Tuberculosis is an infectious disease, commonly called TB, caused in humans by the bacterium Mycobacterium tuberculosis.

Causes and types

Tuberculosis is usually transmitted in airborne droplets expelled when an infected person coughs or sneezes. Inhaled droplets enter the lungs and the bacteria multiply. The immune system usually seals off the infection at this point, but in some cases the infection spreads to the lymph nodes. It may also spread to other organs in the bloodstream, which may lead to miliary tuberculosis, a potentially fatal form of the disease, or to meningitis (inflammation of the membranes around the brain and spinal cord), bone infection, genitourinary infection, or pericarditis (inflammation of the membranes around the heart). In other cases, bacteria held in a dormant state by the immune system become reactivated months, or even years, later. Reactivation may occur when old age, poor health, or reduced immunity increase susceptibility to the infection. The infection may then progressively damage the lungs.

Symptoms 

The primary infection is usually without symptoms. Progressive infection in the lungs causes coughing (sometimes bringing up blood - haemoptysis), chest pain, shortness of breath, fever and sweating, poor appetite, and weight loss. Pleural effusion (collection of fluid between the lung and chest wall) or pneumonia may develop.The lung damage may be fatal.

Diagnosis 

A diagnosis is made from the symptoms and signs, from a chest X-ray, and from tests on the sputum. Alternatively, a bronchoscopy may also be carried out to obtain samples for culture.

Treatment 

Treatment is usually with a course of three or four drugs, taken daily for two months, followed by daily doses of isoniazid and rifampicin for four months. However, TB bacteria are increasingly resistant to the drugs used in treatment, and others may have to be used and treatment carried out for a longer period. If the full course of drugs is taken, most patients recover.

Prevention 

Tuberculosis can be prevented by BCG vaccination, which may be offered just after birth or routinely at age 10–14. Contacts of an infected person are traced and, if necessary, are treated early to reduce the risk of the infection spreading.

Tuberculosis in detail - technical

Essentials

Tuberculosis is caused by organisms of the Mycobacterium tuberculosis complex, including M. tuberculosis (the most important), M. bovis, and M. africanum. It has been present since antiquity and is the second leading infectious cause of death after HIV infection. An estimated 2 billion people worldwide carry latent infection, when M. tuberculosis persists within cells and granulomas, with the potential to reactivate to cause disease decades later.

Tuberculosis is one of the most important diseases in the history of humanity, and remains an extraordinary burden on human health today. Archaeological evidence demonstrates that tuberculosis was present in antiquity, and large epidemics of the disease emerged in Europe in the Middle Ages. While contemporary physicians consider tuberculosis to be one of the classic infectious diseases, recognition of the clinical manifestations of the disease has evolved over the past two millennia. The Greek term phthisis was used by Hippocrates to describe the wasting disease later known as tuberculosis. While the Greeks recognized various clinical manifestations of tuberculosis, understanding of the connection between the forms was limited. In the Middle Ages, the study of anatomy and the correlation of pathological findings with clinical syndromes led to a better understanding of the disease. The term ‘tuberculosis’ was used first only in the early 19th century, derived from the tubercles characterized in the study of pathological features of the disease.

The impact of tuberculosis on the humans population cannot be overstated, as the disease has killed hundreds of millions of people over the centuries and has had economic and social effects perhaps unparalleled in the history of medicine. Between 1700 and 1950, tuberculosis was a great killer in the developed world, earning the sobriquet “the captain of the men of death” from John Bunyan, and “the White Plague” from René and Jean Dubos. The inspiration that artists have drawn from tuberculosis, portrayed in literature, opera, and art, testifies not only to the importance of the disease within their contemporary societies, but also to the extent to which tuberculosis affected artists themselves. The annals of art are filled with those who succumbed to tuberculosis including Keats, Chopin, the Bronte sisters, Stevenson, Poe, and many, many others.

The conquest of tuberculosis through the development of vaccines, drugs, and diagnostics was a principal goal of biomedical research in the 19th and 20th centuries. The first description of the tubercle bacillus as the cause of tuberculosis by Robert Koch in 1882 was a scientific landmark. The postulates established by Koch for determining the microbial aetiology of disease have continuing influence today, and molecular correlates of those derived by Koch further strengthen the ingenuity of his thesis. Koch also developed the microscopic and culture methods for detecting tubercle bacilli, still widely used today. Calmette and Guérin developed an effective vaccine for tuberculosis in the early 20th century, but use of the vaccine was not broad enough to control the disease and it may no longer be effective (see below). The discovery of streptomycin by Schatz and Waksman in 1943 was a major triumph; both Koch and Waksman received the Nobel Prize for their work. The development of additional antimicrobial agents against tuberculosis in the 1950s, 1960s, and 1970s, and the evaluation of chemotherapy in elegant studies conducted by the British Medical Research Council, the United States Public Health Service, and the United States Veterans Administration led to a marked apathy about tuberculosis in the closing decades of the 20th century.

Despite the availability of curative chemotherapy for more than half a century, however, tuberculosis continues to kill more than 1.5 million people/year, and causes an enormous amount of suffering and disability. In 1994, the World Health Assembly declared that tuberculosis was a global health crisis, and the situation has only grown more serious since then. Epidemics of HIV-related tuberculosis and multidrug-resistant disease have expanded in recent years, and global control of tuberculosis remains a formidable challenge.

The unique biological properties of the causative organism, Mycobacterium tuberculosis complex, allow for a long incubation period between the time of infection and the development of symptoms. Latent tuberculosis infection can persist for decades before causing disease, or can persist for the lifetime of an infected person without ever causing clinically evident illness. Because latent infection creates a large reservoir of carriers of the infection, disease elimination is difficult to envisage.

Aetiology

Tuberculosis is a granulomatous disease caused by organisms of the M. tuberculosis complex, including M. tuberculosis, M. bovis, and M. africanum, of which M. tuberculosis is the most important. M. tuberculosis and the other mycobacteria are small rod-shaped or curved bacilli in the order Actinomycetales, family Mycobacteriaceae, with a unique thick cell wall composed of glycolipids and lipids. The lipid-rich coat of the mycobacteria renders these organisms resistant to acid decolorization following carbol-fuchsin staining, hence the term ‘acid-fast bacilli’. Classification of the mycobacteria was based for many years on the staining and growth properties described by Runyon, but this unwieldy system has been largely replaced with modern techniques that identify mycobacteria by specific DNA sequences and, to a lesser extent, biochemical assays. Mycobacteria are frequently considered according to the diseases they cause more than their behaviour in the laboratory: M. tuberculosis complex causes tuberculosis; M. leprae causes leprosy; and the nontuberculous mycobacteria, including rapid growers, are associated with a wide range of manifestations, particularly in immunocompromised hosts.

The organisms of the M. tuberculosis complex are remarkably slow growing, with a generation time between 20 and 24 h. The exceedingly slow intrinsic reproductive rate of M. tuberculosis contributes both to its behaviour as a pathogen and to difficulties in recovering the organism in cultures. Moreover, M. tuberculosis is able to persist in a latent form within cells and granulomas for many years, and can reactivate to cause disease decades after infection is acquired. Tubercle bacilli are not known to form spores, but both typical bacilli and nonstaining forms of the bacteria persist in cells and tissues, as evidenced by detection of DNA, years after infection is acquired, and retain the capacity to replicate and produce clinical illness. These unique biological characteristics make the tubercle bacillus exceedingly difficult to combat and control.

Epidemiology

Global incidence

Despite the widely held belief that tuberculosis was waning during the 1980s, global tuberculosis incidence has been steady or increasing for several decades. In Western Europe and North America, the incidence of tuberculosis peaked in the 1700s and 1800s, and then declined over a period of years before the development of chemotherapy. Improvements in hygiene and nutrition, along with reductions in household crowding, were credited with these trends. Following the introduction of curative treatment for tuberculosis in the era following the Second World War the incidence of disease fell even further, and tuberculosis deaths were greatly decreased. The success in controlling tuberculosis experienced in the western nations was not replicated in developing countries, and increasing epidemics of the disease have been occurring in these areas. In addition, progress in tuberculosis control in the western nations ironically led to neglect of public health programmes that were responsible for reductions in morbidity. As a consequence of inattention to control, the United States of America experienced a resurgence of tuberculosis between 1985 and 1992, with a 21% increase in the annual number of reported cases during that time. In the United Kingdom, tuberculosis incidence has levelled off in recent years, with an annual incidence of 11 cases per 100 000 people since 1991. Worldwide, tuberculosis continues to kill more than 1.5 million people per year, making it the second leading infectious cause of death after HIV infection. In fact, tuberculosis is a leading cause of death in AIDS, and HIV-related tuberculosis deaths are attributed to AIDS not tuberculosis. If these deaths were attributed to tuberculosis, then tuberculosis would remain the leading infectious cause of death worldwide.

The World Health Organization (WHO) estimates that 2 billion people, or one-third of the world’s population, are infected with M. tuberculosis. From this seedbed of latent infection, 9.3 million new cases of active disease and 1.7 million deaths were attributed to tuberculosis in 2007. Disease due to M. tuberculosis is most common in developing nations, both in absolute numbers and incidence of new cases. Twenty-two countries account for 80% of all cases of tuberculosis; India and China are responsible for 23% and 17% of cases, respectively. In general, the highest incidence of disease is found in the countries of sub-Saharan Africa where HIV infection has contributed to extraordinary increases in case rates. The greatest number of cases arise in the populous nations of Asia, which have moderately high rates of disease per capita. The global incidence of tuberculosis is increasing slightly, though population growth is resulting in higher numbers of cases each year. Declines in incidence in the developed world have been offset by increasing rates in the HIV-ravaged countries of Africa and by escalating incidence in Eastern Europe in the aftermath of the collapse of communism and its public health infrastructure.

Effect of age

Tuberculosis typically affects young adults, with peak incidence in those aged 25 to 44 years. The dynamics of tuberculosis within a particular country or region, however, reflect both historical trends in tuberculosis transmission and current risk factors and practices of disease control. For example, in Western Europe tuberculosis is seen in two demographic groups: elderly native Europeans who were presumably infected many years ago and who experience reactivation of latent infections as they age or become immunocompromised, and younger immigrants from high-incidence countries in the developing world. In the United States of America tuberculosis is seen in young adults who have immigrated from endemic areas and in those with HIV infection, whereas reactivation tuberculosis in older people is increasingly uncommon. In the developing world, tuberculosis most commonly occurs in young adults, with rapidly escalating rates in those with HIV infection. In all countries where tuberculosis is prevalent, young children who acquire tuberculosis from adults account for a small proportion of all cases. Interestingly, children between the ages of 5 and 15 years have extremely low rates of tuberculosis, even in areas with a high disease burden.

Infection and disease

The epidemiology of tuberculosis can be considered as a function of two distinct but related phenomena: the likelihood of becoming infected with M. tuberculosis and the probability of developing disease once infection has occurred. Risk factors for becoming infected relate to exposure to infectious cases. Throughout the world, living with someone who has infectious tuberculosis is the most important risk factor for acquiring infection. The longer the duration of undiagnosed tuberculosis, the greater the severity of disease, and the more intimate the contact, the greater the chance of becoming infected. Exposure to infectious cases in other environments, including health care facilities, prisons, and the workplace, is another important route of infection. In areas of the world where tuberculosis is relatively widespread, exposure in the community is commonplace and probably unavoidable. In low prevalence countries, community exposure is most likely to occur in distinct pockets of increased incidence, such as poorer areas of large cities or neighbourhoods with high HIV prevalence.

Effect of host immunity

After M. tuberculosis infection is acquired, the risk of developing disease is dependent on host immunity. As discussed below, several conditions have been identified that increase the risk of active disease in a person with latent tuberculosis infection, most notably HIV infection. Reactivation from latent tuberculosis infection is an important mechanism for the development of adult tuberculosis. However, studies using DNA fingerprinting techniques show that a significant proportion of tuberculosis cases thought to be due to reactivation are actually recently acquired due to reinfection or new infection, particularly in high HIV prevalence settings.

Effect of M. tuberculosis strain

Interestingly, strain differences in M. tuberculosis have not been associated with the risk of disease, although inoculum size is associated with probability of becoming ill. For example, household contacts of heavily sputum acid-fast bacilli smear-positive cases of tuberculosis who become infected have a higher incidence of active disease than contacts of acid-fast bacilli smear-negative cases who become infected. On the other hand, while there is some evidence that specific strains of M. tuberculosis may more successfully infect contacts than other strains, the risk of disease in those infected with these transmissible strains is not elevated.

Susceptibility

Tuberculosis is a disease traditionally associated with specific population groups, notably the poor, alcohol and drug abusers, and, more recently, those with HIV infection. The increased incidence of tuberculosis in impoverished populations is probably multifactorial, involving increased risk of infection (e.g. due to crowded living conditions and a higher background prevalence of disease in the community) and increased risk of developing disease after infection (e.g. due to malnutrition). Similar reasons may explain the higher rates of tuberculosis seen in cigarette smokers and alcohol and drug abusers, with suppression of host cellular immunity either directly or indirectly caused by substance abuse. The more recent association of tuberculosis and HIV infection is clearly related to development of cellular immunodeficiency in those with HIV, but in many settings those at highest risk for HIV infection are also more likely to be latently infected with M. tuberculosis than others.

