areas of tissue necrosis containing large numbers of mycobacteria. At the other end, in which immune responses are relatively intact, indolent non-caseating granulomas containing few organisms are seen. The latter are typically seen in chronic skin tuberculosis (lupus vulgaris) and histologically the lesions resemble those seen in tuberculoid leprosy and sarcoidosis. Most tuberculosis patients fall between these two extremes. The tuberculous process may involve serous cavities, usually the pleural cavities but sometimes the pericardial cavity. Such involvement appears to be primarily due to a hypersensitivity reaction to antigens of the tubercle bacillus and is characterized by an 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.

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

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Host Immune Responses to M. Tuberculosis

A A

B Figure 56.10 (A) Classical caseating granuloma due to M. tuberculosis. Note the central area of caseous necrosis surrounded by a rim of epithelioid cells, Langhans giant cells and lymphocytic 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. B Figure 56.9 (A) Extensive pulmonary tuberculosis with cavitation. (B) Postmortem lung showing several cavities and extensive lung involvement due to 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.

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 disturbances in host immunity (Table 56.3) determine whether infection by M. tuberculosis is contained or progresses to overt disease, whether it follows an acute or chronic course and whether lesions

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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Tuberculosis

Table 56.3 Factors affecting susceptibility to tuberculosis

Age Geographical origin Immune suppression Extremes of age: below the age of 5 years, and old age Asians, Africans, North American Indians 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 Stress Environmental factors Mycobacterial factors HLA-DR allele, NRAMP gene, vitamin D receptors Excess corticosteroid production Exposure to populations of environmental mycobacteria Strain variation in virulence

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 importance 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 protective immunity, it has long been recognized that T lymphocytes may also mediate harmful tissue-destroying hypersensitivity reactions 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 cytokines are responsible for the activation of macrophages and granuloma formation. IFN plays a major role in the activation of macrophages, the principal effector cells in the killing of mycobacteria. 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 vegetarians a few years after migrating from sunny countries to more gloomy and dismal environments, such as the UK.8 Factors contributing 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, associated 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 preimmunized 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

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.

are localized or widespread.7 There is a constant battle between the various immune defence mechanisms of the host and strategies 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 hostorganism 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.

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Epidemiology of Tuberculosis

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.

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 relevant T cell populations, thereby determining the subsequent maturation pathways of the T lymphocytes. This raises the possibility 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 antimycobacterial properties than the isolated activated macrophage, as the centres of the granulomas are acidic, anoxic and contain high levels of free fatty acids, all of which inhibit mycobacterial growth. Once a cavity has formed and the anoxic and acidic contents have been replaced by air enriched with carbon dioxide, bacterial growth increases enormously.

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 lymphocyte 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 tuberculosis 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 positivity 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 phenomenon 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 underlying endocrinological cause. A reasonable hypothesis, for which there are supportive animal data, is that the three periods correspond to age-related changes in the ratio of cortisol to the antiglucocorticoid 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.

Mycobacterial factors
Mycobacteria have evolved several strategies for avoiding the various host defence mechanisms and a large number of determinants of virulence have been described in M. tuberculosis.12 Some of these are involved in early events after infection and others are of more importance at later stages. It is probable that the relative importance of determinants of virulence varies according to the lineage or family of the bacillus as they appear, at least in the mouse, to elicit different patterns of immune responsiveness. Of prime importance is the ability of mycobacteria to avoid being killed by phagocytes (Figure 56.11). Within the macrophage, survival of mycobacteria depends principally on their ability to inhibit phagosome maturation and to block phagosomelysosome fusion.13 Advances in genomic analysis have revealed the molecular basis of differences between the attenuated BCG vaccine strains and virulent tubercle bacilli. Several regions of the genome are missing from BCG and one of these contains three genes associated with virulence, two of which code an immunodominant antigen ESAT-6 (Early Secretory Antigenic Target, 6 kDa), which is involved in tissue invasion.14

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 3 of BCG vaccination (p. ). Recent observations suggest that envi-

EPIDEMIOLOGY OF TUBERCULOSIS
As discussed above, not all those who are infected develop overt tuberculosis, and the interval between infection and disease may be years or decades. On the basis of skin-testing surveys, the WHO has estimated that one-third of the worlds human population,

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Tuberculosis

1. Blocking uptake mechanism (a) Via Mannose receptor (b) Block Ca2+ signalling by complement receptor

Complement receptor

Macrophage

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

H+ 3. Alterations to vesicles (a) Failed maturation (b) Blocked proton pump (c) Altered fusion pattern 4. Block apoptosis

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 treatment in many countries, the prevalence of active disease is much higher than the incidence of new cases. In 2004, there were an estimated 14.6 million people with active tuberculosis, of whom 6.1 million had infectious forms of the disease and infected some 100 million people, over 1% of the worlds population. In the same year, an estimated 1.7 million people, principally young adults, died of tuberculosis, with 98% of deaths occurring in the developing nations. This amounts to around 5000 deaths every day.

LAM

MOLECULAR EPIDEMIOLOGY OF TUBERCULOSIS

5. Control cell signalling (a) Activate phosphotyrosine phosphatase (SHP-1) (b) Block signalling via IFN receptors (c) Block class II expression and antigen presentation 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.

IFN Receptor

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, cavitating, 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 contagion parameter. On average, an untreated source case infects

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 position 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 virulence. 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-

10

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Impact of Drug and Multi-drug Resistance

Table 56.4 The estimated incidence, prevalence and mortality of tuberculosis, 2004 INCIDENCE ALL FORMS WHO region Number thousands (% of global total)
2573 (29) 363 (4) 645 (7) 445 (5) 2967 (33) 1925 (22) 8918 (100)

SMEAR-POSITIVE Per 100 000 population Number thousands Per 100 000 population

PREVALENCE Number thousands Per 100 000 population

MORTALITY Number thousands Per 100 000 population

Africa The Americas Eastern Mediterranean Europe South-east Asia Western Pacic Total
Data from WHO.15

356 41 122 50 182 111 140

1098 161 289 199 1327 865 3939

152 18 55 23 81 50 62

3741 466 1090 575 4965 3765 14 602

518 53 206 65 304 216 229

587 52 142 69 535 307 1692

81 5.9 27 7.8 33 18 27

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 combinations 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 pandemic and infection by HIV is now the most important predisposing 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 developing post-primary tuberculosis later in life, the chance rises to 50% in an HIV-positive person. The annual risk of a person coinfected with the tubercle bacillus and HIV developing tuberculosis 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 timescale 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 HIVpositive 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 coinfected with HIV and where the number of cases of tuberculosis is rising by 4% each year. This dual infection is having a devastating 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 prevalence achieved targets for treatment outcomes under the WHO DOTS strategy (p. ) for tuberculosis control. In African countries 4 with a high prevalence of HIV infection, only one in three tuberculosis 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 population, 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 problems 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

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Tuberculosis

No estimate 024 2449 5099 100299 300 or more

HIV prevalence in new TB cases, all ages (%) No estimate 04 519 2049 50 or more

B Figure 56.12 (A) Estimated TB incidence rates, 2006 (all forms). (B) Estimated HIV prevalence rates in new TB cases, 2006.

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Impact of Drug and Multi-drug Resistance

antituberculosis agents18 (Table 56.5). There are two types of resistance, 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 resistance is the result of selective replication of bacterial mutants (which occur spontaneously in all bacterial populations) in patients treated with inadequate or inappropriate drug regimens or poorly formulated combination drugs and in those in whom therapy is poorly managed. The contributing factors to acquired resistance include: Poor compliance in taking therapy Irregular supplies of drugs Addition of single drugs to failing regimens in the absence of bacteriological control Unacceptably high cost to the patient 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 antituberculosis drugs, although ensuring that the patients receive all the prescribed agents, can lead to drug or multi-drug resistance if taken irregularly.22 In addition, it is important to obtain combination preparations from WHO-approved manufacturers as poor formulation can reduce the bioavailability of the component drugs. By denition, tuberculosis caused by strains resistant to rifampicin and isoniazid, irrespective of other resistances, is termed multi-drug resistant tuberculosis (MDRTB). Patients with MDRTB do not respond to standard short-course therapeutic regimens and

must be treated for extended periods with regimens that are more costly and more likely to cause adverse side-effects. Under ideal operational conditions, a high proportion of patients with MDRTB are curable but the cost of managing them can be as much as 100 times that of cases of drug-susceptible disease. As a consequence, there is a risk that patients will go untreated in resource-poor regions and pass the infection on to others. Owing to limited laboratory resources, the exact global incidence of MDRTB is uncertain. Despite this limitation, the WHO has undertaken prevalence surveys which showed that acquired resistance is commoner than primary resistance and that the relative prevalence of both varies enormously from region to region.21 Examples are given in Table 56.5. In most parts of the world, about 1% of new cases are multidrug-resistant but a number of hot-spots with a very high prevalence of drug resistance have been found, including several countries of the former Soviet Union, China (Henan and Liaoning provinces), Equador and Israel. By contrast, low prevalences were found in African countries. According to WHO estimates, around 460 000 cases of MDRTB arise annually, half in new cases and half in previously treated cases.15 More recently, tuberculosis resistant to almost all known agents has been described. Cases of MDRTB additionally resistant to two or more of the six classes of second-line drugs (p. ) are 5 termed extensive or extreme drug resistant tuberculosis (XDRTB).23 On 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 highlighted by an outbreak in the Kwazulu-Natal province of South Africa in which, of 544 patients studied, 221 had MDRTB and of