Effect of the HIV epidemic

The impact of HIV infection on the epidemiology of tuberculosis is striking. As will be discussed below, HIV infection is the most potent known biological risk factor for tuberculosis. The relative risk of tuberculosis in an HIV-infected person is 200 to 1000 times greater than in someone without HIV infection. The risk of tuberculosis increases shortly after HIV seroconversion, doubling within the first year. As a result of the extraordinary risk conferred from HIV infection, the majority of tuberculosis patients in many sub-Saharan countries are HIV seropositive. The incidence of active tuberculosis in HIV-infected patients not receiving antiretroviral therapy in the United States of America, with latent tuberculosis infection defined by a positive tuberculin skin test, is about 10% per year. Of note, an annual incidence rate of about 10% is described in HIV-infected patients in South Africa regardless of tuberculin skin test status. In addition, HIV infection is the unifying theme in many nosocomial outbreaks of tuberculosis, as infection is spread among immunocompromised patients receiving medical care at the same facility. It is increasingly apparent that control of tuberculosis will not be possible globally without control of HIV infection.

Effect of drug resistance

Another very important trend in tuberculosis epidemiology is the growing problem of drug-resistant tuberculosis. Drug-resistant tuberculosis is divided into two categories: primary resistance, which is the presence of drug resistance in someone who has never had treatment for tuberculosis, and secondary resistance, which is the presence of resistance in a patient who has previously been treated for tuberculosis. Primary resistance results from acquiring an infection that is already drug resistant, while secondary resistance is the result of inappropriate therapy that selects for resistant mutants of M. tuberculosis. A global survey of resistance performed by the WHO and the International Union Against Tuberculosis and Lung Disease found that the median prevalence of primary drug resistance was 10%, and the median prevalence of acquired resistance was 36%. Moreover, ‘hot spots’ of drug-resistant tuberculosis were identified on all continents. The most notable of these are in the former Soviet nations where multidrug-resistant (MDR) tuberculosis, defined as resistance to at least rifampicin and isoniazid, is identified in 10 to 20% of all cases. Multidrug-resistant tuberculosis treatment is exceedingly difficult, since the drugs used are less effective, more costly, and poorly tolerated due to drug-related side effects. Furthermore, failure to control the spread of drug-resistant tuberculosis has led to the outbreak of extensively drug-resistant (XDR) tuberculosis, which is defined as multidrug-resistant tuberculosis plus resistance to fluoroquinolones and at least one injectable second-line agent (capreomycin, amikacin, or kanamycin). Extensively drug-resistant tuberculosis been responsible for high rates of mortality in HIV-infected individuals in South Africa and is reported in more than 70 countries globally. Drug-resistant tuberculosis (MDR or XDR) will likely continue without effective implementation of directly observed therapy, short-course (DOTS) and development of more rapid diagnostic tests to detect drug resistance.

Pathogenesis

The development of active tuberculosis, like all infectious diseases, is a function of the quantity and virulence of the invading organism and the relative resistance or susceptibility of the host to the pathogen. Indeed, one lineage of tuberculosis known as the W/Beijing family of strains is predominant in south-east Asia, but widely distributed in India and South Africa. W/Beijing strains of M. tuberculosis have been associated with outbreaks of drug-sensitive and drug-resistant tuberculosis and may be more virulent than other strains. Genetic host factors also play a key role in innate nonimmune resistance to M. tuberculosis. For example, the human gene SLC11A1, which has been mapped to chromosome 2q, may help determine susceptibility to tuberculosis, according to a study in Africa.

Transmission

Tubercle bacilli are transmitted between people by aerosols generated when an infectious person coughs or otherwise expels infectious pulmonary or laryngeal secretions into the air. M. tuberculosis bacilli excreted by this action are contained within droplet nuclei, extremely small particles (less than 1 µm) that remain airborne for long periods and are disseminated by diffusion and convection until they are deposited on surfaces, diluted, or inactivated by ultraviolet radiation. Individuals breathing air into which droplet nuclei have been excreted are at risk of acquiring tubercle bacilli by inhaling these nuclei and having them deposited in their alveoli, where a productive infection may occur. Transmission of tuberculous infection by other routes, such as inoculation in laboratories and aerosolization of bacilli from tissues in hospitals, has been documented, but these are an insignificant means of spread. M. bovis can be acquired from contaminated milk from tuberculous cows, but modern animal husbandry practices and the pasteurization of milk has virtually eliminated this mode of infection throughout most of the world.

Natural history of tuberculosis in humans

People who are in contact with someone with infectious tuberculosis may acquire infection, as described above. Factors that affect the likelihood of infection being transmitted include the severity of the disease in the index case (e.g. extent of radiographic abnormalities, cavitation, frequency of cough), the duration and closeness of exposure, and environmental factors such as humidity, ventilation and ambient ultraviolet light. Several studies in diverse locations and circumstances have shown that approximately 20 to 30% of close contacts of an untreated tuberculosis patient become infected with M. tuberculosis, as demonstrated by the development of a reactive tuberculin skin test.

Immune response

Deposition of tubercle bacilli in the alveoli results in a series of protective responses by the cellular immune system that forestall the development of disease in the majority of infected people. Alveolar macrophages ingest tubercle bacilli, which then multiply intracellularly and eventually cause cell lysis with release of organisms. Killing of M. tuberculosis within macrophages is prevented by inhibition of phagolysosome formation by the tubercle bacilli through a process that is not understood. Additional alveolar macrophages engulf progeny bacilli, resulting in further intracellular growth and cell death. Over a period of weeks as tubercle bacilli proliferate within macrophages and are released, infection spreads to regional lymph nodes, elsewhere in the lungs, and systemically. Foci of tubercle bacilli can be established in multiple organs, including the lymph nodes, brain, kidneys, and bones. In most people, specific immunity is developed after several weeks and consists of activated T lymphocytes mediating a Th1 type response. Macrophages act as antigen-presenting cells, interacting with CD4 lymphocytes primed for M. tuberculosis antigens. Activated CD4 lymphocytes produce both IL-2, which promotes activation of additional T lymphocytes, and interferon-γ, which binds with receptors on macrophages and promotes intracellular killing of organisms. Tumour necrosis factor-α production is induced in macrophages, and this too promotes killing of intracellular bacilli. The specific role of CD8 cells in the control of tuberculosis has not been fully elaborated, although there is evidence that cytotoxic T lymphocytes may play a role in containing a tuberculous infection. In addition, CD8 lymphocytes also produce interferon-γ and participate in granuloma formation. Recent evidence also supports a role of innate immunity in combatting tuberculosis infection.

The classic immunological response to infection with tubercle bacilli is the walling off of viable bacilli in granulomas. Granulomas are collections of cells surrounding a focus of M. tuberculosis, usually within macrophages but sometimes extracellularly, that serve to contain the infection. Granulomas consist of macrophages, CD4 and CD8 lymphocytes, fibroblasts, giant cells, and epithelioid cells that produce an extracellular matrix of collagenous and fibrotic materials which are continually remodelled and can become calcified. A calcified granuloma at the initial site of infection in the lung is referred to as a Ghon complex, while the combination of a Ghon complex and a calcified regional lymph node is called Ranke’s complex.

The development of the cellular immune response to M. tuberculosis is accompanied by the development of delayed-type hypersensitivity (DTH) to specific antigens from tubercle bacilli. While DTH is distinct from the cell-mediated immunity that provides protection from disease, this sensitivity to tubercle-derived proteins has proved enormously useful for diagnosing tuberculosis infection. The use of purified protein derivatives (PPD) of tuberculin is the basis for estimating the prevalence of latent tuberculosis infection in populations, is essential in studying the natural history of tuberculosis infection, and is frequently helpful in evaluating patients with suspected tuberculosis disease. The difference between DTH and immunity to tuberculosis is underscored by the observation that 80 to 90% of patients with active disease, and therefore clearly not immune, have positive tuberculin tests.

For the majority of people acquiring a new tuberculous infection, the development of cell-mediated immunity to the organism is protective and holds the bacilli in check, though viability is usually maintained. A small proportion of them will be unable to contain the infection and will progress to active tuberculosis disease, often referred to as primary tuberculosis. Factors associated with early progression of infection to disease include immunosuppression, particularly with HIV infection, a higher inoculum of organisms, malnutrition, and, perhaps, concomitant illness. While rates of active disease in young children who are contacts of cases are no higher than for older contacts, young children with primary tuberculosis do develop more severe forms of tuberculosis than adults, including disseminated disease and tuberculous meningitis.

Reactivation

Those who successfully contain the organism have a latent tuberculosis infection that may reactivate later in life. Based on studies of latent tuberculosis infection acquired in childhood or adolescence, the lifetime risk of reactivation of M. tuberculosis is about 10%. Table 1lists conditions that are associated with an increased risk of reactivating latent tuberculosis infection. The most potent of these is HIV infection, which increases the rate of reactivation by as much as 1000-fold. Immunosuppression from malignancy, cytotoxic therapy, corticosteroids, and other agents that alter cellular immune responses also increase the likelihood that latent tuberculosis infection will reactivate. Other important factors that increase the risk of tuberculosis include diabetes and endstage renal disease, injection drug use (independent of HIV infection), low body weight, gastrointestinal surgery, and silicosis. Cigarette smoking is associated with increased tuberculosis incidence, as is alcohol abuse. Recently, the use of inhibitors of tumour necrosis factor-α for the treatment of rheumatoid arthritis or inflammatory bowel disease has been associated with increased risk of tuberculosis. Rates of tuberculosis are usually higher in older people than in younger adults in developed countries, but this may represent a higher prevalence of latent infection in older cohorts, rather than immunological senescence.

Table 1  Incidence of active tuberculosis in people with a positive tuberculin skin test, by selected risk factors

 

Risk factor	Number of tuberculosis cases/100 person-years
Recent tuberculosis infection:
Infection <1 year past	2–8
Infection 1–7 years past	0.2
HIV infection	3.5–14
Injection drug use
HIV seropositive	4–10
HIV seronegative	1
Silicosis	3–7
Radiographic findings consistent with prior tuberculosis	0.2–0.4
Weight deviation from standard:
Underweight by ≥15%	0.26
Underweight by 10–14%	0.20
Underweight by 5–9%	0.22
Weight within 5% of standard	0.11
Overweight by ≥5%	0.07
Diabetes mellitus	0.3
Renal failure	0.4–0.9
None of the above factors	0.01–0.1

Clinical features

Classification of tuberculosis infection and disease

Infection with M. tuberculosis can result in clinical manifestations ranging from asymptomatic carriage of latent bacilli to life-threatening pneumonia. Classification of the different stages of M. tuberculosis in humans by the American Thoracic Society (ATS) is shown in Table 2. This system is used more for public health purposes than for clinical management, but is useful because it reflects the natural history of M. tuberculosis and categorizes patients according to the type of evaluation and treatment they may need.

Table 2  American Thoracic Society classification system for tuberculosis

 

Classification	Description
TB0	No exposure, no infection
TB1	Exposed to tuberculosis, infection status unknown
TB2	Latent infection, no disease (positive PPD tuberculin test)
TB3	Active tuberculosis
TB4	Inactive tuberculosis, healed or adequately treated
TB5	Possible tuberculosis, status unknown (‘rule out’ tuberculosis)

PPD, purified protein derivative.

The ATS category 0 refers to someone without any tuberculosis exposure history and a negative tuberculin skin test (if performed). Category 1 includes those people exposed to an infectious case of tuberculosis but in whom no evidence of infection is found. This is a temporary category used during the evaluation of contacts of tuberculosis cases; repeat tuberculin testing several months after the exposure would result in these individuals being reclassified to another category. Category 2 is defined as latent tuberculosis infection without evidence of disease, and is based on a positive tuberculin skin test without clinical or radiographic signs of illness. Category 3 is confirmed active tuberculosis disease requiring treatment. As discussed below, this category is further divided according to site of disease and laboratory features, including results of acid-fast bacilli smears. Category 4 is defined as inactive tuberculosis. Patients in this category do not have active disease on the basis of clinical and laboratory evaluations, but are known to have previously had tuberculosis. This category includes those who have been treated and cured of active tuberculosis, as well as individuals who have spontaneously recovered from tuberculosis without treatment. Finally, category 5 refers to patients in whom tuberculosis is suspected, but who are still undergoing evaluation. Depending on the degree of suspicion of the diagnosis, such people might be started on presumptive therapy for tuberculosis pending the outcome of cultures and other laboratory assessments. Like category 1, this is a temporary category for patients in the middle of an evaluation, and all patients in this group are reclassified on the basis of diagnostic studies.

Clinical presentation of active tuberculosis

This is highly variable, depending on the site and extent of disease and the immune status of the host. Historically, active tuberculosis has been classified as ‘primary’ or ‘post-primary’ on the basis of both the presumed duration of infection and the clinical features of the disease. Recent studies using molecular epidemiological techniques, however, suggest that this classification may be unreliable. For example, the ‘classic’ presentation of reactivation tuberculosis has been seen in patients whose infection is clearly newly acquired, such as in nosocomial outbreaks where DNA fingerprinting confirms recent transmission. For practical purposes, tuberculosis is generally divided into pulmonary and extrapulmonary forms, with considerable clinical heterogeneity within these categories.

Pulmonary tuberculosis

Pulmonary tuberculosis is usually a subacute respiratory infection with prominent constitutional symptoms. The most frequent symptoms of pulmonary tuberculosis are cough, fever, night sweats, and malaise. Cough in pulmonary tuberculosis is initially nonproductive, but often progresses to sputum production and, in some instances, haemoptysis. The sputum is generally yellow in colour, and is neither malodorous nor thick. Haemoptysis may be seen in patients with untreated tuberculosis, but is also a feature of treated tuberculosis; damage from prior tuberculosis may result in bronchiectasis or residual cavities that can either become superinfected or erode into blood vessels or airways, producing haemoptysis. Extremely advanced tuberculosis may also present with bloody sputum. Rarely, the bleeding is massive leading to shock, asphyxia, and death.

Chest pain is not a prominent symptom in pulmonary tuberculosis, although musculoskeletal pain from coughing may be noted. In patients with tuberculous pleurisy, however, chest pain may be present, particularly on inspiration. Radicular pain across the chest may be associated with spinal tuberculosis. Dyspnoea alone may be a sign of extensive parenchymal destruction, large pleural effusions, endobronchial obstruction, or pneumothorax.

Patients with tuberculosis also experience loss of appetite and weight loss or cachexia, often out of proportion to their diminished intake of food. Elevations in tumour necrosis factor-α are hypothesized to be the cause of cachexia in tuberculosis. Other symptoms with mild severity such as emotional liability, irritability, depression, and headache are frequent.

The duration of symptoms varies greatly, but most patients will report weeks to months of feeling ill before presentation. In surveys of populations with high rates of disease and poor access to medical care, a history of cough for more than 3 weeks was strongly associated with a diagnosis of active tuberculosis. Untreated tuberculosis is associated with high mortality, but many patients may have persistent symptoms for years. A study of untreated pulmonary tuberculosis in the pretherapy era found that after 5 years 50% of patients had died, 25% had spontaneously healed, and 25% were chronically ill with pulmonary disease. A subset of patients has rapidly progressive disease, the so-called ‘galloping consumption’ of old. Nowadays this is most often seen in patients with HIV infection or other forms of severe immunosuppression. These patients have an escalating course of severe pulmonary symptoms over a period of several weeks, often in the setting of disseminated disease. Failure promptly to diagnose and treat these patients results in death.

Physical findings in pulmonary tuberculosis are limited and not generally helpful in making a diagnosis. Fever is an irregular and unreliable feature, and while most patients complain of fevers before presentation, only one-half to three-quarters of patients with confirmed tuberculosis have a documented fever. Examination of the chest may reveal dullness to percussion and rales, although these findings are highly variable and nonspecific. Signs of consolidation are usually absent. The classic post-tussive rales described in the last century are not often present and are not specific to tuberculosis. Patients with disseminated tuberculosis may have lymphadenopathy, hepatomegaly, or evidence of central nervous system involvement, but these are not generally seen in typical pulmonary tuberculosis. Finger clubbing and cyanosis are findings associated with prolonged and advanced pulmonary disease. Thus, the diagnosis of tuberculosis almost always rests on the patient’s history and epidemiological characteristics, in conjunction with laboratory studies described below. The most important step in making a timely diagnosis of tuberculosis is to think of it in the first place.

Radiological evaluations play a critical role in the diagnosis of pulmonary tuberculosis. Disease due to M. tuberculosis can involve any portion of the lungs, and radiographic findings are usually only suggestive, not diagnostic, of tuberculosis. The typical radiological manifestations of pulmonary tuberculosis are upper lobe infiltrates that may show cavitation. M. tuberculosis exhibits a unique predilection for the upper zones of the lungs for reasons that are not well understood. Latent infection characteristically reactivates in the apical segments of the upper lobes, or the superior segments of the lower lobes. The infiltrates are often fibronodular and irregular, and may be diffuse and associated with volume loss. Cavities, when present, are rarely symmetrical and do not usually have air–fluid levels, such as those seen in pyogenic lung abscesses. 

The classic radiographic presentation described above is neither pathognomonic nor highly sensitive for pulmonary tuberculosis. Several other lung infections, notably the pulmonary mycoses, can present with similar findings. More importantly, one-third to one-half of patients with pulmonary tuberculosis lack the classic radiographic findings described. Lower lung zone infiltrates, mid-lung focal infiltrates, pulmonary nodules, and infiltrates with mediastinal or hilar adenopathy are also seen. HIV-infected tuberculosis patients, in particular, most often present with these ‘atypical’ findings, and up to 5% of them may have a normal chest radiograph in the setting of sputum cultures that yield M. tuberculosis. The lack of typical radiographic features should not, therefore, deter the clinician from considering the diagnosis in a patient with a clinical history compatible with and symptoms of tuberculosis.

CT is increasingly used to evaluate pulmonary disorders, including tuberculosis. While the classic findings described above do not usually require confirmation with a more sensitive test, CT scanning is sometimes used to evaluate radiographic findings that are not readily explained after an initial assessment. CT scans of the chest in patients with tuberculosis may reveal a greater extent of involvement than conventional radiographs, including multiple nodules, small cavities, and multilobar infiltrates. However, CT scanning can only suggest the possibility of tuberculosis in a patient with other signs and symptoms consistent with the diagnosis, and further evaluation is still required.

The laboratory diagnosis of pulmonary tuberculosis relies on the microbiological evaluation of sputum or other respiratory tract specimens. A definitive diagnosis requires growth of M. tuberculosis from respiratory secretions, while a probable diagnosis can be based on typical clinical and radiographic findings with either acid-fast bacilli-positive sputum or other specimens, or typical histopathological findings on biopsy material. These latter approaches, however, have a variable lack of specificity depending on the prevalence of disease due to nontuberculosis mycobacteria in the population.

Throughout most of the world, sputum acid-fast staining is the sole test used to confirm the diagnosis of pulmonary tuberculosis. In the settings where it is utilized, the positive predictive value of the sputum acid-fast smear is very high, as the likelihood of nontuberculous mycobacterial disease is quite low. In industrialized countries, disease due to the nontuberculous mycobacteria is relatively more common and reliance on smears without cultures is potentially misleading. Despite the best efforts of clinicians, a confirmed diagnosis of tuberculosis cannot be established in some patients who have the disease, and a response to presumptive therapy forms the basis for establishing the diagnosis. Further details on the microbiological approach to diagnosis are provided below.

Extrapulmonary tuberculosis

In the United States of America extrapulmonary tuberculosis is defined as disease outside the lung parenchyma; in the United Kingdom it is defined as disease outside the lungs and pleura. This seemingly subtle distinction has considerable epidemiological impact, however, as pleural tuberculosis is the most common extrapulmonary site of disease in the United States of America.

During the initial seeding of infection with M. tuberculosis, described earlier, haematogenous dissemination of bacilli to several organs can occur. These localized infections, as in the lung, can progress into primary tuberculosis or become walled off in small granulomas where bacteria may remain dormant if they are not killed by cell-mediated immune responses. Extrapulmonary tuberculosis, therefore, can either be a presentation of primary or reactivation tuberculosis.

Extrapulmonary tuberculosis may be generalized or confined to a single organ. In otherwise immunocompetent adults, extrapulmonary tuberculosis is found in 15 to 20% of all tuberculosis cases. In young children and immunosuppressed adults, rates of extrapulmonary disease are substantially higher, appearing in more than one-half of HIV-related tuberculosis cases and one-quarter of tuberculosis cases under 15 years of age. Children less than 2 years old have high rates of miliary and meningeal disease.

The organs most frequently involved in extrapulmonary tuberculosis are listed in Table 3. To some extent the frequency with which specific organs are involved reflects the pathophysiology of the disease. Infection spreads from the lungs, the primary site of inoculation, by lymphatic and haematogenous routes. The tissues and organs most likely to be affected are the pleura, lymph nodes, kidneys and other genitourinary organs, bone, and central nervous system. Although infection is transiently spread in the blood, tuberculosis bacteraemia is unusual and is seen most often in patients with HIV infection and low CD4 lymphocyte counts.

Table 3  Common sites of extrapulmonary tuberculosis

 

Site	Percentage of extrapulmonary cases
Pleura	20–25
Lymphatics	20–40
Genitourinary	5–18
Bone/joint	10
Central nervous system	5–7
Abdominal	4
Disseminated	7–11

The clinical presentation of extrapulmonary tuberculosis depends largely on the organ involved. Both pulmonary and extrapulmonary disease are found in up to 50% of patients with HIV-related tuberculosis, so it is important to consider the possibility of extrapulmonary pathology when pulmonary tuberculosis is diagnosed in an HIV-infected patient (and vice versa). Pulmonary involvement is seen in up to one-quarter of patients with tuberculous meningitis and to lesser degrees with other sites of disease.

Pleural tuberculosis

This is the result of two distinct pathophysiological sequences, which present in strikingly different manners. Most pleural tuberculosis is associated with primary infection and is the result of seeding of the visceral pleura with relatively small numbers of tubercle bacilli via direct extension from adjacent lung tissue. A large proportion of patients with this form of tuberculous pleurisy will have obvious pulmonary disease, although findings may be subtle. The duration of symptoms is generally brief, e.g. several weeks, and patients complain of fever, chest pain, and nonproductive cough. Other constitutional and respiratory symptoms may be present. Unlike pneumococcal pneumonia, which presents abruptly, tuberculous pleurisy starts more insidiously.

The second form of pleural tuberculosis occurs when larger numbers of bacilli invade the pleural space and multiply, producing frank empyema. Tuberculous empyema is seen in older patients, almost all of whom have extensive pulmonary disease. Patients present with prolonged symptoms of cough, chest pain, fever, cachexia, and night sweats. Pneumothorax is a common complication of tuberculous empyema and may be associated with a more rapid disease course.

The radiographic picture in tuberculous pleurisy reflects the underlying pathophysiology of the disease. Patients with the primary type of pleurisy tend to have small unilateral effusions, and up to one-half have visible parenchymal lesions on plain radiographs. In patients with tuberculous empyema, the effusions are larger and more likely to be loculated, and adjacent pulmonary involvement is often evident.

The diagnosis of pleural tuberculosis can be approached along several lines. When pulmonary parenchymal involvement is manifest, sputum smears and cultures have a high yield, and the diagnosis of pleural disease can be inferred from the pulmonary findings. When pulmonary findings are minimal or the initial test results unrevealing, analysis of pleural fluid is essential. Acid-fast stains of pleural fluid are usually negative in patients with primary tuberculous pleurisy as the number of organisms in the pleural space is small. Repeated sampling will show organisms in less than one-half of cases. Similarly, culture results may be negative. The pleural fluid is usually serous and exudative, with a protein concentration that is more than 50% of the serum level, normal or low glucose, and a slightly acidic pH. The pleural fluid white blood cell count is usually in the range of 1000 to 10 000 per µL with a lymphocytic predominance. Lactate dehydrogenase levels are generally elevated, as are adenosine deaminase levels. All of these tests are nonspecific and cannot reliably distinguish tuberculosis pleurisy from other pleural diseases.

Pleural biopsy is frequently useful in establishing a diagnosis of tuberculous pleurisy. Percutaneous biopsy of the pleura reveals granulomatous inflammation in up to 80% of patients, and cultures obtained at the time of biopsy are positive in over one-half of patients. If a first attempt fails to provide a diagnosis, a second biopsy may be successful. More recently thoracoscopy has been utilized to improve the yield of biopsy by visualizing biopsy targets rather than blindly sampling with a percutaneous pleural needle.

Lymphatic tuberculosis

This can occur in any location, but classic scrofula involving the cervical or supraclavicular chains is the most common presentation. Mediastinal and hilar lymphatic tuberculosis is a feature both of primary and disseminated disease, but discovery of these lesions is usually incidental. The pathophysiology of lymphatic tuberculosis is thought to result from drainage of bacilli in the lungs into supraclavicular and posterior cervical lymph node chains. In contrast, lymphatic disease caused by nontuberculous mycobacteria usually involves anterior cervical, preauricular, or submandibular lymph nodes, suggesting acquisition through the oropharynx. In patients with HIV infection, multiple lymph node groups may be involved including axillary, inguinal, mesenteric, and retroperitoneal.

Symptoms in lymphatic tuberculosis are generally limited, unless the disease is disseminated. Painless swelling of a lymph node is the most common presentation. Constitutional symptoms are not prominent in most cases. Examination of the area may reveal several enlarged lymph nodes, as only about 20% of patients have disease of a solitary node.

The diagnosis of lymphatic tuberculosis usually depends on cultures from affected nodes. Biopsies may show granulomatous changes and acid-fast bacilli. Such findings are nonspecific, however, and cannot distinguish tuberculous from nontuberculosis lymphadenitis. As discussed elsewhere, the presence of a positive tuberculin skin test in the setting of typical biopsy findings is strongly suggestive of tuberculosis; in the setting of suspected lymphatic tuberculosis, these findings warrant presumptive therapy.

Genitourinary tuberculosis

This encompasses a broad array of clinical entities, ranging from disease of the kidneys to endometrial, prostatic, and epididymal disease. The most common of these is renal tuberculosis, which results from haematogenous seeding of the renal cortex during the primary infection. The pathogenesis of other genitourinary sites is either from downstream extension of renal infection over time or from haematogenous seeding at the time of the initial acquisition of M. tuberculosis.

Renal tuberculosis is probably underdiagnosed because it is frequently asymptomatic. Many cases of genitourinary tuberculosis are diagnosed as a result of routine urinalyses that detect sterile pyuria. The development of symptoms reflects a more advanced stage of disease, associated with considerable tissue destruction. When genitourinary tuberculosis is symptomatic, the most common symptoms are localized and include urinary symptoms and flank pain. In men, tuberculosis can cause prostatitis and epididymitis, both of which can present with pain resulting from swelling. In women, genital tract tuberculosis may be symptomatic when it involves the ovaries and Fallopian tubes; pelvic pain is also a feature of endometrial tuberculosis. Menstrual abnormalities and infertility may be the only signs of genital disease, however.