Table 56.5 Prevalence of combined primary and acquired drug resistance, as percentage of tested isolates, by country or region, 19961999 Country or region
Uruguay Venezuela Malaysia Nepal Botswana Cuba South Africa Central African Republic Guinea Peru Mexico Uganda Mozambique India (Tamil Nadu State) Sierra Leone Estonia
Data from WHO 2004.21

Any form of resistance

4.6 4.7 5.1 6.4 7.7 8.3 10.2 10.5 15.9 18.4 20.6 22.1 23.1 24.1 27.7 40.8

Poly-resistance (two or more drugs)

0.4 1.9 0.6 1.4 2.5 1.5 3.5 3.8 6.0 7.1 9.1 8.1 10.0 13.4 8.7 26.8

Multi-drug resistance
0.2 0.4 0.1 1.4 2.0 0.9 2.5 1.1 1.5 4.3 7.3 0.8 3.5 7.1 2.6 15.1

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Tuberculosis

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.

Tuberculin reactivity
Tuberculin reactivity is a risk factor for the development of tuberculosis as it is usually indicative of past infection by the tubercle bacillus, but the relation between such reactivity and risk of disease is not straightforward. In general, small reactions imply no increased risk, or even a degree of protection, but large reactions imply increased risk, though considerable regional variations in the risk in relation to reaction size occur.

FACTORS AFFECTING DYNAMICS OF TUBERCULOSIS IN POPULATIONS

An epidemic wave of tuberculosis in England began in the sixteenth 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 susceptible 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 prevalence of the disease in a community.24 The decline in the incidence 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 relationship between the incidence of tuberculosis and the improvement of social conditions is by no means straightforward. While some workers claim that the decline in the incidence of tuberculosis 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 tuberculosis will decline as socioeconomic conditions improve worldwide while those holding the second view stress the need for specic tuberculosis control measures and health advocacy.

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 widespread belief that treatment with steroids predisposes to tuberculosis although the evidence for this is weak. Nevertheless, isoniazid chemoprophylaxis for 1 year is recommended for patients on longterm steroid therapy with one or more of the following: a history of inadequately treated tuberculosis, an abnormal chest radiograph, 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 pregnancy 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.

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 facilitated by overcrowding, poor ventilation and low levels of ultraviolet light conditions frequently linked to poverty.

CONTACT TRACING AND EXAMINATION

Most tuberculosis is spread within households, although miniepidemics occur in schools, prisons, hospitals and other situations 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-

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Diagnosis of Tuberculosis

positive source case. Procedures for contact tracing vary according to local facilities and the prevalence of tuberculosis in the community. 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 investigations. 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 aspirates 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 imaging (MRI) and radioisotope scans. 3. Molecular techniques utilizing nucleic acid amplication systems the polymerase chain reaction (PCR) and related techniques. 4. Haematological and biochemical investigations such as haemoglobin levels, erythrocyte sedimentation rate (ESR) and liver function tests may be required in overall patient management but have limited diagnostic roles. 5. Tuberculin skin tests and other immunological tests including interferon- assays. In resource-poor settings, clinical acumen and simple microscopy are the mainstay of diagnosis and in many cases a trial of therapy is commenced on clinical suspicion only. One of the most frustrating challenges in tuberculosis management has been the lack of a 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 difcult, 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 smearpositive 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-engineered, simplied tests are needed at the point-of-care, at district hospital laboratories, and at central laboratories. Different diagnostic strategies sputum concentration methods, uorescence microscopy, improved mycobacterial culture system also need to be evaluated for their impact on case detection. Diagnostic algorithms, 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 infrastructural 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 smearnegative 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

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Tuberculosis

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 examination 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 ZiehlNeelsenstained 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, physiotherapy and the inhalation of nebulized twice normal (hypertonic) 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 experienced 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 neutralized immediately or transported to the laboratory without delay. Where facilities permit, breoptic bronchoscopy is an excellent means of obtaining bronchial washings and brushings and transbronchial 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.

tively rapid results, usually 212 days after inoculation. The original automated systems were based on the detection of radioactive carbon dioxide released during bacterial utilization of a 14C-labelled substrate. In more recent systems oxygen utilization or CO2 production resulting from bacterial growth is indicated by changes in the colour of dyes or the unquenching of uorescent substances.34

Radiological imaging
The advantage of a chest radiograph in the diagnosis of tuberculosis is that of speed, but the equipment is expensive to obtain, maintain and operate (see also Chapter 26). Experienced radiologists are required in order to interpret the often rather non-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 populations. Mass miniature radiography is, on grounds of effectiveness and cost-effectiveness, rarely used for routine screening of the general population. Fluoroscopy is of very limited diagnostic value and, as it also poses a serious radiation hazard to the operator, it should be universally abandoned. Radiology is very sensitive although, exceptionally, the radiograph may appear normal in patients with smear-positive pulmonary tuberculosis. Although radiology is not 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, unilateral or bilateral patchy shadows in any part of the lung elds and calcication. Conditions mimicking tuberculosis include unresolved pneumonias, atypical pneumonia, carcinoma, sarcoidosis, Kaposis sarcoma and mycetoma. High-resolution CAT scanning, where available, may help to distinguish these conditions. Even when CAT scanning is performed the diagnosis may be 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 resonance imaging (MRI) with appropriate contrast enhancement is useful in diagnosis and management of space-occupying lesions in cerebral 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 diagnostic yield by up to 50%. Its disadvantage is the delay, usually 36 weeks, between receipt of the specimen and the emergence of visible growth. A range of media for cultivation of mycobacteria have been described. The most widely used is the solid egg-based LwensteinJensen medium but several other egg-based and nonegg-based media are also available. Liquid media such as Kirschner and Middlebrook broth allow a large inoculum to be used, thereby enhancing the likelihood of obtaining a positive result. Liquid media, supplemented with mixtures of antimicrobial agents to suppress growth of bacteria other than mycobacteria and of fungi, are used in automated culture systems (e.g. MGIT) that give rela-

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 problems 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 techniques36 (Figure 56.13). Kits are now available commercially and are proving rapid, sensitive and specic in most circumstances, with sensitivities approaching 100% and specicities from 85% in non-pulmonary samples to 95% for sputum. The

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Diagnosis of Tuberculosis

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 mentioned 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 vaccination but a reaction of 15 mm or more in diameter in a vaccinated child is a very likely indication of infection by the tubercle bacillus.

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.

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 nonspecic. 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 cerebrospinal, 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 specicity of serodiagnostic tests, usually based on the enzyme-linked immunosorbent assay (ELISA) technique, limits their diagnostic value.

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.

Tuberculin test
This is a standard and widely used diagnostic test but its interpretation is far from straightforward.37 The test is usually positive in patients with tuberculosis although, due to genetic factors, it is negative in a minority of patients. The dermal response is suppressed to a varying extent in malnourished persons and those suffering from advanced tuberculosis, sarcoidosis, chronic renal failure, cancer and viral infections including HIV, measles, chickenpox and glandular fever. It is also suppressed in those receiving anticancer chemotherapy, immunosuppressive drugs and high doses of corticosteroids. The test does not clearly distinguish between active tuberculosis, past infection by the tubercle bacillus and BCG vaccination. In some regions sensitization by environmental mycobacteria induces low levels of tuberculin cross-reactivity. Misleading negative results may be due to faulty stor-age of the material or poor technique. The usual form of tuberculin employed in epidemiological and diagnostic work is puried protein derivative of tuberculin (PPD), the strength of which is expressed in international units (IU).