The diagnosis of genitourinary tuberculosis depends on the anatomical site of the disease. Renal tuberculosis, as noted, is suggested by sterile pyuria, and the diagnosis rests on isolation of organisms in the urine. Early morning urine samples are more likely to grow M. tuberculosis than spot samples obtained at other times. In patients with symptoms of upper urinary tract illness, radiological studies are often helpful. The kidneys may appear calcified on abdominal radiographs. Intravenous pyelography may show distorted or dilated calyces or renal pelvis, papillary necrosis, cavitation or abscesses of the renal parenchyma, or intrarenal or ureteral obstructions. Use of renal ultrasonography or CT scanning may be more sensitive for identifying the abnormalities of renal tuberculosis, but contrast radiography is the technique with which the greatest experience has accrued. When tuberculosis of the bladder is suspected, cystoscopy with biopsy may lead to the identification of granulomas before identification of organisms by culture. Diagnosis of prostatic, testicular, or epididymal tuberculosis is usually accomplished with cultures obtained by fine needle aspiration or transurethral resection of the prostate. Cervical and endometrial tuberculosis can be diagnosed by biopsy with culture.

Tuberculous meningitis summary

This is the most common central nervous system manifestation of tuberculosis. It is much more likely to occur in children under the age of 15 years and in HIV-infected patients than in immunocompetent adults. Although meningitis accounts for only a small fraction of all cases of tuberculosis, it is a devastating form of the disease that is uniformly fatal if left untreated.

The pathogenesis of meningeal tuberculosis varies with the age and immunological status of the patient. Reactivation of microscopic granulomas in the meninges was found by Rich to cause diffuse meningeal infection. These foci of infection are probably implanted at the time of primary bacillaemia. When these lesions rupture into the subarachnoid space they invoke an inflammatory response leading to tuberculous meningitis. Meningeal disease can also complicate miliary disease, especially in children. Likewise, adults can acquire meningeal disease during bacillaemia of miliary disease, but this is not the usual pathogenesis of meningeal infection. Rarely, invasion into the spinal canal from a paraspinous or vertebral focus can also be the source of central nervous system involvement.

The clinical features of tuberculous meningitis are the consequence of the pathophysiological process underlying the disease. Meningeal and leptomeningeal bacterial replication results in a robust inflammatory reaction, often localized to the base of the brain. The number of bacilli present is usually limited, and the severity of illness is a function of the host response. Meningeal inflammation causes increases in cerebrospinal fluid pressure and can also cause cranial neuropathies. Patients complain of headache, neck stiffness, meningism, and an altered mental status, including irritability, clouded thinking, and malaise; as the disease progresses, symptoms worsen considerably.

The clinical spectrum of tuberculous meningitis has historically been categorized in three stages, defined by the British Medical Research Council in 1948. Stage 1 consists of a prodrome lasting for 1 to 3 months. Nonspecific symptoms such as fever, malaise, and headache predominate. In this stage, patients are conscious and rational, but may have signs of meningism. Focal neurological signs are absent and there are no signs of hydrocephalus. In stage 2 disease, single cranial nerve abnormalities such as ptosis or facial paralysis appear, and paresis and focal seizures may occur. Kernig’s and Brudzinski’s signs have been noted as well as hyperactive deep tendon reflexes. Prominent signs include alterations in mentation, behavioural change, impaired cognitive ability, and increasing stupor. Headache and fever are also common features of this stage of disease.

In stage 3, patients are comatose (Glasgow coma scale 8 or below) or stuporous and often have multiple cranial nerve palsies and hemiplegia or paraplegia. By this stage, hydrocephalus is common and chronic inflammation in the enclosed space of the skull may result in significant intracranial hypertension. Seizures may be a prominent feature.

Fever, headache, altered level of consciousness, and meningism are present in the majority of patients in most large studies, although no one single sign or symptom has any reliable degree of sensitivity or specificity. Children can be especially difficult to diagnose as symptoms such as fever, vomiting, drowsiness, or irritability are commonly seen in many minor viral illnesses.

Transient tuberculous meningitis that presents as an aseptic meningitis and resolves without treatment has been described. Benign presentations of meningeal tuberculosis are uncommon in clinical practice, and when the diagnosis is made, treatment is mandatory, even in the patient with seemingly trivial symptoms.

The diagnosis of tuberculous meningitis is often difficult and requires a high degree of suspicion. In the setting of disseminated disease, signs of tuberculosis in other organs, particularly the lungs, are often present. Between 25 and 50% of patients with meningitis in most series also have radiographic evidence of pulmonary tuberculosis, either active or healed. The critical features of tuberculous meningitis, however, are found in the cerebrospinal fluid. Patients with tuberculous meningitis usually have elevated cerebrospinal fluid pressure. An exudative fluid with a mononuclear cell pleocytosis is characteristic. Cerebrospinal fluid is usually clear and the protein is generally in the range of 100 to 500 mg/dl. Hypoglycorrhachia is typical, with cerebrospinal fluid glucose less than 50% of the serum value. The white blood cell count rarely exceeds 1000 per µL, and cell counts below 500 are typical. In early meningitis, the cells may be predominantly neutrophils, but mononuclear cells predominate in most instances. Acid-fast stains of concentrated cerebrospinal fluid are only positive in one-third or fewer of patients, and cultures are positive in only one-half, although repeated sampling increases the yield.

The disastrous consequences of failing to diagnose tuberculous meningitis, coupled with the low yield of cerebrospinal fluid acid-fast stains and cultures, has prompted the development of additional tests for establishing a diagnosis. Adenosine deaminase was initially reported to be exceptionally accurate for tuberculous meningitis. Subsequent experience, however, has found it to be insufficiently specific to distinguish tuberculosis from a variety of other acute and chronic meningitides. Several other tests based on identification of mycobacterial antigens or specific antibodies have been evaluated, but none has been found to be reliable. Nucleic acid amplification tests such as polymerase chain reaction (PCR) have great appeal, but the sensitivity and specificity of available assays are only moderately good. Thus, the diagnosis of tuberculous meningitis often rests on the astute judgment of a clinician with a high degree of suspicion based on epidemiological and clinical clues. Presumptive therapy is frequently necessary.

Tuberculous meningitis in more detail

Epidemiology

Tuberculous meningitis (TBM) kills or disables half those who have the condition and is the most dangerous form of infection with Mycobacterium tuberculosis. Fortunately, it is a relatively uncommon manifestation of TB and represents around 1% of all forms of the disease. In Western countries, its incidence has fallen in parallel with TB as a whole, but for those in the less developed world TBM remains a common cause of bacterial meningitis, particularly in populations with a high prevalence of HIV infection.

Before the arrival of HIV, most cases of TBM were in young children and occurred as a complication of primary infection. Now an increased proportion of cases occur in adults with HIV coinfection. HIV infection greatly increases the risk of all forms of TB, but in particular the extrapulmonary forms such as TBM, and the risk increases as the CD4 count declines.

Pathogenesis

Understanding of the pathogenesis of TBM has progressed little since the studies of Rich and McCordock in the 1920s and 1930s. They demonstrated, through postmortem examinations of children and experiments on rabbits, that the pathogenesis of TBM requires two steps. During the first step the meninges and brain parenchyma are seeded by blood-borne bacteria with the formation of small subpial or subependymal foci of infection (or the Rich foci). In children the bacteraemia usually occurs during primary pulmonary infection and may be subclinical, whereas in adults this step may occur after new pulmonary infection or reactivation of old foci. The second step requires the rupture of a Rich focus with release of bacteria into the subarachnoid space. This heralds the onset of meningitis, which, if left untreated, will result in severe and irreversible neurological pathology. In 75% of children the onset of TBM is less than 12 months after the primary infection.

Pathology

Three processes are responsible for the neurological pathology of TBM. An adhesive exudate develops around the basal cisterns and can obstruct cerebrospinal fluid causing hydrocephalus and compromise efferent cranial nerves. Granulomas can coalesce to form tuberculomas, or an abscess in unusual cases, causing diverse clinical consequences dependent on their anatomical location. And an obliterative vasculitis can cause infarction and stroke syndromes, commonly involving the basal ganglia, internal capsule, and territory of the middle cerebral artery. The severity of these complications is believed to depend on the intracerebral inflammatory response and strongly predicts outcome.

In less than 10% of cases TBM occurs with spinal involvement, usually manifest as paraplegia. Vertebral tuberculosis (Pott’s disease) accounts for around a quarter of cases and may be associated with fusiform paravertebral abscesses or a gibbus. Extradural cord tuberculomas cause more than 60% of cases of nonosseous paraplegia, although tuberculomas can occur in any part of the cord. Tuberculous radiculomyelitis is a rare accompaniment to TBM, characterized by a subacute paraparesis, radicular pain, and bladder dysfunction. MRI reveals loculation and obliteration of the spinal subarachnoid space with nodular intradural enhancement.

Clinical features

If left untreated, TBM follows a slowly progressive course that leads to death in almost all cases. The first symptoms are nonspecific and unlikely to raise the suspicion of TBM. Infants may become irritable or go off their feeds, whereas older patients may complain of malaise, insomnia, lethargy, anorexia, and gradually worsening headache. These prodromal symptoms can last from 2 weeks to 8 weeks until the classic features of meningitis become more apparent. Patients commonly present to hospital at this stage, when the infection is well established. They will usually complain of headache and vomiting; many will present confused or comatose. Examination reveals neck stiffness in most, although it is rarely as marked as in acute pyogenic bacterial meningitis. Cranial nerve palsies are found in 25% of patients, with nerves VI, III, and VII being most commonly affected. Ten per cent of patients will present with a mono- or hemiparesis. Fundoscopy reveals papilloedema in half of patients and, occasionally, choroidal tubercles. Rarely, TBM presents as an acute meningoencephalitis that can be difficult to distinguish from pyogenic bacterial or viral meningitis. Seizures are rare in adults with TBM, but more common in children. HIV infection does not appear to alter the clinical presentation of TBM, although evidence of other extrapulmonary disease is more likely in HIV-infected patients.

Diagnosis

The diagnosis and treatment of TBM before the onset of coma are the greatest contribution that a physician can make to improve outcome. However, making the diagnosis is challenging because the clinical features of the disease are nonspecific, small numbers of bacteria in the cerebrospinal fluid reduce the sensitivity of conventional bacteriology, and alternative diagnostic methods are incompletely assessed.

The presenting clinical features of TBM are insufficiently specific to enable the diagnosis to be made on the history and examination alone. Recall of recent exposure to TB may be helpful, particularly in children, as may evidence of active extrameningeal TB on examination. Chest radiography reveals active or previous TB infection in 50%; the appearance of miliary TB is particularly useful as it strongly suggests multiorgan involvement. Skin testing with the purified protein derivative of M. tuberculosis is probably of limited value, except in infants.

Examination of the cerebrospinal fluid is an essential part of diagnosing TBM and is a safe procedure for most patients with TBM. Hydrocephalus is not a contraindication to lumbar puncture. cerebrospinal fluid pressures are usually raised (mean 30 cmH₂O) and the cerebrospinal fluid is typically clear and slightly xanthochromic. Much is made in the older literature of the formation of a spider’s web clot in the cerebrospinal fluid from patients with TBM but the diagnostic utility of this phenomenon has never been systematically tested and is probably exaggerated. The total number of white cells in the cerebrospinal fluid varies from fewer than 5/µl to 1500/µl. Most patients will have 300 to 500 cells/µl cerebrospinal fluid but older and immunosuppressed people may have low or even normal counts. The cells are a mixture of neutrophils and lymphocytes, although lymphocytes usually form 70 to 90% of the total. Occasionally, TBM can present with a short history with 1500 to 2500 WBCs/µl in the cerebrospinal fluid, most of which are neutrophils. Cerebrospinal fluid total protein concentrations are raised in 95%, typically between 1 and 2 g/l; concentrations of more than 3 g/l suggest spinal block. The ratio cerebrospinal fluid:blood glucose concentration is less than 0.5 in 95% and is a useful way of distinguishing TBM from other lymphocytic meningitides, especially viral meningitis, in which cerebrospinal fluid:blood glucose is usually more than 0.5.

Attempts have been made to identify the clinical and cerebrospinal fluid findings predictive of TBM. In children, a history longer than 6 days, optic atrophy, focal neurological deficit, abnormal movements, and neutrophils forming less than half the total cerebrospinal fluid leucocytes were independently associated with TBM. A diagnostic rule developed in Vietnamese adults to distinguish TBM from bacterial meningitis calculated weighted scores for the variables predictive of TBM (score in brackets): age less than 36 years (0), 36 years or more (+ 2); peripheral blood white cell count fewer than 15 000 × 10³/ml (0), 15 000 × 10³/ml or more (+ 4); duration of symptoms more than 6 days (− 5), 6 days or less (0); cerebrospinal fluid white cells fewer than 900/µl (0), 900/µl or more (+ 3); and cerebrospinal fluid neutrophils less than 75% of total cells (0), 75% or more (+ 4). A total score of less than 4 indicated TBM, and a score of 4 or more indicated bacterial meningitis; when applied prospectively the rule was 86% sensitive and 79% specific. However, the performance will probably differ where TB prevalence is lower and HIV prevalence higher than in Vietnam.

CT and MRI of the brain provide diagnostic information, but there are few data to indicate whether the findings can help discriminate TBM from other cerebral disorders. Basal meningeal enhancement, hydrocephalus, tuberculoma, and infarction are the cardinal neuroradiological features of TBM. Indeed, the presence of basal meningeal enhancement, tuberculoma, or both, was 89% sensitive and 100% specific for the diagnosis of TBM in one study. Pre-contrast hyperdensity in the basal cisterns may be a highly specific radiological sign of TBM in children. Cranial MRI is better at defining brainstem and cerebellum pathology, tuberculomas, infarcts, and the extent of inflammatory exudates, but there are no data to suggest that MRI is better than CT in discriminating TBM from other disorders. Cryptococcal meningitis, viral encephalitis, sarcoidosis, meningeal metastases, and lymphoma may all produce similar radiographic findings. The major role of neuroradiology has been in the management and follow-up of the complications of TBM requiring neurosurgery.

The culture of M. tuberculosis from the cerebrospinal fluid is the gold standard diagnostic test for TBM, but takes 2 to 6 weeks and is therefore too slow to aid clinical decision-making. Demonstrating acid-fast bacilli of M. tuberculosis in the cerebrospinal fluid after Zeihl–Neelsen staining is the oldest and most widely available rapid diagnostic test, but the performance varies widely depending upon the volume of cerebrospinal fluid examined, the duration of microscopy, and the skill of the operator. Most laboratories find acid-fast bacilli in the cerebrospinal fluid of only 10 to 20% of those with TBM. Meticulous microscopy and the examination of large (> 5 ml) volumes of cerebrospinal fluid can improve the sensitivity of both staining and culture to more than 60% and 80% respectively. HIV infection is also associated with better performance of bacteriology because there are higher concentrations of bacteria in the cerebrospinal fluid.

Whether molecular techniques can improve on conventional bacteriology is still unclear. In theory, nucleic acid amplification, such as that based on the PCR, should improve on bacteriology, but studies addressing their diagnostic role have failed to demonstrate an improvement because of low numbers of cases and inadequate bacteriological diagnostic comparison. A systematic review and meta-analysis calculated that commercial nucleic acid amplification assays for the diagnosis of TBM were 56% sensitive (95%CI 46–66%) and 98% specific (95%CI 97–99%). These data suggest that the sensitivity of these assays is still too low—approximately half those with a negative test will actually have the disease—and may not improve upon careful bacteriology. Studies published after the meta-analysis reinforce this conclusion and indicate that before the start of treatment careful bacteriology is as good, or better, than the currently available commercial nucleic acid amplification assays, but these methods retain their sensitivity in the face of anti-TB chemotherapy and are more useful once treatment has started. Unfortunately, there is no single test that will allow the physician to confidently rule out TBM.

Many other approaches to the diagnosis of TBM have been attempted and shown preliminary promise, but none has proved sufficiently reproducible, sensitive, specific, and practical for widespread clinical use. Commercial immunological assays based on the production of interferon-γ after stimulation with M. tuberculosis-specific antigens (ESAT6 and CFP10)—the T-SPOT and QuantiFERON-TB assays—have been a major advance in the diagnosis of latent TB infection, but their potential role in TBM diagnosis has not been established. Published data from small numbers of patients with TBM using an ELISPOT assay (used in the T-SPOT test) on cerebrospinal fluid suggested that it lacks sensitivity and, until further evaluation is complete, these assays cannot be recommended for the routine laboratory diagnosis of TBM.

In summary, a high index of clinical suspicion is required to diagnose TBM and, given the fatal consequences of delayed treatment, clinicians should be encouraged to initiate ‘empirical’ therapy in the setting of compatible clinical, epidemiological, and laboratory findings.

Differential diagnosis

TBM usually presents as a subacute lymphocytic meningitis and the differential diagnosis will depend on the age of the patient, geographical location, and immune status. In immunocompetent individuals the major differential diagnoses are partially treated pyogenic bacterial meningitis and viral meningoencephalitis. Various neoplastic infiltrations of the meninges (e.g. carcinomas, leukaemias, and lymphomas) may be more common at the extremes of age. Neurosarcoidosis can be very difficult to distinguish from TBM, as may neurosyphilis. Geographical region can suggest specific alternative diagnoses, e.g. meningitis caused by Angiostrongylus cantonensis or Gnathostoma spinigerum in south-east Asia, or by Coccidioides spp., Histoplasma spp., or cysticercosis in the Americas, can all mimic TBM. The immunosuppressed patient represents an important group often at high risk for diseases caused by mycobacteria, fungi, and herpesviruses. Cryptococcal meningitis is the major differential diagnosis of TBM in HIV-infected patients but can usually be distinguished on the basis of a cerebrospinal fluid Indian ink stain, fungal culture, or the cryptococcal antigen test. Cerebral toxoplasmosis can be difficult to differentiate from cerebral tuberculosis, especially when multiple tuberculomas are present, and cytomegalovirus (CMV) and herpes simplex virus (HSV) 1 and 2 meningoencephalitis can also cause diagnostic confusion with TBM. In most of these cases careful microbiological examination of the cerebrospinal fluid (for fungi and mycobacteria, in particular), selected use of nucleic acid amplification assays (M. tuberculosis, Toxoplamsa gondii, CMV, and HSV), and serological tests (syphilis) will allow a diagnosis to be made.

Treatment

The treatment of TBM follows the model of a short course of chemotherapy for pulmonary TB: an ‘intensive phase’ of treatment with four drugs, followed by a prolonged ‘continuation phase’ with two drugs. The first 2 months of treatment should be with isoniazid, rifampicin, pyrazinamide, and streptomycin, ethambutol, or ethionamide. The British Thoracic Society (BTS) and the Infectious Disease Society of America (IDSA) favour ethambutol as the fourth drug, although they acknowledge the lack of evidence from controlled trials. Others, particularly in South Africa, advocate ethionamide, which penetrates healthy and inflamed meninges more effectively than ethambutol or streptomycin, but can cause severe nausea and vomiting. In adults, daily single doses of 300 mg isoniazid, 600 mg rifampicin, and 2000 mg pyrazinamide provide adequate levels in the sera and cerebrospinal fluid of patients with TBM. Higher doses of these drugs are unnecessary and may result in a higher incidence of hepatotoxicity. Some advocate higher doses in children, notably in South Africa, but this approach cannot be recommended in adults. Unlike the treatment of pulmonary TB, interruptions in anti-TB chemotherapy are an independent risk factor for death from TBM.

British and American guidelines suggest between 9 and 12 months of total anti-TB treatment for TBM, although a recent systematic review concluded that 6 months might be sufficient provided that the likelihood of drug resistance is low. Isoniazid and rifampicin are considered mandatory in the continuation phase and the BTS suggests that therapy should be extended to 18 months in those unable to tolerate pyrazinamide in the intensive phase. Others recommend that pyrazinamide be given throughout treatment because of its excellent penetration across the blood–brain barrier, although there is no supporting evidence from controlled trials.

TBM caused by M. tuberculosis resistant to one or more first-line anti-TB drugs is an increasingly common problem. Isoniazid resistance alone does not appear to have a major impact on outcome from TBM, which is surprising given isoniazid’s excellent penetration into cerebrospinal fluid and its potent early bactericidal activity. However, the combination of rifampicin and isoniazid resistance (multidrug resistance) has a major impact such that most patients will die unless second-line therapy is started early. Detecting TBM caused by multidrug-resistant organisms is difficult: patients are likely to be dead before the results of conventional susceptibility tests (which take 6–8 weeks) are available and rapid, molecular-based assays for detecting resistant organisms in cerebrospinal fluid have not been properly evaluated. In addition, the best combination, dose, and duration of second-line agents for the treatment of multidrug-resistant TBM are not known. Indeed, there are no published controlled trials addressing this issue for any form of TB. Until more data become available the treatment of multidrug-resistant TBM should follow the principles of treating drug-resistant pulmonary disease: never add a single agent to a failing regimen; use at least three previously unused drugs, one of which should be a fluoroquinolone; streptomycin resistance does not confer resistance to other aminoglycosides, therefore amikacin or kanamycin can be used; and treat for at least 18 months.

Adjunctive corticosteroids

The use of adjunctive corticosteroids has been controversial ever since they were first suggested for the management of TBM more than 50 years ago. A meta-analysis and systematic review of all controlled trials published before 2000 concluded that corticosteroids probably improved survival in children, but small trial sizes, poor treatment allocation concealment, and possible publication bias did not support clear treatment recommendations. In 2004, a controlled trial of adjunctive dexamethasone in 545 Vietnamese adults with TBM revealed that dexamethasone treatment was strongly associated with a reduced risk of death after 9 months of treatment (RR 0.69, 95%CI 0.52–0.92, p= 0.01), but did not prevent severe disability in the survivors. The effect of dexamethasone was consistent across all grades of disease severity, dispelling a previously held belief that corticosteroids benefited only those with more severe disease, but did not demonstrate a significant effect on death or disability in those infected with HIV. Current evidence suggests that all HIV-uninfected patients with TBM should be given dexamethasone, regardless of age or disease severity. A clear benefit of dexamethasone in HIV-infected patients has not been demonstrated, but the trial in Vietnam suggested that it was safe and might improve survival.

There are no data from controlled trials comparing different corticosteroid regimens, so the choice of regimen should be based on those used in the published controlled trials. In adults, the following regimen was shown to improve outcome in Vietnam: those with a Glasgow Coma Scale (GCS) score of less than 15 or focal neurological deficit at the start of treatment received intravenous drug for 4 weeks (0.4 mg/kg per 24 h week 1, 0.3 mg/kg per 24 h week 2, 0.2 mg/kg per 24 h week 3, and 0.1 mg/kg per 24 h week 4) followed by 4 mg total oral drug, reducing each week by 1 mg until 0. Those without coma or neurological signs received intravenous drug for 2 weeks (0.2 mg/kg per 24 h week 1, 0.1 mg/kg per h week 2), followed by the same oral reducing course described above. In children, the South African trial demonstrated improved survival with 4 mg/kg per day of prednisolone for the first month of treatment.

Response to therapy and treatment of complications

Ninety per cent of deaths from TBM occur in the first month of treatment. The response to therapy is slow and can follow a fluctuant course. Indeed, a rapid and sustained response over a few days suggests an alternative diagnosis. Headache is often present for many weeks, even in uncomplicated cases. Fever rarely disappears within a week, and pyrexia is often observed for 6 to 8 weeks. The degree of neck rigidity at presentation varies considerably and can take 4 to 6 weeks to resolve. The cerebrospinal fluid mirrors the slow clinical response: cell counts remain elevated for 1 to 2 months, cerebrospinal fluid glucose remains low for a similar duration, and total cerebrospinal fluid protein can rise before falling slowly over many months. Transient episodes of high fever, worsening headache, and increased nuchal rigidity can occur during the first 2 months of treatment, particularly in those with more severe disease. Distinguishing self-limiting events from the onset of more serious complications is difficult. New focal neurological signs, or a fall in conscious level, rarely accompanies these transient deteriorations. Cranial imaging should be arranged urgently if new clinical signs develop during treatment. Hydrocephalus, cerebral infarction, the expansion of intracranial tuberculoma, hyponatraemia, and poor adherence to therapy are the foremost reasons for severe acute deterioration. The expansion of intracranial tuberculoma after the start of treatment is a widely reported complication and frequently labelled as a ‘paradoxical’ treatment reaction. Recent data suggest that 75% with TBM develop tuberculomas during therapy but only small proportions are symptomatic. Most authors suggest treatment with prolonged high-dose corticosteroids if the tuberculoma causes clinical deterioration, although there are no controlled trials to support these recommendations. There are case reports to suggest that adjunctive thalidomide may help in the management of symptomatic expanding tuberculomas. Rarely, tuberculomas coalesce to form an abscess and neurosurgical drainage may be indicated.

Hydrocephalus is a common and serious complication of TBM and can be treated with diuretics (furosemide and/or acetazolamide), serial lumbar punctures, or ventriculoperitoneal/atrial shunting. There are no data from controlled trials that determine which method of treatment is best. Some advocate early shunting in all patients with hydrocephalus, whereas others recommend shunting only for patients with noncommunicating hydrocephalus. External ventricular drainage has been used to predict response to ventriculoperitoneal shunting but without success; others suggest that monitoring lumbar cerebrospinal fluid pressure can predict response to medical treatment. Without clear evidence physicians must balance possible benefit with the resources and experience of their surgical unit and the significant complications of shunt surgery.

Severe hyponatraemia is a common and often overlooked cause of deterioration on therapy. With the pathogenesis unclear, the best way of correcting the plasma sodium is uncertain. Sodium and fluid replacement are probably indicated in hypovolaemic hyponatraemia, whereas fluid restriction may be more appropriate in those who are euvolaemic with evidence of SIADH. There is anecdotal evidence to suggest that fludrocortisone replacement therapy and demeclocycline may be useful.

Prognosis and sequelae

TBM kills or severely disables half of the people who have the condition. Outcome is even worse in those coinfected with HIV as more than half die. Whether highly active antiretroviral therapy can improve survival is uncertain and under active investigation.

The severity of TBM has been divided into three grades, a categorization that takes its name and definitions from the 1948 British Medical Research Council (MRC) study of streptomycin in TBM treatment (Table 4). The grades are still used because they are good predictors of outcome: less than 10% of patients die with grade I disease, whereas 50% with grade III will not survive. A number of studies have assessed the clinical and laboratory parameters that predict outcome. Univariate analyses have suggested extremes of age, advanced stage of disease, concomitant extrameningeal TB, and evidence of raised ICP are associated with a poor outcome. Studies that have adjusted for the effect of covariables using multivariate analyses have consistently shown that treatment before the onset of coma improves outcome. A study of 434 Turkish adults revealed convulsions, coma, and delayed or interrupted treatment to be independent predictors of death. Extrameningeal TB, cranial nerve palsy, focal weakness, multiple neurological abnormalities, and drowsiness at diagnosis independently predicted later neurological disability. Permanent sequelae occur in 10 to 30% of survivors: intellectual impairment is common in infants and young children and a quarter of all patients will have cranial nerve deficits, including blindness, deafness, and squints. Ten per cent will have permanent mono-, hemi-, or paraparesis.