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

Table 56.6 The grades of reactions of the Heaf test

Grade 0 Grade I Grade II Grade III Grade IV No reaction At least four discrete papules Conuent papules forming a ring A disc of induration A disc of induration greater than 10 mm in diameter or vesiculation of the disc

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Tuberculosis

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 tuberculin testing, the production of interferon-gamma by peripheral blood lymphocytes when exposed to antigens of M. tuberculosis in vitro has been utilized for the development of commercially available diagnostic tests. Increased specicity is achieved by selecting antigens present in M. tuberculosis but not in BCG or environmental mycobacteria. Studies to date indicate that these assays are of potential value but more extensive evaluations in a range of populations and settings are required for the 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 children (see also Chapter 23) and adults. Children are usually infected by the aerogenous route and develop primary pulmonary complexes as described below. The most usual source is an adult with tuberculosis in the family. Less frequently they are infected by drinking milk containing M. bovis, usually with implantation of the bacilli in the tonsil or intestinal wall. Primary inoculation lesions due to infection of cuts and abrasions and congenital tuberculosis resulting from intrauterine infection are rarely encountered. Guidelines for the management of tuberculosis in children, including those who are infected with HIV, are available from the WHO.39

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 tuberculosis to have normal chest X-rays, although a computed tomography (CT) revealed enlarged mediastinal nodes in 60% of such radiologically normal children.42 Gross enlargement of the intrathoracic lymph nodes or endobronchial spread of the disease causes obstruction of the bronchi and the children present with cough and wheezing. Partial blockage of a major bronchus may limit exhalation, resulting in hyperination 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 tuberculosis, although sometimes in a form that is not clinically or radiologically obvious, such as renal tuberculosis.43 There are two main types resulting from, respectively, transplacental infection and aspiration or inhalation of infected amniotic 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. Intrathoracic lymphadenopathy, sometimes extensive enough to cause respiratory obstruction, and miliary disease are common. The tuberculin test is often negative but there are numerous tubercle bacilli in the lungs and/or liver which are usually demonstrable by examination of tracheal or gastric aspirates or neneedle 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.

Clinical presentations of tuberculosis in children

Many children with primary tuberculosis have no obvious symptoms 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 specimens are obtained, acid-fast bacilli are only demonstrable in a minority of cases, especially in regions where facilities for extensive modern bacteriological investigations are not available. Bacteriological 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.

Hypersensitivity reactions
Primary tuberculosis in childhood is sometimes associated with hypersensitivity reactions: phlyctenular conjunctivitis and erythema nodosum (Figure 56.15). Phlyctenular conjunctivitis is characterized by conjunctival itching or pain, lacrimation and photophobia, usually in one eye. Small, grey, translucent nodules are seen near the limbus of the cornea and the blood vessels in the adjacent conjunctiva are dilated. A leash of small blood vessels extends to the edge of the conjunctival

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

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Tuberculosis in Children

From score sheet A

Score 1 6

Score 7 or more

No radiograph

Chest radiograph

Not diagnostic

? atypical pneumonia

Diagnostic TB Wide mediastinium Miliary shadows Cavity, etc.

Start TB treatment

High dose antibiotic q.i.d. 7 days

Poor response

Different antibiotic q.i.d. 7 days

Poor response

Good response B

Not TB

Good response

Not TB

A Figure 56.14 (A,B) Paediatric tuberculosis management ow chart.

Figure 56.15 Erythema nodosum due to tuberculosis.

Erythema nodosum also usually occurs in association with primary tuberculosis and affects a similar age group as phlyctenular conjunctivitis. 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 tuberculosis, 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, systemic fungal infections, lymphoproliferative disorders and after treatment with certain drugs, notably sulphonamides.

sac. Occasionally corneal ulceration occurs. More usually, the condition regresses over several days but recurrent attacks may occur. The condition occurs most frequently in children aged between 5 and 10 years and is much more frequent in girls than in boys. Some cases have followed BCG vaccination and streptococcal infection. It usually occurs soon after primary infection but a few cases have been reported in children with calcied primary complexes.

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-

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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 meningitis, 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 specic 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 opportunistic infections such as Pneumocystis carinii pneumonia (PCP). The tuberculin test is often negative. In the absence of sophisticated 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.

Figure 56.16 Chest X-ray showing right lower lobe consolidation due to tuberculosis.

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 localizing pathology in cryptic sites (Figure 56.2156.23).

Complications
The complications of post-primary pulmonary tuberculosis include pleural effusion and empyema, pneumothorax or pyopneumothorax 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 lymphatic route is uncommon when patients are relatively immuno-

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.

competent, but it is seen in many patients infected with HIV or with other conditions compromising their immunity. A late complication is chronic obstructive airways disease and cor pulmonale secondary to extensive pulmonary brosis. Other, much rarer, late complications include aspergillomas (Figure 56.24) developing in healed cavities and amyloidosis.

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Post-primary Pulmonary Tuberculosis

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. 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 56.21 CT of the chest showing tuberculous cavity.

Figure 56.19 Post-primary tuberculosis. Right upper lobe tuberculous consolidation in a 15-year-old HIV-positive patient.

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 amoebiasis 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, disseminated cancer and diabetes mellitus.

Management
The management of pulmonary tuberculosis involves prescription of an appropriate antituberculosis drug regimen, management of

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Figure 56.22 CT scan of the chest showing pleural effusion.

Figure 56.24 Chest X-ray showing a fungal (Aspergillus) ball in a tuberculous cavity.

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 diminished air entry on the affected side and, if the effusion is large, the mediastinum may be shifted to the opposite side.

Figure 56.23 CT scan of the chest showing calcied empyema of old treated tuberculosis.

Diagnosis
complications, supervision of the patient until the course of therapy has been completed and active contact tracing. Antituber7 culosis therapy is described on pp. . 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 acidfast 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.

TUBERCULOUS PLEURAL EFFUSION AND EMPYEMA

Pleural effusions occur in both primary and post-primary tuberculosis 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 transitory and due, in part, to a hypersensitivity reaction to antigens

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Disseminated Tuberculosis

Differential diagnosis
Tuberculous pleural effusions must be differentiated from those secondary to pneumonia, cardiac failure, malignancy, pulmonary embolism and infarction and amoebiasis.

Management
The basic management is as for pulmonary tuberculosis as described above. Small effusions usually resolve on antituberculosis therapy but larger ones may require needle aspiration. Corticosteroid treatment prevents recurrence of large effusions and subsequent constrictive brosis which may compromise pulmonary 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.

Figure 56.25 Chest X-ray: miliary tuberculosis. Note enlarged paratracheal nodes.

Miliary tuberculosis
In cases in which the immune responses are intact, disseminated disease is characterized by the formation of widespread, multiple, discrete granulomas macroscopically resembling millet seeds (Latin: milium, a millet seed), hence the name miliary tuberculosis. Classically, this was a disease of young children but nowadays it occurs in those of all ages. The symptoms are non-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 transbronchial biopsy through a breoptic bronchoscope. The tuberculin test is usually positive in early cases but becomes negative as the disease advances.

Figure 56.26 Miliary tuberculosis. Chest X-ray of an HIV-positive patient showing extensive bilateral shadowing.

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

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Tuberculosis

Figure 56.27 Postmortem lung specimen showing miliary tuberculosis. Figure 56.30 Choroidal tubercules.

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 immunosuppressed, as well as in others whose immune responses are suppressed, or weakened due to old age. In contrast to miliary tuberculosis, the widespread lesions show very little cellular inltration 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 diagnosis 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 mycobacterial DNA by PCR.

Figure 56.28 Miliary tuberculosis involving the spleen.

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 56.29 Grouped erythematous papules on the skin of the face in miliary tuberculosis.

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Bone and Joint Tuberculosis

lowed in frequency by the large joints of the lower limb (hip, knee and ankle) and then the large joints of the upper limb (shoulder, elbow and wrist). Multiple lesions, often cystic, may occur in disseminated tuberculosis and are easily mistaken for metastatic carcinoma.45

Spinal tuberculosis
Spinal tuberculosis, also termed Potts disease, after Sir Percival Pott (17131788), a surgeon at St Bartholomews Hospital, London, is a cause of severe deformity and handicap. Although any part of the spine may be affected, lesions most often occur at or near the 10th thoracic vertebra. The disease process usually begins in an intervertebral disc and subsequently involves the anterior parts of the adjacent vertebrae (Figure 56.31). Erosion of the bone by the disease process causes vertebral collapse with anterior wedging and, in severe cases, the characteristic angular spinal deformity or gibbus (Figure 56.32). Cold abscesses are common and may track along fascial planes and emerge at the skin surface well away from the site of disease. Thus psoas abscesses secondary to disease in the lumbar vertebrae may emerge in the thigh below the inguinal ligament. Tuberculosis of the cervical spine may present as a retropharyngeal abscess. The usual presenting feature is chronic back pain, often with stiffness and limitation of movement. An unwillingness to pick something off the 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 malnourished 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 infections 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 prevention 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.

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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.

in clinical practice tuberculous meningitis, solitary spaceoccupying lesions in the brain or spinal cord and disseminated miliary lesions.48
Figure 56.33 Tuberculous osteomyelitis. Radionuclide bone scan shows abnormal, increased tracer uptake in D7. The vertebra has collapsed, with spinal cord compression resulting in paraplegia. The excreted activity is seen in the urinary catheter.