Prevention 

Although the efficacy of BCG immunization to prevent pulmonary TB is controversial, its ability to prevent disseminated TB (including TBM) in young children is widely accepted. Meta-analyses have shown that BCG immunization at birth prevents around 70% of all cases of childhood TBM and is a highly cost-effective intervention in settings with a high prevalence of TB. Whether the protection lasts into adulthood is uncertain.

Table 4  The British Medical Research Council disease severity grades for tuberculous meningitis

Grade	Clinical criteria
I	Alert and oriented without focal neurological deficit
II	GCS score 14–10 with or without focal neurological deficit or GCS 15 with focal neurological deficit
III	GCS score <10 with or without focal neurological deficit

GCS, Glasgow Coma Scale.

TBM can also be prevented by treating the household contacts of newly diagnosed cases of pulmonary TB. The BTS recommend either 6 months of isoniazid or 3 months of isoniazid and rifampicin for Mantoux-positive contacts to prevent progression to active disease.

Central nervous system tuberculomas

These are an unusual manifestation and are seen in a small proportion of patients with tuberculous meningitis. Tuberculomas are the result of enlarging tubercles that extend into brain parenchyma rather than into the subarachnoid space. Patients with HIV infection appear to have an increased risk of central nervous system tuberculomas, but the disease is far less common than toxoplasmosis, even in areas where tuberculosis is highly prevalent. Central nervous system tuberculomas may appear with clinical features of meningitis or of intracranial mass lesions. In the absence of meningeal involvement, seizures or headaches may be the only symptoms. The diagnosis is suggested by brain imaging, with MRI scanning being more sensitive than CT scanning. Biopsy of the lesion is required for diagnosis, and material should be submitted for histopathological staining and culture.

Bone and joint tuberculosis

These may affect several areas, but vertebral tuberculosis (Pott’s disease) is the most common form, accounting for almost one-half of cases. Haematogenous seeding of the anterior portion of vertebral bone during initial infection sets the stage for later development of Pott’s disease. Infection grows initially within the anterior vertebral body, then may spread to the disc space and to paraspinous tissues. Destruction of the vertebral body causes wedging and eventual collapse. Patients usually complain of back pain, with constitutional symptoms less prominent. Neurological impairment is a late complication, but delays in diagnosis are common and many patients experience neurological sequelae. Imaging studies of the spine usually reveal anterior wedging, collapse of vertebrae, and paraspinous abscesses. The diagnosis is established with bone biopsy or curettage, or by culture of the drainage from a paraspinous abscess.

Miliary tuberculosis and disseminated tuberculosis

These are terms used interchangeably to describe widespread infection and the absence of minimal host immune responses. The term ‘miliary tuberculosis’ is derived from the classic radiographic appearance of haematogenous tuberculosis, in which tiny pulmonary infiltrates with the appearance of millet seeds are distributed throughout the lungs. Miliary tuberculosis is a more common consequence of primary tuberculosis infection than reactivation, and is seen more frequently in children and immunocompromised adults. Primary miliary tuberculosis presents with fever and other constitutional symptoms over a period of several weeks. Clinical evaluation may reveal lymphadenopathy or splenomegaly and choroidal tubercles on retinoscopy. Laboratory tests may show only anaemia. The chest radiograph is initially normal but later develops the typical miliary pattern. Involvement of multiple organ systems is the rule, usually liver, spleen, lymph nodes, central nervous system, and urinary tract. Patients with reactivation of latent infection who present with miliary disease may have a more fulminant course, although progression to severe disease without treatment is the rule in all patients. The diagnosis is made on tissue biopsy and culture, as sputum smears are usually negative, reflecting the small numbers of bacilli typically present in respiratory secretions.

Other forms of extrapulmonary tuberculosis are less common than those listed above, and the diagnosis is based on a combination of clinical suspicion and the results of biopsies and cultures. Abdominal, ocular, adrenal, and cutaneous tuberculosis are all rarely encountered in the modern era, even in immunocompromised patients.

Laboratory diagnosis

Evaluation of patients for M. tuberculosis infection or disease relies on both nonspecific and specific tests. Imaging studies, body fluid chemistries and cell counts, and histochemical staining, as described above, are useful and important tests for the diagnosis of tuberculosis. Specific studies for identifying mycobacterial infections include the tuberculin skin test, acid-fast microscopy, and mycobacterial culture.

Tuberculin skin testing

Tuberculin skin testing (TST) involves the intracutaneous injection of purified proteins of M. tuberculosis (purified protein derivative, or PPD tuberculin) that provokes a cell-mediated delayed-type hypersensitivity reaction which produces a zone of induration. Tuberculin originated with Robert Koch who prepared a tubercle sensitin that he thought would cure tuberculosis. Administration of Koch’s tuberculin, of course, did not cure the disease, and hypersensitivity reactions to the agent were sometimes severe or fatal, bringing Koch great discredit.

Fortunately, it was recognized that because tuberculin induced reactions in people who were infected with tuberculosis the substance might prove a better diagnostic test than treatment. Over a period of years refinements were made in the preparation of tuberculins, and in 1939 Seibert and Glenn produced the reference lot of tuberculin, called PPD-S, which has served as the international standard. Current tuberculin preparations are composed of a variety of small tuberculous proteins derived from culture filtrates and stabilized with a polysorbate detergent to prevent precipitation. The standard dose of tuberculin is 5 tuberculin units (TU) of PPD-S, equivalent to 0.1 mg tuberculin in a volume of 0.1 ml. Commercial and other tuberculin products are standardized against PPD-S to ensure bioequivalence.

Tuberculin testing is used to identify people with M. tuberculosis infection, and the test cannot distinguish those who have disease from those with latent infection. Injection of tuberculin into an infected individual invokes a delayed-type hypersensitivity response. Specific T lymphocytes sensitized to tuberculous antigens from prior M. tuberculosis infection cause a local reaction at the site of injection. Inflammation, vasodilation, and fibrin deposition at the site result in both erythema and induration of the skin. Induration is the key feature of a tuberculin response, and the result of tuberculin testing is categorized according to the amount of induration measured.

Tuberculin skin testing should be done by the Mantoux method, as this is the only technique that has been standardized and extensively validated. Using a tuberculin syringe and small gauge needle, 0.1 ml of PPD-S is injected intracutaneously in the volar surface of the forearm causing a small wheal. Injection into the subcutaneous space will result in uninterpretable results. Multipuncture devices should not be used. The amount of induration should be measured 2 to 5 days after the injection; measurements performed precisely 48 to 72 h later are not essential. The transverse diameter of induration should be measured in millimetres using a ruler. The edge of the induration can be seen and marked, or the margins can be detected using the ballpoint pen method, in which the pen is rolled over the skin with light pressure and its progress is stopped at the demarcation of the indurated area.

Criteria for the interpretation of tuberculin skin tests vary according to clinical and epidemiological circumstances. Cut-off points for positive tests developed by the ATS and the Centers for Disease Control and Prevention (CDC) are listed in Table 4. A cut-off point of 5 mm induration is used for individuals who are at high risk of tuberculosis infection, or at high risk of disease if infected. Such people include the close contacts of infectious patients and patients with radiographic abnormalities consistent with tuberculosis. The rationale for the 5-mm cut-off in these patients is that the prior probability of infection is high. A 5-mm cut-off is also used for HIV-infected patients and those immunocompromised by corticosteroids or other agents. Failure to diagnose tuberculosis infection in these people could be calamitous, so a lower threshold is used to maximize sensitivity. The use of control antigens such as candida or tetanus toxoid to aid the interpretation of tuberculin tests in HIV-infected patients has been shown to be of no value and is not recommended.

A cut-off point of 10 mm induration is used for people from populations with a high prevalence of tuberculosis or for individuals with conditions that increase the risk of developing active disease if infected. This would include immigrants from endemic areas, residents of some inner cities, and health care workers, as well as patients with diabetes, renal disease, silicosis, and other medical conditions associated with an elevated risk of reactivation of latent tuberculosis. Finally, a cut off of 15 mm is used in people who have no risk factors for tuberculosis infection or disease. In most instances, these patients presumably would not be tested.

Tuberculin testing does have limitations in both sensitivity and specificity. The 5-TU dose of tuberculin used diagnostically is based on studies in the 1940s that showed that 99% of chronic tuberculosis patients responded to this dose, while fewer than 20% of those without disease and no history of tuberculosis exposure had a response. Subsequent research suggested that the lack of specificity of tuberculin testing may be the result of cross-reactions due to exposure to nontuberculous mycobacteria. For example, use of tuberculin derived from M. avium intracellulare (PPD-B) induces larger reactions than PPD-S in healthy people from areas where this organism is widespread in the environment. Another important cause of nonspecific reactions to tuberculin is vaccination with bacille Calmette-Guérin (BCG). While the reactogenicity of BCG vaccines differs according to the strain, immunization with BCG can produce falsely positive skin test results. Reactions induced by BCG tend to be smaller than true-positive reactions, and wane over a period of several years. Studies in populations with high rates of BCG coverage indicate that tuberculin testing can still be used to predict those who are most likely to be infected with M. tuberculosis, even though precision is reduced because of cross-reactions.

Table 5  Criteria for tuberculin positivity, by risk group

 

Reaction ≥5 mm induration	Reaction ≥10 mm induration	Reaction ≥15 mm induration
HIV-positive persons	Recent immigrants (i.e. within the last 5 years) from high-prevalence countries or regions	Persons with no risk factors for tuberculosis
Recent contacts of infectious tuberculosis patients	Injection drug users
Persons with fibrotic changes on chest radiograph consistent with prior tuberculosis	Residents and employees of the following high-risk congregate settings: Prisons and jails Nursing homes and other long-term facilities for older people Hospitals and other health care facilities Residential facilities for patients with AIDS Homeless shelters
Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of ≥15 mg/day prednisone for 1 month or more)	Persons with the following clinical conditions that place them at high risk: Silicosis Diabetes mellitus Chronic renal failure Some haematological disorders (e.g. leukaemias and lymphomas) Other specific malignancies (e.g. carcinoma of the head or neck and lung) Weight loss of ≥10% of ideal body weight Gastrectomy Jejunoileal bypass
Others	Mycobacteriology laboratory personnel
	Children <4 years of age or infants, children, and adolescents exposed to adults at high-risk

False-negative tuberculin tests result from both errors in applying and interpreting the test and from anergy. Errors in injection of tuberculin are common, and inter-reader variability in measuring results is high. Fortunately, if there is doubt about the interpretation of a skin test, multiple readers can measure the result over a period of days, or the test can be repeated and reinterpreted. Specific anergy to tuberculin is seen in several situations. Approximately 10 to 20% of patients with culture-confirmed pulmonary tuberculosis fail to respond to tuberculin as a result of anergy. These patients often will mount a response after their disease has been treated. HIV-infected patients have a high prevalence of anergy, both to tuberculin and other antigens. Only 10 to 40% of patients with low CD4 counts and confirmed tuberculosis respond to tuberculin. Transient anergy is associated with acute viral infections such as measles, live virus vaccinations, and other acute medical illnesses.

Alternative methods: interferon-g production by sensitized T cells

Tuberculin skin testing is frustratingly crude and somewhat cumbersome, but despite its limitations has proved superior to numerous more ‘modern’ assays including antibody tests and other in vitro immunodiagnostics. Recently, however, the use of assays to detect interferon-γ production by sensitized T cells in response to challenge with specific antigens from the RD1 region of the M. tuberculosis genome has shown promise as an alternative to tuberculin testing. Two commercial assays, one an enzyme-linked immunospot (T-SPOT-TB) and one an enzyme-linked immunosorbent assay (ELISA) (Quantiferon TB Gold-In Tube) are now approved in several countries for in vitro diagnosis of tuberculosis infection. These assays are more than 90% sensitive for active tuberculosis and more specific than tuberculin testing in BCG-vaccinated individuals, correlate better than tuberculin skin testing with exposure to a point source of infection, and may not be compromised by immunosuppression related to HIV infection. In some studies, these assays have greater sensitivity than tuberculin skin testing and almost always have better specificity. In evaluating individuals with latent tuberculosis infection, however, the lack of a gold standard of diagnosis makes comparisons difficult. However, emerging evidence suggests that interferon-γ release assays may be more accurate than tuberculin testing in predicting which people are at greatest risk of developing subsequent active tuberculosis disease. Thus, the assays have enormous potential and may contribute to improved detection of both active and latent tuberculosis infections.

Microscopic staining

Microscopic staining of acid-fast bacilli is the method most widely used to diagnose tuberculosis throughout the world. Acid-fast staining is inexpensive, rapid, and technologically undemanding, making it an attractive technique for identifying mycobacterial infections. The waxy glycolipid matrix of the mycobacterial cell wall is resistant to acid–alcohol decolorization after staining with carbol-fuchsin dyes, and red bacilli are visible after counterstaining. Both the Ziehl-Neelsen method (which requires heat fixation) and the Kinyoun method utilize methylene blue or malachite green counterstains, and have similar sensitivities for identifying acid-fast bacilli in clinical specimens.