Tuberculous meningitis
This is the most common form of CNS tuberculosis and constitutes a medical emergency as diagnostic and therapeutic delays have very serious consequences; namely, a high mortality and a high incidence of serious neurological complications in those who survive. It is most often seen in infants but it may occur at any age.48 It is usually a manifestation of primary tuberculosis and there may be radiological evidence of a primary pulmonary complex. The disease commences with the rupture of a meningeal or subcortical lesion with liberation of tubercle bacilli into the CSF and the development of many tubercles on the meninges. The ensuing meningeal 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 auditory 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 endarteritis 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 nonspecic symptoms such as general malaise, low-grade fever, apathy, irritability, personality changes, depression and intermittent headache but with no focal signs and little or no evidence of meningitis. Symptoms may be limited or even absent in immunosuppressed patients, including those who are HIV-positive. Stage 2. The patient is mentally confused and/or has focal neurological signs such as cranial nerve palsies. Other

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 tuberculosis 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 periosteal inammation and subperiosteal new bone formation, occasionally 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

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Tuberculosis of the Central Nervous System

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 pressure, and may reveal lymphocytes, a raised protein level and decreased glucose level although these parameters may sometimes be normal. In some cases there is a high polymorph count, which suggests tuberculous meningitis of rapid onset or a nonacid-fast bacterial infection. A chest X-ray may be helpful as pulmonary tuberculous lesions are evident in about half the patients. The diagnosis is conrmed by the microscopical detection of acidfast bacilli in centrifuged samples of CSF, although a very thorough 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.

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.

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. Ethambutol 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), ethionamide (20 mg/kg) and pyrazinamide (40 mg/kg). The use of steroids has been a source of controversy as, although steroids suppress hypersensitivity reactions and the formation of basal exudates, some workers claimed that, while they lowered mortality, they allowed more very seriously disabled children to survive. An extensive review established that the data were inconclusive,50 and a more recent study in patients over the age of 14 indicated that, irrespective of severity and HIV status, treatment with dexamethasone lowered mortality but did not reduce the incidence of subsequent neurological disability.51 Until more rm data are available, national guidelines should be followed.

Figure 56.36 Post-contrast enhanced cranial CT (see also Figure 56.35).

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.

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Figure 57.39 Postmortem kidney specimens showing caseating tuberculous lesions.

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 56.40 Non-enhanced CT scan through the lower abdomen. Large parenchymal deposits of calcication involving both kidneys as a result of earlier tuberculous infection.

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 manifestation of haematogenous spread from a primary focus of tuberculosis, 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 56.38 T1-weighted MRI, post-contrast. (see also Figure 57.37).

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Abdominal Tuberculosis

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. Secondary 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 tuberculosis 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.

Figure 56.41 Hysterosalpingogram showing distortion of Fallopian tubes due to chronic tuberculous salpingitis.

be required for relief of ureteric or urethral obstruction, shrunken bladders or, rarely, for the removal of grossly damaged and nonfunctioning kidneys in the presence of symptoms. Ureteric obstruction 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 containing 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 obstruction, 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 peritonitis 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.

Diagnosis
Examination of the urine may reveal a few white cells, red cells and protein. Care is required in the interpretation of acid-fast bacilli seen in urine as various environmental mycobacteria occur as contaminants of the lower urethra and external genitalia. Diagnosis is 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 biopsies and culture of cervical secretions and menstrual blood.

Management
Treatment of all forms of genitourinary tuberculosis is by standard short-course antituberculosis therapy. Surgical intervention may

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Figure 56.43 Abdominal CT scan. Left psoas abscess. Pus aspirate grew M. tuberculosis.

Figure 56.42 Renal tuberculosis. Note loss of calyceal architecture and ureteric obstruction.

Diagnosis of abdominal tuberculosis

Figure 56.44 Abdominal CT, post-contrast, at level of splenic hilum.

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 radiographs show signs of pulmonary tube tuberculosis in about onethird of patients. Where available, ultrasonography or CT scanning may demonstrate 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 anaesthetic.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 contaminated sputum in patients with post-primary pulmonary tuber-

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Skin Tuberculosis

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 56.47 Chronic granulomatous skin lesions due to M. tuberculosis on the nose and around the mouth (lupus vulgaris).

Figure 56.46 Chronic skin lesion on forehead due to M. tuberculosis.

culosis (tuberculosis oricialis cutis). The latter may occur on or near the mouth, and also on the anus as a result of implantation of tubercle bacilli from swallowed sputum Lesions resulting from direct extension of disease from underlying 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 lymphadenopathy. It is, in common with other forms of primary tuberculosis, often self-limiting.

Figure 56.48 Verrucous plaque, chronic granulomatous reaction and supercial ulceration of the foot due to skin tuberculosis: tuberculosis verrucosa cutis.

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56.

Tuberculosis

Figure 56.51 Tuberculous mastitis affecting the left breast.

Figure 56.49 Lupus vulgaris of the face. Chronic ulcerating granulomatous lesion due to M. tuberculosis.

Figure 56.52 Chronic granulomatous skin lesions on the face due to M. tuberculosis (lupus vulgaris).

Figure 56.50 Chronic ulcerating lesion with parotid stula due to parotid gland tuberculosis.

Extension of disease from underlying structures results in sinus formation. The usual cause is a spread from an underlying tuberculous 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 semitranslucent nodules which may subsequently coalesce and ulcerate. When compressed with a glass slide the nodules often have an opalescent apple jelly appearance. It is due either to haematogenous dissemination of tubercle bacilli from internal organs or

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Supercial Lymph Nodes

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 disseminated 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 aetiology 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 encountered erythema induratum (Bazins disease) and tuberculosisassociated 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.

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. Constitutional symptoms occur in less than half the patients. Subsequently, 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

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 HIVpositive patients. Lymphadenopathy in children aged 5 years or below is occasionally caused by other mycobacterial species (see Chapter 57).

Figure 56.54 Cervical lymphadenopathy due to tuberculosis in an HIV-positive Zambian adult.

Figure 56.53 Enlarged tuberculous cervical lymph nodes exuding caseous material (open tuberculosis).

Figure 56.55 Enlarged posterior auricular lymph node in an HIVpositive adult. M. tuberculosis was isolated from a lymph node aspirate.

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56.

Tuberculosis

Figure 56.58 Section of the heart showing chronic tuberculous pericarditis. Note the 2 cm thick band of tuberculous caseation.

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.

thy must be differentiated from other infections, lymphomas and other neoplasms, sarcoidosis and branchial cysts. Tuberculous lymphadenopathy responds to standard shortcourse 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 Transkei heart.65 Exudates cause distension of the pericardium, exerting 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, breathlessness, 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 pericardial 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 56.57 Supraclavicular lymphadenopathy due to M. tuberculosis.

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 biopsies 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-

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Tuberculosis in HIV-Infected Persons

Ocular tuberculosis
The eye may be involved in disseminated tuberculosis as, for example, choroidal lesions in miliary tuberculosis or by direct invasion from surrounding skin in lupus vulgaris (Figure 56.52).66,67 Primary lesions under the eyelids rarely occur in young children exposed to source cases. The eyelids are swollen, the eye becomes irritable and the disease may spread to the pre-auricular lymph nodes. Phlyctenular conjunctivitis, a hypersensitivity reaction sometimes seen in children with primary tuberculosis is described above (p. ). The optic nerve may be damaged in tuberculous meningitis, sometimes leading to blindness.

Adrenal gland
Tuberculosis is a well-recognized but uncommon cause of hypoadrenalism or Addisons disease and is the result of haematogenous spread of tubercle bacilli to the adrenal gland.68 The clinical features of Addisons disease include weakness, weight loss, low blood pressure, amenorrhoea and gastrointestinal symptoms. A characteristic hyperpigmentation of the skin, most notably over the elbows and the lower back, occurs in fair-skinned persons. Pigmented patches also occur in the mouth, a useful sign in darkskinned patients. Diagnosis of hypoadrenalism is 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.
Figure 56.59 Constrictive tuberculous pericarditis: X-ray shows pericardial calcication.

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 hepatomegaly but the liver is frequently involved in disseminated tuberculosis. The liver is also usually involved in congenital tuberculosis due to infection via the umbilical artery.

68 weeks reduces the size of the effusion and associated mortality and also the long-term incidence of constrictive sequelae. Unless contraindicated, steroid therapy should therefore be given for this form of tuberculosis. Healing with brosis and calcication 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 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 strongest 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

Tuberculosis of upper respiratory tract

Tuberculous laryngitis is usually due to the implantation of tubercle 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 corticosteroid 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.

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

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56.

Tuberculosis

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) generated 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 onehalf of those dying of an AIDS-dening condition had active tuberculosis, many showing brous and calcied lesions of tuberculosis 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 immunosuppression are seen.71 For practical purposes, there are three identiable histological stages of cellular immune responses which correlate well with the stage of HIV disease granulomatous response, hyporeactive response and anergic response. The susceptibility to, and clinical characteristics of, tuberculosis show only a partial correlation with the CD4+ lymphocyte counts as qualitative 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+ lymphocyte count and develop typical, well-formed granulomas containing 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 therefore 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 tuberculosis 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, coagulative 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 clinical manifestations are not entirely dependent on the degree of depletion of CD4+ lymphocytes. Around 30% of cases of tuberculosis in HIV-positive patients are extrapulmonary. If tuberculosis occurs in the early stages of HIV infection when immunity is only slightly compromised, the clinical characteristics are similar to post-primary tuberculosis occurring in HIV-negative persons. Thus disease is often localized to the apices of the lungs; there is lung destruction and cavitation and abundant acid-fast bacilli are seen on sputum microscopy. HIV-positive patients with more advanced immunodeciency present with atypical pulmonary disease characterized 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 negative sputum smears for acid-fast bacilli is a challenge for the clinician. In studies in HIV-positive African patients with respiratory illness and negative sputum smears, bronchoscopy with bronchoalveolar lavage or induction of sputum demonstrated that about one-third had tuberculosis. Another third had other respiratory 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 molecular 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.