The major limitation of acid-fast staining is that a relatively large number of bacilli must be present to be seen microscopically. Acid-fast smears are generally negative when there are fewer than 10 000 bacilli/ml of sputum, and many microscope fields need to be examined to identify bacilli even when there are 10 000 to 50 000 bacilli/ml. Thus, up to 50% of patients with sputum cultures positive for M. tuberculosis have negative acid-fast smears. In settings where the sputum smear is the only test done to confirm tuberculosis, a large number of smear-negative cases go undetected. This is a serious problem for patients without cavitary tuberculosis, who tend to have fewer bacilli in their sputum, including many HIV-infected tuberculosis patients in developing countries.

Improving the yield of sputum smears

Several techniques can be used to improve the yield of sputum smears. The most important method is enrichment of the specimen through concentration of the sputum. Centrifugation of sputum allows examination of the bacilli-rich pellet, which improves the sensitivity of smears substantially. Treatment of sputum with mucolytic agents is also helpful in identifying organisms by both smear and culture. Use of fluorochrome procedures to identify mycobacteria is more sensitive, but less specific, than acid-fast stains. Auramine O or auramine-rhodamine dyes are used on concentrated smears and examined under a fluorescence microscope. This technique allows much more rapid screening of slides than the traditional methods, but confirmation of positive results with Ziehl-Neelsen or Kinyoun staining is essential, as false-positive fluorochrome results are not uncommon.

The proper collection of specimens is also important for optimizing the results of microscopy and culture. Early morning sputum specimens tend to have a higher yield than specimens collected at other times, and overnight sputum collections have provided even greater sensitivity. Morning gastric aspirates have a moderate yield for acid-fast bacilli in children, who generally have a difficult time producing sputum. Sputum induction with hypertonic saline is useful in evaluating patients with minimal or no sputum production, and the use of fibreoptic bronchoscopy is often advocated for patients with negative sputum smears. In several series, however, the yield of postbronchoscopy spontaneous sputum samples was higher than for the bronchoalveolar lavage fluid. While the goal of sputum collection is to collect a pure lower respiratory tract sample, specimens that appear to consist primarily of upper respiratory tract or oral secretions are often smear or culture positive in patients with pulmonary tuberculosis.

Examination of multiple specimens increases the sensitivity of sputum microscopy for acid-fast bacilli. The first smear identifies 70 to 80% of patients, the second another 10 to 15%, and the third another 5 to 10%. Review of additional specimens has little value.

In addition to the modest sensitivity of acid-fast staining, the specificity of this technique can also present problems. The morphological properties of the mycobacteria are sufficiently similar to make distinguishing M. tuberculosis from nontuberculous mycobacteria impossible on the basis of acid-fast smears. This is not a serious problem where tuberculosis is common and nontuberculous mycobacterial infections are unusual. However, in many industrialized countries, disease due to the nontuberculous mycobacteria is relatively common, and distinguishing these types of infections has important therapeutic and public health implications. Thus, while sputum microscopy is useful because of its rapidity and low cost, it should be supplemented with culture or other more sensitive and specific tests whenever feasible.

Culture, nucleic acid amplification, and susceptibility testing

Culture of M. tuberculosis

This is the gold standard for confirming the diagnosis of tuberculosis. A variety of media are available that support the growth of mycobacteria, including egg-based and potato-based solid media and several broth-based media. The intrinsic growth rate of M. tuberculosis makes the recovery of the organism in culture a slow process. In traditional egg-based media such as Lowenstein–Jensen, growth of colonies of M. tuberculosis takes between 3 and 6 weeks, and 7H11 agar requires an average of 3 to 4 weeks to show colonies. Obviously, the slow pace of these traditional culture systems interferes with optimal patient management, and more rapid techniques are required.

Several faster (not rapid) systems for detection of mycobacteria in culture have been commercially developed. The radiometric BACTEC system utilizes ¹⁴C palmitate in 7H12 broth to more quickly detect mycobacterial growth. The reliance of this technology on radioisotopes, however, makes it an unattractive approach, and other methods are emerging to take its place.

The Mycobacterial Growth Indicator Tube (MGIT) is a broth-based system that uses fluorescence detection to monitor growth. Both manual and automated systems are available. Once growth is detected, staining to identify acid-fast organisms and species identification need to be performed. The time to detection of mycobacteria using MGIT is considerably faster than conventional solid media, and the yield can be appreciably higher. Contamination of cultures with bacteria and fungi is common, and laboratory cross-contamination remains a concern. Nevertheless, the use of MGIT can increase case detection rates and speed the time to detection of tuberculosis.

Many clinical laboratories use more than one culture system for mycobacteria, both to increase the overall recovery rate and to provide quality control. In addition, if one culture becomes contaminated, alternative cultures can still be utilized.

Preparation of specimens for mycobacterial culture

This follows the same steps as outlined for acid-fast smears. In addition, specimens being submitted for culture also require decontamination to prevent overgrowth by more rapidly multiplying bacteria. Sodium hydroxide (NaOH) and N-acetyl-L-cysteine (NALC) are commonly used together for mucolysis and decontamination. By necessity, decontamination also inactivates >50% of mycobacteria in a specimen, thereby reducing the potential yield of the culture. Failure to decontaminate, however, leads to bacterial overgrowth and uninterpretable results. Lack of growth as a result of overdecontamination and bacterial overgrowth resulting from underdecontamination underscore the importance and utility of obtaining multiple specimens for culture, when possible. As with sputum smears, the yield of mycobacterial culture increases with evaluation of additional specimens.

Speciation

After mycobacterial growth has been identified, speciation of the organism is required. Conventional techniques for identification of mycobacterial species involve characterization of colony morphology, pigmentation, rate of growth, and biochemical tests. Niacin reduction, nitrate reduction, and lack of catalase activity at elevated temperatures are all characteristic of M. tuberculosis. Species identification using these methods is time consuming and tedious, and further delays the diagnosis of tuberculosis.

The use of nucleic acid probes has dramatically simplified speciation of mycobacteria in recent years. DNA probes that react with specific mycobacterial rRNA sequences to form DNA–RNA hybrids that can be readily detected by chemoluminescence are commercially available for M. tuberculosis, M. avium complex, M. kansasii, and M. gordonae. These probes can be performed within hours of detection of mycobacterial growth, and significantly accelerate the diagnosis of specific pathogens. The sensitivity of these probes is approximately 90 to 95%, depending on the species, with specificities approaching 100%. Cultures that fail to respond to any of the DNA–RNA probes are almost always due to another mycobacterial species, but final identification depends on the laborious biochemical techniques of old.

The difficulties of identifying mycobacteria in patient specimens accentuate the need for rapid and sensitive diagnostic methods for tuberculosis. If any infection seems suited to diagnosis by nucleic acid amplification assays, it would appear to be tuberculosis. Multiple studies of ‘in-house’ PCR assays for M. tuberculosis have shown modest sensitivity and specificity. PCR inhibitors in sputum have been a knotty problem in the molecular diagnosis of pulmonary tuberculosis, although sensitivity has been lower than culture in nonrespiratory specimens as well. Recently, several commercial nucleic acid amplification tests have been introduced or are nearing approval, including assays based on reverse transcription (RT)-PCR, transcription-mediated amplification, ligase chain reaction, and strand displacement amplification. All of these techniques use specific M. tuberculosis DNA sequences (most use the M. tuberculosis transposon IS6110) as targets for nucleic acid amplification. The great advantage of these assays is that they can provide results within 1 day of the collection of specimens. Their disadvantage is that they are uniformly less sensitive than culture, particularly in sputum smear-negative patients. Early studies also suggested that specificity was excellent overall but was reduced in smear-positive samples; further refinements in these assays have resulted in improved sensitivity and specificity, but their diagnostic role in smear-negative sputum or extrapulmonary disease is limited by their moderate sensitivity. Furthermore, the cost of nucleic acid amplification tests may be too high for routine use in resource-limited settings where tuberculosis is endemic.

Evaluations of nucleic acid amplification assays under field conditions have generally shown favourable results. When using these tests, however, clinicians must not forget fundamental clinical and epidemiological principles regarding the diagnosis of tuberculosis: a negative test in a patient suspected of having tuberculosis should not exclude the diagnosis, nor should a positive test confirm it if clinical circumstances do not support the diagnosis. While both the positive and negative predictive values of nucleic acid amplification tests are high (70–90% and >90%, respectively), misclassification of patients does occur, and it is important to use mycobacterial culture to validate the results of these rapid assays.

Drug susceptibility testing

Susceptibility testing of M. tuberculosis isolates is essential for both clinical management and public health purposes. Susceptibility tests for the first-line antituberculosis drugs should be performed on at least one culture at the time of diagnosis for all patients. If the initial isolate is susceptible to the first-line agents and treatment proceeds without incident, additional susceptibility tests are not required. Susceptibility testing should be performed for patients who relapse with tuberculosis and for patients who are treatment failures after 3 to 4 months of therapy.

Susceptibility testing for M. tuberculosis uses standard concentrations of antituberculosis drugs to measure inhibition of bacterial growth in culture. Drugs tested routinely include isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin. Testing of second-line antituberculosis drugs is only done when resistance to the first-line agents is documented or strongly suspected.

Susceptibility testing is generally performed on subcultures of the primary isolate, though direct inoculation of sputum or other specimens can be performed in the case of a strongly positive acid-fast bacilli smear. The standard method for measuring susceptibility to antituberculosis drugs is the proportions method. The organism is grown on agar plates in the presence of known concentrations of specific drugs. Growth on the plates is then compared with growth on control plates. By convention, if the test plate shows a colony count that is >1% of the control value, the isolate is resistant. Laboratories will report the isolate as being susceptible or resistant to the concentration of the drug used in the assay.

Another method for susceptibility testing is to use the MGIT system, in which culture bottles contain antituberculosis drugs. Growth indices are compared to control cultures to determine susceptibility. The MGIT system provides results more quickly than the proportions method, is automated, but is more expensive. Recently, the microscopic examination of growth in wells that are filled with liquid culture medium (MODS) has been reported to enable detection within about 10 days and permit rapid assessment of drug resistance. This technique has some promise in resource-limited settings, but it is labour intensive and needs further validation in endemic countries.

The use of molecular methods to determine drug susceptibility is promising but not currently in routine use. Specific mutations in M. tuberculosis have been identified which confer resistance to antituberculosis drugs. For example, mutations in a small region of the rpoB gene of M. tuberculosis are responsible for more than 90% of all rifampicin resistance. Sequencing of this portion of the genome using a variety of techniques has been shown to be feasible in research laboratories. Rapid identification of rifampicin resistance by molecular methods (line probe assay) would be of enormous clinical benefit, as almost all rifampicin-resistant M. tuberculosis isolates are also resistant to isoniazid and are, by definition, multidrug resistant. Thus early detection of resistance mutations would allow early initiation of appropriate treatment and infection control measures. Molecular diagnosis of other types of resistance is more difficult, as the genetic basis of resistance to other drugs is either heterogeneous or not completely understood.

Treatment of active tuberculosis

The treatment of tuberculosis requires the use of a combination of antimycobacterial drugs active against the strain of M. tuberculosis causing the patient’s disease. The use of multiple agents is necessitated by the emergence of drug resistance when single agents are used. Mutations that confer resistance to antimycobacterial drugs arise spontaneously in wild-type populations of M. tuberculosis in frequencies ranging from 1 in 10⁵ to 1 in 10⁸ bacilli. In the presence of large numbers of organisms, such as are present during active pulmonary disease, a single agent will kill susceptible bacilli, but naturally drug-resistant mutants will survive and eventually emerge to cause drug-resistant disease. Since the mechanisms of resistance are genetically distinct and arise independently, multiple drug resistance within a single organism is exceedingly rare in nature. The use of two or more agents with different mechanisms of action assures that populations of drug-resistant bacilli are not selected for during therapy.

Antituberculosis drugs

These are divided into first-line and second-line agents. The first-line agents are widely available and used routinely in the treatment of tuberculosis, while the second-line agents are generally less potent, more toxic, and less readily available. Exceptions are the newer fluoroquinolones, such as moxifloxacin and gatifloxacin, which appear to have good activity against M. tuberculosis in a mouse model. The ability of moxifloxacin to reduce the time to sputum conversion might shorten the duration of tuberculosis treatment, but this remains to be confirmed in ongoing clinical trials. Second-line drugs are reserved for the treatment of drug-resistant tuberculosis. Table 6 lists the first-line antituberculosis drugs, their activity in the treatment of tuberculosis, and common toxicities.

Regimens currently used for the treatment of tuberculosis have been developed on the basis of trials conducted by the British Medical Research Council since the late 1970s. By combining drugs that target both rapidly growing bacillary populations and slow-growing or semidormant organisms within cells, modern short-course chemotherapy can successfully cure drug-susceptible pulmonary tuberculosis in 6 months. The regimens recommended for treatment of drug-susceptible tuberculosis are shown in Table 7. Treatment of extrapulmonary tuberculosis is generally for the same duration as for pulmonary disease, with the exceptions of bone and joint and central nervous system tuberculosis, which are treated for 12 months.

The dynamics of mycobacterial growth are such that treatment need be administered only once daily, and can be given as infrequently as twice a week. The long generation time of M. tuberculosis and a postantibiotic effect of antituberculosis drugs make more frequent drug dosing unnecessary. The dosages for drugs are listed in Table 8 according to the frequency with which they are administered.