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Tuberculosis in HIV-Infected Persons

Table 56.7 Comparison of the clinical and radiological characteristics of post-primary tuberculosis in non-immunosuppressed and immunosuppressed persons Characteristic
Pulmonary cavitation Localization by brosis Intrathoracic lymphadenopathy Pleural effusions Miliary disease Atelectasis Lymphatic and haematogenous dissemination Adverse drug reactions Tuberculin test Relapse following therapy Mortality rate

Non-immunosuppressed
Prominent Marked Uncommon Present Uncommon Uncommon Uncommon Uncommon Positive Uncommon Low

Immunosuppressed
Diminished or absent Limited Common Very common Common Common Common Common Small reaction or negative Frequent Increased

of typical pulmonary tuberculosis but in the more profoundly immunosuppressed atypical appearances are common, including vague, spreading opacities suggestive of pneumonia, predominantly lower lobe disease, pleural effusions, air-uid levels, widespread pulmonary mottling and intrathoracic lymphadenopathy. On the other hand, there is signicantly less cavitating disease and atelectasis. Radiological features may change rapidly in appearance. Classical miliary lesions are seen in a minority of HIVpositive 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

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 antituberculosis drugs Immune reconstitution inammatory syndrome (IRIS) Increased recurrence rates after completion of treatment.

Extrapulmonary tuberculosis in HIV-positive adults

Frequent manifestations of extrapulmonary tuberculosis seen in HIV-infected persons in sub-Saharan Africa include pleural disease, lymphadenopathy (usually asymmetrical), pericardial disease and widely disseminated disease. Tuberculosis affecting the CNS, genitourinary tract and bone marrow is, in contrast to the industrialized countries, infrequently reported but this probably 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 symptoms and signs related to the site of disease. Lymphadenopathy is a frequent manifestation of tuberculosis in HIV-infected persons and can present in a variety of ways. While usually chronic and cryptic, it may also occasionally be acute and resemble an acute pyogenic infection. Diagnosis of lymph node tuberculosis can be made by simple techniques such as staining needle aspirates for acid-fast bacilli, naked eye inspection of biopsied lymph nodes for macroscopic caseation and microscopy of smears from the cut surface of a lymph node. The CSF may be normal or near-normal in HIV-infected patients with tuberculous meningitis and clinical features can easily be confused with those of cryptococcal menin-

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 HIVnegative patients with tuberculosis. On the other hand, HIVpositive 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, rendering 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 accelerates 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,

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56.

Tuberculosis

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. Antiretroviral 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 immunity is only partly restored.74 Since opportunistic infections are a cause of mortality in HIVpositive persons with tuberculosis, interventions with prophylactic 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 reduction 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.

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 nonnucleoside 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 nonnucleoside reverse transcriptase inhibitors, causing serum levels to be decreased to sub-therapeutic levels.
9

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 biphasic. 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/mm3 and a rapid rise in this count after starting antiretroviral therapy. Clinicians treating tuberculosis in HIV-positive patients receiving antiretroviral therapy need to be aware of this phenomenon.

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, particularly children, who were given regimens including thiacetazone and included cases of StevensJohnson syndrome (Figure 56.61)

Drug resistance
Although several outbreaks of MDRTB have been reported from industrialized countries among HIV-infected patients, HIV infection itself does not induce MDRTB, but it fuels the spread of this dangerous condition by increasing susceptibility to infection and accelerating transmission between persons, especially in closed 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 Southeast Asia,21 the problems faced by many tuberculosis programmes in sub-Saharan Africa, including the difculties 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, clinicians, 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.

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Human Tuberculosis of Bovine Origin

HIV with large increases in tuberculosis cases has threatened to overwhelm National Tuberculosis Control Programmes in subSaharan Africa. The health staff in many African countries have the same HIV-seroprevalence rates as the general adult population, 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 effective healthcare, including tuberculosis control.

Recurrence after treatment

Recurrence rates of tuberculosis (dened as return of clinical features of active tuberculosis, positive sputum smears for acid-fast bacilli or positive sputum cultures for M. tuberculosis) after completion of antituberculosis therapy are increased in HIV-positive patients. Recurrence rates have been observed at between 18 and 22 per 100 person-years of observation. It is not known to what extent endogenous reactivation or exogenous reinfection contributes to the recurrence of tuberculosis in HIV-infected patients in sub-Saharan Africa but recent evidence suggests that the latter commonly occurs. Information on this issue would be of value in determining strategies, such as isoniazid prophylaxis, to prevent recurrence of tuberculosis. Patients who relapse with smearpositive pulmonary tuberculosis are treated with the WHOrecommended retreatment regimen shown below in Table 56.9. Preventive therapy is described on p. .

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 nonpulmonary 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 pyrazinamide 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-tohuman 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 tuberculosis eradication programmes.

10

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 programmes 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 strategy 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-

Figure 56.62 Lymphadenopathy (tonsillar node) with sinus formation in tuberculosis due to M. bovis.

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 Enzootic or Sporadic or high prevalence low prevalence
55 36 34 8 1 8

Not reported
25 16 12

No data
18 9 2

Number of countries with test and slaughter policy

7 7 12

Africa Asia Latin America and Caribbean

Data from Cosivi et al.78

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56.

Tuberculosis

Figure 56.63 Chronic skin tuberculosis due to M. tuberculosis (secondary to tracking and sinus formation from lymph node involvement).

If the patient regularly receives at least two drugs to which the bacilli are susceptible, the chance of the emergence of drug resistance is very small. In view of the increasing prevalence of resistance 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

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 replicating 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 compartments. 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, pyrazinamide 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.

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 advocated 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.

11

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 available 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 antileprosy drug clofazimine and combinations of aminopenicillins and -lactamase inhibitors, such as amoxicillin with sulbactam,

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Treatment of Tuberculosis

Table 56.9 The WHO-recommended short-course antituberculosis drug regimens in four categories of patients81 Treatment category
I

Denition of treatment category

New smear-positive pulmonary TB; new smear-negative pulmonary TB with extensive parenchymal involvement; concomitant HIV disease or severe forms of extrapulmonary TB

Initial phasea
Preferred 2 HRZE

Continuation phase
4 HR Or 4 (HR)3 4 (HR)3 Or 6 HE 5 HRE 5 (HRE)3

Optional 2 (HRZE)3 Or 2 HRZE II Previously treated sputum smear-positive pulmonary TB: relapse; treatment after default Preferred 2 HRZES/1 HRZE Optional 2 (HRZES)3/1 (HRZE)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 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 III New smear-negative pulmonary TB (other than Category I); less severe forms of extrapulmonary TB Specially designed standardized or individualized regimens

Preferred 2 HRZES/1 HRZE Optional 2 (HRZES)3/1 (HRZE)3 Preferred 2 HRZE Optional 2 (HRZE)3 Or 2 HRZE 4 (HR)3 Or 6 HE 4 HR 4 (HR)3 5 (HRE)3 5 HRE

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.

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 tubercle bacilli but little or no activity against near-dormant bacilli. It is cheap and cross-resistance with other drugs does not occur. Effective concentrations of the drug are obtained in all tissues and the CSF. Isoniazid is converted to an inactive form by the process of acetylation which is under genetic control, with some people being rapid acetylators and others slow acetylators. About 50% of Caucasians and Africans and 8090% of Chinese and Japanese are

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 antituberculosis therapy but adverse side-effects and interactions with other drugs are more pronounced in slow acetylators. The rate of acetylation is reduced in renal failure. Adverse side-effects of isoniazid are uncommon and are mostly neurological, including restlessness, insomnia, muscle twitching and difculty in starting micturition. Dermatological side-effects have been observed in HIV-positive patients (Figure 56.64). More serious but rare sideeffects include peripheral neuropathy, optic neuritis, encephalopathy and psychiatric disorders including anxiety states, confusion, depression and paranoia. The risk of neurological side-effects is greatly reduced by giving pyridoxine (vitamin B6)

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Figure 56.65 Erythema multiforme skin reaction due to rifampicin.

again. Corticosteroid therapy may be required for the respiratory shock syndrome.

Ethambutol
Figure 56.64 Extensive skin reaction due to isoniazid.

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-positive 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 concentrations 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 function 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, thrombocytopenic 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

This has bactericidal activity in the early, intensive, phase of treatment and is reported to enhance the activity of other antituberculosis agents by increasing mycobacterial cell wall permeability. 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 considerable 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 therefore 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 treatment, severe hepatotoxicity is uncommon except in patients with pre-existing liver disease. Its principal metabolite, pyrazinoic acid, inhibits renal excretion of uric acid, occasionally resulting in gout requiring treatment with allopurinol. An unrelated arthralgia, notably of the shoulders and responsive to analgesics, also occurs.

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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.

Figure 56.66 Reaction to antituberculosis drugs: Target lesions due to pyrazinamide.

Other side-effects include anorexia, nausea and photosensitization of the skin.

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.

Second-line drugs
These are indicated in cases of drug resistance and, very occasionally, 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, thioamides, 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 abandoned on account of its poor activity, widespread resistance to it and the high risk of severe and sometimes fatal skin reactions, including exfoliative dermatitis and StevensJohnson syndrome, particularly in those who are infected with HIV.

p-Aminosalicylic acid
This was one of the early antituberculosis drugs but is now rarely used as it has only bacteristatic activity, commonly causes gastrointestinal upsets and is of limited availability.

Cycloserine
This is a bacteriostatic drug which has unpleasant side-effects including headache, dizziness and psychiatric complications. It is usually the last drug of choice.

Other (including experimental) agents

After three decades of neglect, there is now a Gates Foundationfunded Global Alliance for TB Drug Development, which has considerable interest and activity in the development of new antituberculosis drugs. Among the rifamycins, rifabutin is used as an alternative to rifampicin in HIV-positive patients receiving antiretroviral therapy (p. ). There is anecdotal evidence for efcacy of 12 the antileprosy drug clofazimine and of amidopenicillins in combination 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

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 complication is more likely in older patients and the damage may be permanent if the drug is not stopped immediately when the symptoms commence. Deafness occasionally occurs and, if an aminoglycoside is given during pregnancy, it can lead to impaired hearing in the child. A further uncommon complication is anaphylaxis. Other aminoglycosides active against tubercle bacilli are kanamycin and amikacin which, in common with streptomycin, must be given by intramuscular injection and are ototoxic and nephrotoxic.

Immunotherapy
The use of adjunct immunotherapy to treat tuberculosis is a subject of growing interest. Administration of exoogenous IFN or

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IL-2 and other agents might augment host cell mediated immune (CMI) responses in active TB, improve or accelerate clearance of tubercle bacilli, and improve clinical outcomes. A substantial body of evidence indicates that the response to therapy in drugsensitive disease may be accelerated, and treatment potentially shortened, by antigranuloma strategies targeted at eliminating dormancy. Immunomodulators such as: corticosteroids, HSP65DNA, TGF inhibitors, HE2000, IL-4 inhibitors, intravenous immunoglobulin, rHuIFN, Eternacept therapeutic vaccines, and other drugs and biologics have the potential to shorten treatment, by modulating the host response and helping the immune system eliminate persistent organisms. Strategies studied to date in mouse models have been found to reduce the Th2 inhibitory effect on the protective Th1 response, either by inhibiting IL-4 production, or by downregulating the Th2 response. In animal models, impressive treatment shortening times have been observed, and further human testing under appropriate study designs is warranted. In addition to the treatment shortening described above, immunomodulation might improve treatment outcomes using immunomodulators as adjunctive therapies to existing regimens in all groups of patients, including those with MDRTB and XDRTB. Agents under investigation include cytokines such as IFN and a heat-killed preparation of an environmental mycobacterium, M. vaccae. Although clinical trials of single doses of the latter as an adjunct to standard drug therapy yielded variable results,87 repeated doses improved the cure rate of those with MDRTB, even when they received very inappropriate drug therapy.88 Further studies are therefore required, especially in regions where extreme drug resistance is encountered.

Adverse drug reactions and interactions

Adverse reactions are discussed in the descriptions of the individual drugs above and summarized in Table 56.10. Drug interactions require careful attention, notably in HIVpositive 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 isoenzyme 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, indinavir, 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 rifamycins 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 uconazole. 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 coadministration 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

ISONIAZID Common Rare Anorexia, nausea, vomiting, fever, skin rashes, peripheral neuropathy Vertigo, convulsions, optic neuritis and atrophy, psychiatric disturbance, haemolytic anaemia, aplastic anaemia, dermal reactions including pellagra, purpura and lupoid syndrome, gynaecomastia, hyperglycaemia, arthralgia

Adverse reactions

RIFAMPICIN Common Rare Orange-red discolouration of urine, anorexia, nausea, vomiting, diarrhoea, skin rashes Dyspnoea, hypotension with or without shock, Addisonian crisis, haemolytic anaemia, acute renal failure, thrombocytopenia with or without purpura, transient leucopenia or eosinophilia, menstrual disturbances, muscular weakness, pseudomembranous colitis

PYRAZINAMIDE Common Uncommon Rare Anorexia, fever, nausea, vomiting Hepatitis, nausea and vomiting, urticaria, skin rash, nausea, arthralgia Sideroblastic anaemia, photosensitization, gout, dysuria, aggravation of peptic ulcer

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Table 56.10 continued Agent

ETHAMBUTOL Uncommon Rare Optic neuritis, arthralgia Hepatitis, cutaneous hypersensitivity including pruritis and urticaria, photosensitive lichenoid eruptions, paraesthesia of the extremities, interstitial nephritis

Adverse reactions

STREPTOMYCIN Uncommon Rare Vertigo, ataxia, deafness, tinnitus, cutaneous hypersensitivity Renal damage, aplastic anaemia, agranulocytosis, peripheral neuropathy, optic neuritis with scotoma, severe bleeding due to antagonism of Factor V, neuromuscular blockade in patients receiving muscle relaxants or with myaesthenia gravis

OTHER AMINOGLYCOSIDES Uncommon Rare THIACETAZONE Common Uncommona Rare Gastrointestinal upsets, cutaneous hypersensitivity, vertigo, conjunctivitis Hepatitis, erythema multiforme, exfoliative dermatitis, StevensJohnson syndrome, haemolytic anaemia Agranulocytosis Cutaneous hypersensitivity, vertigo, deafness Renal damage, hypoglycaemia, hypokalaemia

P-AMINOSALICYLIC ACID Common Uncommon Rare Gastrointestinal upsets Cutaneous hypersensitivity, hepatitis, hypokalaemia Acute renal failure, haemolytic anaemia, thrombocytopenia, hypothyroidism

ETHIONAMIDE/PROTHIONAMIDE Common Uncommon Rare Gastrointestinal upsets, salivation, metallic taste Cutaneous hypersensitivity, hepatitis Alopecia, convulsions, deafness, diplopia, gynaecomastia, hypotension, impotence, psychiatric disturbance, menstrual irregularity, hypoglycaemia, peripheral neuropathy

CAPREOMYCIN AND VIOMYCIN Common Uncommon Rare CLOFAZIMINE Common Uncommon Rare CYCLOSERINE Common (especially exceeding 500 mg) Uncommon Rare OFLOXACIN Uncommon Rare Gastrointestinal upsets, headache, dizziness, insomnia, cutaneous hypersensitivity reactions Restlessness, convulsions, psychiatric disturbances including psychotic reactions and hallucinations, oedema of face, tongue and epiglottis, disturbance of taste and smell, anaphylactoid reactions Drowsiness, sleep disturbance, headache, tremor, vertigo, confusion, irritability, aggression and other personality changes, psychosis (sometimes with suicidal tendencies) Convulsions, cutaneous hypersensitivity, hepatitis, megaloblastic anaemia Congestive heart failure Discolouration of skin and body uids, nausea, vomiting, abdominal pain, diarrhoea Dryness of skin, ichthyosis, photosensitivity Intestinal obstruction Eosinophilia (with capreomycin), pain and induration at injection site Loss of hearing, vertigo, tinnitus, electrolyte disturbances including hypokalaemia, leucopenia or leucocytosis Renal impairment, hepatitis, thrombocytopenia

Severe thiacetazone-induced skin reactions are common in HIV-positive persons.

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Table 56.11 Interactions between antituberculosis drugs and other therapeutic agents
Drugs whose effects are opposed by rifampicin Antiretroviral agents Corticosteroids Diazepam Haloperidol Opioids Phenytoin Quinidine Theophylline Drug potentiating the effects of rifampicin Drug whose effects are opposed by isoniazid Drugs whose effects are potentiated by isoniazid Drug potentiating the effects of isoniazid Drugs opposing the effects of isoniazid Drugs whose effects are potentiated by streptomycin Drug potentiating the effects of quinolones Drugs whose effects are potentiated by quinolones Drugs opposing the effects of quinolones Trimethoprimsulfamethoxazole (cotrimoxazole) Enurane Phenytoin Insulin Antacids (inhibit absorption) Neuromuscular blocking agents Cimetidine Aminophylline Theophylline Antacids, iron preparations, sucralfate, didanosine (all inhibit absorption) Prednisolone Carbamazepine Azathioprine Ciclosporin Digoxin Imidazoles Oral contraceptives Propranolol Tolbutamide Warfarin

Treatment of tuberculosis in patients receiving antiretroviral agents

Although patients with HIV-related tuberculosis can be prescribed concomitant therapy such as antiretroviral agents, careful management 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/mm3 and in those whose CD4 counts are unknown; for 8 weeks in those with CD4 counts of 200350/mm3, while those with counts of >350/mm3 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

Table 56.12 Antituberculosis drug regimens with concomitant antiretroviral regimens Antituberculosis regimen
Rifampicin Isoniazid Pyrazinamide Ethambutol Rifabutin Isoniazid Pyrazinamide Ethambutol

Months of therapy
16 16 12 12 16 16 12 12

Antiretroviral therapy
Triple non-nucleoside reverse transcriptase inhibitors (NRTI)

Nelnavir, indinavir, amprenavir, efavirenz or nevirapine

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 ulceration 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

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Table 56.13 Sequence of reintroduction and challenge doses for restarting therapy CHALLENGE DOSE Agent Likelihood of the Day 1 drug causing the reaction and sequence of reintroduction
Least/rst 50 mg 75 mg 250 mg

Day 2

Day 3

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 aminoglycosides are eliminated entirely by the kidney and are nephrotoxic their use should be avoided whenever possible. Careful monitoring of drug levels in patients, especially those on dialysis, is required for successful therapy and the avoidance of adverse drug reactions.90

Isoniazid Rifampicin Pyrazinamide Ethambutol

300 mg 300 mg 300 mg Full dose 1g Full dose

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 monitored, 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 jaundice. Patients who are seriously ill with tuberculosis may be treated with streptomycin and ethambutol even in the presence of jaundice.

100 mg 500 mg Full dose 125 mg 500 mg Full dose

Streptomycin Greatest/last

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 dexamethasone 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, antituberculosis therapy should be recommenced with other drugs. Alternatively, 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 hypersensitive 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.

Pregnancy
The standard 6-month regimens may be safely used during pregnancy. Streptomycin, other aminoglycosides, capreomycin and viomycin should be avoided as they may damage the inner ear of the fetus, leading to impairment of hearing. Ethionamide and prothionamide should also be avoided as they have been shown to be teratogenic. Pyridoxine 10 mg daily prevents damage of fetal nerves by isoniazid. Vitamin K should be given to newborn infants of mothers receiving rifampicin to lower the risk of haemorrhagic complications.

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

Special treatment situations Renal insufciency

Rifampicin, isoniazid, pyrazinamide, ethionamide and prothionamide 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

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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 empirical 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 overemphasized. Practical advice has been published by the WHO and, whenever possible, expert advice should be obtained. Inadequate 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 tuberculosis (XDRTB) in some regions and to the very real danger of disease untreatable by conventional means.

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 ameliorate 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 prednisolone twice daily for 46 weeks, followed by a reduction of the daily dose by 5 mg each week, is usually adequate. For more serious conditions, including tuberculous meningitis and pericarditis, 30 mg of prednisolone twice daily for 4 weeks should be administered, or longer if indicated, followed by a tailing off as above. Pleural effusions usually respond to 20 mg twice daily for 2 weeks. The dose in children, depending on severity, is 13 mg/kg. It is important to note that rifampicin leads to a more rapid metabolism of steroids and the dose of steroids should therefore be increased by one-half for up to 4 weeks in patients receiving rifampicin. The use of steroids in the treatment of severe drug reactions is described on p. .

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 lifethreatening Life-threatening tuberculosis. Some physicians consider that steroids reduce mortality in those very seriously ill with tuberculosis 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 condition remains controversial. National guidelines should be followed Genitourinary tuberculosis. Corticosteroids relieve ureteric obstruction and prevent further obstructive scarring and shrinkage of the bladder Lymph node tuberculosis. Corticosteroids are indicated when massive enlargement of a lymph node causes respiratory dis-

13

Preventive therapy
Few aspects of tuberculosis control have generated more controversy than treatment of latent infection in order to prevent the emergence of active tuberculosis. Such so-called preventive therapy is distinct from chemoprophylaxis which is given to uninfected persons at a high risk of being infected and developing the disease, such as a young child exposed to a source case in the home. In some countries, such as the USA, where tuberculosis is very uncommon in most states and where BCG vaccination is no longer used, preventive therapy is given to tuberculin reactors. In such circumstances, isoniazid monotherapy, usually for 1 year, is given on the assumption that very few viable bacilli are present and the chance of mutation to isoniazid resistance is therefore very small. Such therapy has been shown, under these circumstances, to be effective and, as the chance of reinfection is very low, protection is long-lasting. The major problems encountered in the use of isoniazid monotherapy are those of ensuring compliance and the occurrence of hepatic complications. On account of the latter, some authorities recommend that only those under 35 years of age should receive chemoprophylaxis.96 Another problem is the high incidence of multi-drug resistant tuberculosis in some regions, against which isoniazid monotherapy would afford no protection. It is understandable that healthcare staff are anxious about the risk to their health if reliance is placed on chemoprophylaxis rather than BCG vaccination.

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In general, in view of problems of compliance and organization, preventive therapy has not played a major role in tuberculosis control.97 The advent of the HIV/AIDS pandemic has led to a reappraisal of preventive therapy, as the chance of a dually infected person developing overt tuberculosis is very high. Several placebo-controlled studies of isoniazid monotherapy in patients co-infected with M. tuberculosis and HIV have shown that preventive therapy is effective. Unfortunately, however, the preventive effect of isoniazid is short-lived in HIV-positive persons and rapidly declines after completion of the course of therapy. Indeed, in one study no protection was apparent after 18 months. Thus, repeated courses of preventive therapy or even lifetime medication may be required. The preventive effect is greatest in those who are tuberculin-positive and who have a relatively high lymphocyte count. For this reason, and on account of the difculty of diagnosing infection by M. tuberculosis in tuberculin-negative persons, the WHO recommends that preventive therapy should be restricted to HIV-positive persons who are tuberculin-positive. Isoniazid monotherapy for 9 months is suitable for preventive therapy in HIV-positive persons: continuation of therapy to 12 months adds very little. Shorter prophylactic regimens, such as rifampicin with pyrazinamide for 2 months, have been evaluated but rejected on the basis of an unacceptable level of adverse effects. It is important to ensure that HIV-positive persons receiving preventive therapy do not have active tuberculosis or there is a strong risk of masking the disease and encouraging the emergence of drug resistance. It is also necessary to supervise the therapy and this adds another burden to stretched tuberculosis control services. Policies for the use of preventive therapy vary from country to country. National guidelines should be consulted for indications for chemoprophylaxis and for the recommended drug regimens. Preventive therapy is, however, unlikely to have a major impact on tuberculosis control because of the difculties of implementation.

Surgical treatment
In general, surgery plays a minor role in the treatment of pulmonary tuberculosis, although resection of lesions caused by multidrug resistant tubercle bacilli in those with persistently positive sputum achieves high cure rates with acceptable morbidity.98 Other indications include life-threatening haemoptysis, mycetomas forming in old tuberculous cavities, empyema and respiratory distress due to grossly enlarged mediastinal lymph nodes. Surgery has also been used in cases of localized pulmonary disease due to environmental mycobacteria but the availability of more effective therapeutic regimens is reducing the need for surgical resection. Surgical treatment for extrapulmonary disease is discussed under the appropriate headings.

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 tuberculosis before the advent of HIV disease was missed. Instead, the global tuberculosis problem became so serious that, in 1993, the WHO took the unprecedented step of declaring this disease a global emergency. This declaration led to an intensifying of interest in tuberculosis by the WHO, culminating in the formulation of the Global Plan to Stop Tuberculosis (GPSTB) in 1998. The commitment to stop tuberculosis has been linked to the Advocacy Forum for Massive Effort Against Diseases of Poverty, sponsored by the WHO and UNAIDS and launched in October 2000 in the Swiss city of Winterthur with the aim of conquering tuberculosis, HIV disease and malaria the three infectious diseases that pose the greatest threat to human health and life and are responsible for 1 in 10 of all human deaths.99 Tuberculosis is certainly a disease that affects the poor and is a major cause of poverty as it has a devastating economic impact on a household in a developing country.100 On average, a family loses 30% of its income if a money-earner develops tuberculosis, and 15 years of income if that person dies of the disease. Accordingly, tuberculosis control as a way of alleviating poverty is a key aim of the Millennium Development Goals which set the target of halving, by application of the WHO DOTS strategy and other innovations, the prevalence of tuberculosis, and deaths due to it, by the year 2015.101 Two important related initiatives of the WHO are The Global Alliance for TB Drug Development and The Global TB Drug Facility (GDF).102 The former is an alliance of governments, nongovernmental organizations, pharmaceutical companies and funding agencies committed to the development of new costeffective antituberculosis drugs that will improve and simplify the treatment of tuberculosis, including drug-resistant forms. As a direct result of this commitment, several promising new drugs and regimens are currently being developed and evaluated.82 The GDF was launched in March 2001 to increase access to high-quality antituberculosis drugs. By 2004, the GDF had supplied effective drug regimens to almost 2 million patients in 49 countries and had brought down the cost of treating a patient to under US$10 dollars. The GPSTB has grown into an extensive network of numerous governmental, non-governmental and academic organizations with a secretariat based at the WHO headquarters in Geneva. Full details are available on the GPSTB website (www.stoptb.org). The GPSTB programme is based on the WHO DOTS strategy, a 5-point control strategy formally introduced in 1994 and described below.103 Originally DOTS was an acronym of Directly Observed Therapy, Short Course but it is now the brand name for the overall strategy. In addition GPSTB aims to ensure that countries are able to establish effective tuberculosis control programmes and it disseminates up-to-date news, knowledge and information through various media, including the internet. In addition, it hosts a very valuable e-mail forum for the interchange of ideas and opinions between workers in the 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 vaccines, and to strengthen global partnerships so that the control strategies can be effectively utilized.

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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.

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 microscopical examination of sputum smears is tedious work, it is important to give laboratory staff a variety of examinations to undertake and no member of staff should examine more than 20 sputum smears each day. Quality control, training and attention to job satisfaction are important factors to be attended to in the management of microscopy services. The organization and practice of microscopy and other aspects of the tuberculosis laboratory are discussed in detail elsewhere.29,30

14

Supply of drugs The WHO DOTS strategy

In the expanded DOTS framework for effective tuberculosis control published in 2002,103 the ve elements of the DOTS strategy are dened as: Sustained political commitment to increase human and nancial resources and to make tuberculosis control a nationwide activity integral to national health systems Access to quality-assured tuberculosis sputum microscopy for case detection among people presenting with, or found through surveys to have, symptoms of tuberculosis (most importantly, prolonged cough). Special attention is necessary for case detection among HIV-infected people and other high-risk groups, such as people in institutions Standardized short-course therapy for all cases of tuberculosis under proper case-management conditions, including direct observation of therapy. Proper case-management conditions imply technically sound and socially supportive treatment services Uninterrupted supply of quality-assured drugs with reliable procurement and distribution systems Recording and reporting system enabling outcome assessment of each and every patient and assessment of the overall programme performance. It is essential that a regular supply of good-quality drugs is maintained and that these are available to the patients at no cost to them. Intermittent supplies of drugs are a major cause of treatment failure, the emergence of drug resistance and a loss of public condence in the treatment services. Combination preparations, containing two or more antituberculosis drugs, must only be purchased from manufacturers approved by the WHO, as poorly formulated preparations may not allow adequate levels of the drugs to be absorbed, with a risk of treatment failure and the development of drug resistance.

Supervision of therapy
As a result of the effectiveness of modern short-course therapy, and the rapid loss of infectiousness, patients with no complicating factors can be treated as out-patients and pursue normal occupational and social activities. As hospitalization is thus the exception rather than the rule in many regions, the question of supervision of therapy must be addressed. This, of the ve points of the WHO, DOTS strategy, is the one that calls for particular care and attention in its planning and application.105,106 While non-compliance with therapy is one of the major reasons for the global failure to control tuberculosis, dogmatic assertions on the need for every dose to be taken in the presence of a 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 successful programme, patients pay a nominal fee at the commencement of therapy which is reimbursed, with interest, on successful completion of therapy.107 Supervision strategies must be userfriendly, and must respect the dignity and human rights of the patient. In this respect, it is important to organize services on the basis of local attitudes and related factors and not on dogma.108110

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 efciency 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.

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Bacille CalmetteGurin Vaccination

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

Global strategies for control of tuberculosis and HIV

The WHO DOTS strategy is the best way of controlling tuberculosis 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 associated with HIV infection and the ways that this differs from region to region, operations research is essential to ensure that tuberculosis 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 infection and that additional strategies are required. To this end the GPSTB established a TB/HIV Working Group in 2001 to coordinate 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

Monitoring of tuberculosis control services

This is essential to ascertain whether the above strategies are effective 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 publishes guidelines for establishing such pilot projects.93,113 Projects being evaluated include those based on empirical treatment regimens and the more costly but more effective ones based on individualized treatment regimens according to drug susceptibility patterns determined in the laboratory. DOTS-Plus strategies are in a state of evolution, and up-to-date WHO publications should be consulted for developments and guidelines. It is important that DOTS-Plus programmes are only introduced in regions where optimal DOTS strategies are already in place. The establishment of a DOTS-Plus programme at the expense of a DOTS programme can have a detrimental effect on overall tuberculosis control.

BACILLE CALMETTEGURIN VACCINATION

The only vaccine currently available for the prevention of tuberculosis is Bacille CalmetteGurin (BCG), named after Albert Calmette and Camille Gurin, the French investigators who developed the vaccine from a strain of M. bovis early in the twentieth century. This live attenuated vaccine was intended for oral administration 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 therefore 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
North America Chicago, USA Great Britain Puerto Rico South India Georgia, USA Illinois, USA South India Malawi
a

Year of commencement of trial

1935 1937 1950 1949 1950 1950 1948 1968 1978

Age range at time of vaccination

020 years 3 months 1415 years 118 years All ages 5 years Young adults All ages All ages

Protection afforded (%)

80 75 78 31 31 14 0 0 0

No protection at 7.5-year follow-up but some protection at 15-year follow-up in those vaccinated in infancy.

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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 susceptible 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 diminution or loss of such reactivity is not a reliable indication of loss of protection. BCG is given by intradermal injection or, in neonates, percutaneously by means of multi-puncture devices. Vaccine for intradermal 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 accidental 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 intradermal 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.

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 lymphadenitis 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 prevalence 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 communities. In view of the risk of BCG-related complications, there has been debate as to whether the vaccine should be used in regions where there is a high incidence of HIV infection. Although there is a small increase in the incidence of adverse effects of BCG in children born to HIV-infected women, almost all are mild and in regions with a high incidence of tuberculosis the benets of vaccination greatly outweigh any disadvantages. The WHO recommends that BCG vaccination of infants likely to be exposed to HIV should be based on the risk of tuberculosis. If the risk is high, neonatal vaccination should be given according to the Expanded Programme on Immunization schedule but, if the risk is low, children suspected of being infected with HIV should not receive BCG. In addition, no individuals with symptomatic HIV disease should be vaccinated with BCG.117

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 reactions, subcutaneous abscesses, lymphadenopathy (mostly axillary) 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-

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 postprimary, transmissible, disease and a non-viable one that could be given safely to those infected with HIV would be of very great

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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 immunity 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), adenovirus, 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; Ag85BESAT-6; Mtb72f); and several more candidates are in pre-clinical development. Many current vaccine candidates are based on modications to BCG, yet our understanding of the immunobiology underlying BCGs ineffectiveness remains incomplete. The understanding 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 determine the degree and duration of the protective effect. As efforts to nd effective vaccines continue, existing WHO recommendations for the diagnosis, management and control of tuberculosis must be rigorously applied and extended worldwide.

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 developed countries during the late nineteenth and twentieth centuries and this led to the false assumption that it would do likewise in other parts of the world. Too much emphasis was, however, placed on the concept of the development of population immunity a very dubious proposition and not enough on the very many public health innovations, often introduced only after intense advocacy, that contributed to the decline of tuberculosis in the industrially developed countries. Tuberculosis is a disease of poverty, and the fact that it is both preventable and treatable, and that it has been reduced to a shadow of its former self in many resource-rich countries, attests to the fact that a 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.

Ongoing research
To improve the treatment outcomes of tuberculosis, research led by a number of international organizations and academic institutions is now leading to the discovery of new drug compounds, immunotherapeutics, immune markers of disease, diagnostics and vaccines. The revised Global TB control Plan of the WHO Stop TB Partnership, announced in March 2006, has six elements, the sixth of which is enabling and promoting research for new tools and programme performance.119 Current UNDP/UNICEF/World Bank/WHO Special Programme in Research and Training, Scientic Working Group recommendations120,121 for priority research into tuberculosis are grouped into several areas: 1. Improved diagnostics tuberculosis122 2. Improved clinical management of tuberculosis in HIV-positive and HIV-negative individuals 3. Social, economic and behavioural research and the global tuberculosis agenda 4. Immunopathogenesis and vaccine studies 5. Operational and implementation research

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.

53

Ch056-X4470.indd 53

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56.

Tuberculosis

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 longterm 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 antiglucocorticoid 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.

54

Ch056-X4470.indd 54

7/21/2008 3:45:53 PM

References

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 longterm 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 virusinfected 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 heatkilled 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. Multidrugresistant 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.

55

Ch056-X4470.indd 55

7/21/2008 3:45:53 PM

56.

Tuberculosis

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 multidrugresistant 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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