Isoniazid remains a key component of treatment because of its high bactericidal activity. Rifampicin is essential for short-course therapy because it is active against all populations of bacilli, both within and outside of cells. Pyrazinamide is uniquely active during the first 2 months of therapy, but appears to have no activity thereafter. The addition of pyrazinamide to the treatment regimen allows the duration to be reduced from 9 to 6 months, however. Streptomycin has bactericidal activity against M. tuberculosis, and ethambutol has bacteriostatic activity at lower doses and bactericidal activity at high doses. These agents primarily are given to prevent the emergence of drug resistance, as they appear to add little activity to combination regimens against drug-susceptible tuberculosis.

Table 6  Drugs for the treatment of tuberculosis

 

Agent	Activity	Toxicity
Isoniazid	Bactericidal	Liver, peripheral nerve, hypersensitivity
Rifampicin	Bactericidal	Liver, gastrointestinal, discoloration of body fluids, nausea, haematological
Pyrazinamide	Sterilizing	Liver, hyperuricaemia, gout, malaise, gastrointestinal
Ethambutol	Bacteriostatic (dose-dependent)	Liver, optic neuritis, skin
Streptomycin	Bactericidal	Ototoxicity, kidneys

Table 7  Treatment regimens for tuberculosis in children and adults

 

	Frequency	Drugs
Option 1	Intensive phase, daily	Isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycinb for 8 weeks
	Continuation phase, daily or 2–3 times weeklya	Isoniazid and rifampicin for 16 weeks
Option 2	Intensive phase, daily	Isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycinb for 2 weeks
	Intensive phase, twice weekly	Same drugs for 6 weeksb
	Continuation phase, twice weeklya	Isoniazid and rifampicin for 16 weeks
Option 3	Entire course of therapy, 3 times weeklya	Isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin for 24 weeks

a Intermittent dosing should be directly observed. b In areas where drug resistance is 4%, omit fourth drug.

Drug toxicities

Although antituberculosis therapy is remarkably well tolerated and almost always given on an ambulatory basis, important drug toxicities do exist. The most serious adverse drug reaction during tuberculosis treatment is liver toxicity, which may occur in up to 5 to 10% of treated patients. Isoniazid, rifampicin, and pyrazinamide are all associated with liver toxicity and use of these agents together increases the risk of a reaction. Isoniazid causes more hepatotoxicity than rifampicin or pyrazinamide, however, and is the agent most frequently implicated when reactions occur. Isoniazid can produce an idiosyncratic hepatocellular injury, manifested by elevated liver enzymes and clinical hepatitis. Elevation of transaminases does not always portend the development of hepatitis, but may serve as an important signal to anticipate clinical toxicity. The development of signs and symptoms of hepatitis, such as abdominal pain, nausea, vomiting, or jaundice, requires immediate discontinuation of isoniazid, as continuing treatment may result in death from hepatic failure. Risk factors for developing isoniazid hepatotoxicity include increasing age, chronic liver disease, alcohol abuse, daily dosing of isoniazid, and use of other hepatotoxic drugs, including rifampicin. In addition, individuals with a slow isoniazid acetylation genotype are significantly more likely to develop hepatotoxicity from the drug than intermediate or rapid acetylators. Isoniazid interferes with metabolism of pyridoxine (vitamin B₆) which can result in a sensory neuropathy. Coadministration of pyridoxine with isoniazid abrogates this effect without compromising the antimicrobial activity.

Rifampicin also causes hepatotoxicity, although the characteristic picture of liver disturbances due to rifampicin is cholestasis. However, the incidence of hepatotoxicity when rifampicin is given with isoniazid is substantially greater than when isoniazid is given alone. Rifampicin predictably causes a discoloration of body fluids, resulting in orange-tinted tears, sweat, and urine. Haematological toxicity from rifampicin includes thrombocytopenia and anaemia. Higher doses of rifampicin may produce a hypersensitivity reaction, with fever, rash, and joint swelling. It is for this reason that doses of rifampicin are not escalated during intermittent therapy, whereas the intermittent dosages of the other drugs are increased to deliver weekly doses that are equivalent to daily dosing.

Table 8  Dosage recommendation for the initial treatment of tuberculosis in children and adults

 

Drugs	Daily dose		Twice-weekly dose		Thrice-weekly dose
	Children	Adults	Children	Adults	Children	Adults
Isoniazid (mg/kg)	10–20 (max. 300 mg)	5 (max. 300 mg)	20–40 (max. 900 mg)	15 (max. 900 mg)	20–40 (max. 900 mg)	15 (max. 900 mg
Rifampicin (mg/kg)	10–20 (max. 600 mg)	10 (max. 600 mg)	10–20 (max. 600 mg)	10 (max. 600 mg)	10–20 (max. 600 mg)	10 (max. 600 mg)
Pyrazinamide (mg/kg)	15–30 (max. 2 g)	15–30 (max. 2 g)	50–70 (max. 4 g)	50–70 (max. 3.5 g)	50–60 (max. 3.5 g)	50–60 (max. 3.5 g)
Ethambutol (mg/kg)	15–25 (max. 1.5 g)	15–25 (max. 1.5 g)	50 (max. 4 g)	50 (max. 4 g)	25–30	25–30
Streptomycin (mg/kg)	20–40 (max. 1.0 g)	15 (max. 1.0 g)	25–30 (max. 1.5 g)	25–30 (max. 1.5 g)	25–?30 (max. 1.5 g)	25–30 (max. 1.5 g)

Pyrazinamide is often associated with arthralgias, and may precipitate gout. Pyrazinamide inhibits renal tubular uric acid excretion, resulting in increased serum uric acid levels. Frank gouty arthritis is relatively uncommon with pyrazinamide use, and its frequency is reduced with intermittent dosing. Routine use of allopurinol to prevent gout is not recommended.

The major toxicity of ethambutol is optic neuritis, which is common at doses above 30 mg/kg daily and unusual at doses below 25 mg/kg daily. Patients receiving ethambutol should have baseline tests of visual acuity and colour discrimination, with monthly monitoring while on treatment. Ethambutol use is discouraged in children under 8 years old because of their inability reliably to report visual disturbances. However, the incidence of optic neuritis with the doses of ethambutol typically used is so low that its use in young children is only relatively contraindicated.

Streptomycin was a staple of antituberculosis therapy for many years, but its use has been greatly curbed in recent years. Several studies have demonstrated that regimens containing isoniazid, rifampicin, and pyrazinamide are equally efficacious with or without streptomycin. Streptomycin is given by intramuscular injection, causing discomfort to patients and creating an infection risk for patients and health care workers. In addition, streptomycin can be ototoxic and nephrotoxic. Consequently, ethambutol has replaced streptomycin in many settings around the world.

Monitoring of therapy

Patients receiving therapy for tuberculosis require regular monitoring to assess adherence with therapy, clinical response, and adverse reactions. In the initial phase of therapy, monitoring by a nurse or other trained clinician at least weekly is recommended, and supervision of every dose of medication is suggested by the WHO and other authorities (see below). Patients should be observed for clinical responses, including defervescence, improvement in cough and appetite, and weight gain. Improvement in these symptoms and signs may take several weeks, but usually occurs within 3 weeks after starting treatment. Failure to improve suggests that the patient is not adhering to treatment, has drug-resistant tuberculosis, or has another illness in addition to or instead of tuberculosis.

Treatment response should also be documented with repeated sputum smears and cultures and a follow-up chest radiograph after 2 to 3 months (for pulmonary tuberculosis). All patients should have a repeat sputum smear and culture after 2 months of therapy; those who are smear or culture positive at 2 months should have another at 3 months. Failure to convert sputum smears and cultures to negative with 3 months of therapy is associated with a high risk of treatment failure; patients who are still smear or culture positive at 4 months of treatment are considered treatment failures and should be evaluated for drug-resistant disease. A culture at the end of therapy is recommended to document cure, while an end of therapy radiograph is not necessary.

Monitoring for drug toxicity is also required throughout therapy. At least monthly monitoring for symptoms and signs of liver toxicity is essential, and patients should be advised to stop therapy and seek care if evidence of hepatitis is noted. Routine liver enzyme monitoring is recommended primarily for patients with underlying liver disease or baseline abnormalities in liver enzymes. Patients with symptoms of hepatitis, of course, should have liver studies obtained. As noted above, monthly visual assessment is also recommended when ethambutol is given.

Adherence to therapy and directly observed therapy

Since the 1960s experts in tuberculosis have noted that the success of treatment depends largely on adherence to therapy. Poor adherence to therapy is responsible for treatment failures, early relapses, and the emergence of drug-resistant disease. Two major interventions to improve adherence and prevent poor outcomes are directly observed therapy (DOT) and the use of fixed-dose combination tablets. DOT was first promoted in the 1950s in India, and experience with DOT grew over the ensuing years. Intermittent dosing of tuberculosis therapy, along with the relatively short course of treatment, make supervision of treatment feasible in many settings. Ecological and programmatic studies of DOT programmes have shown that the introduction of DOT improves cure rates for tuberculosis, reduces nonadherence, and reduces the emergence of drug-resistant disease. Two observational studies have shown better survival of HIV-infected tuberculosis patients who receive DOT.

On the other hand, two randomized trials of DOT in developing countries have not found improved treatment completion rates compared with self-administered treatment. These trials have been criticized for demonstrating only that DOT can be done badly, but the lack of randomized studies documenting that DOT per se leads to improved outcomes is of some concern. The data from observational studies are compelling, however, and DOT has been shown to be cost-effective in resource-limited settings and, therefore, is strongly encouraged by many experts and professional organizations.

The use of fixed-dose combination tablets is intended to reduce the risk of selecting for drug resistance, as opposed to improving adherence generally. By combining two, three, or four medications in the same tablet, depending on the regimen being used, the opportunity for patients to receive partial treatment that would select for drug resistance is avoided. The bioequivalence of fixed-dose combinations to individual medications has been established for some, but not all, of the combination products on the market.

The catastrophic state of global tuberculosis control led the WHO to develop the directly observed therapy, short-course (DOTS) strategy. This strategy is a series of policies related to national tuberculosis control practices. The five elements of the DOTS strategy are:

1. 1 Governmental commitment to tuberculosis control
2. 2 A reliable supply of tuberculosis drugs
3. 3 Diagnosis of tuberculosis cases microscopically
4. 4 A registration system for tracking the outcomes of treatment
5. 5 Supervision (DOT) of at least the first 8 weeks of treatment

The DOTS strategy has been extremely successful in focusing attention on serious problems in tuberculosis treatment and control, and implementation of the programme in several countries has produced remarkable improvements in clinical outcomes for patients with tuberculosis. There is strong evidence that the use of the DOTS strategy results in lower rates of drug-resistant tuberculosis. Nonetheless, the WHO estimates that in 1999 only 21% of tuberculosis patients in the world were treated within a DOTS programme. Further expansion of the DOTS strategy and improvements in tuberculosis treatment programmes are clearly needed.

Treatment of multidrug-resistant tuberculosis

This is beyond the scope of this chapter. Patients with drug-resistant tuberculosis should be managed by a physician who is a tuberculosis expert. Effective treatment and cure of multidrug-resistant tuberculosis (MDR-TB) requires prolonged use (about 2 years) of a combination of drugs that include second-line drugs which are less effective than first-line agents, have a greater toxicity, or demonstrate both disadvantages. Supervised therapy is considered mandatory for patients with resistant tuberculosis. Physician mistakes remain one of the leading causes of the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (XDR-TB), and the identification of a drug-resistant isolate of M. tuberculosis should result in immediate expert consultation. It is also clear that addressing drug-resistant tuberculosis cannot be accomplished without addressing the overall tuberculosis control effort.

Treatment of tuberculosis in HIV-infected people

The United States (ATS/CDC/Infectious Disease Society of America) recommendations for the treatment of tuberculosis in HIV-infected adults are, with a few exceptions, the same as those for HIV-uninfected adults, i.e. standard 6-month rifampicin-based therapy. The continuation phase is extended from 6 to 9 months for any patient with cavitary tuberculosis and positive cultures at 2 months, regardless of the HIV status. The optional continuation phase regimen of isoniazid plus rifapentine once weekly is contraindicated in HIV-infected patients because of an unacceptably high rate of relapse, frequently with organisms that have acquired resistance to rifamycins. The development of acquired rifampicin resistance has also been noted among HIV-infected patients with advanced immune suppression treated with twice weekly rifampicin-based or rifabutin-based regimens. Consequently, patients with CD4 cell counts <100 cells/µl should receive daily or three-times weekly treatment. DOT and other adherence-promoting strategies are especially important for patients with HIV-related tuberculosis. Recent studies show improved survival when antiretroviral therapy is given during tuberculosis treatment rather than afterwards. Timing of combined therapy is challenging, however, due to drug interactions and immune reconstitution inflammatory syndrome (see below).

Drug interactions

There are three possible complications that arise when tuberculosis treatment and antiretroviral drugs are coadministered: shared side effects and toxicity, drug interactions arising from the induction of metabolism (cytochrome P450 enzymes) and efflux pumps by rifampicin, and the immune reconstitution inflammatory syndrome. Rifamycins induce the activity of cytochrome P450 enzymes that are important in drug metabolism. Two key antiretroviral drug classes, protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are substrates of cytochrome P450 enzymes. Protease inhibitors are also substrates of P-glycoprotein, which is also induced by rifamycins. The available rifamycins differ in potency as P450 enzyme inducers, with rifampicin being the most potent and rifabutin the least. Coadministration with rifampicin reduces the concentrations of non-nucleoside reverse transcriptase inhibitors to a moderate extent, but dramatically reduces the concentrations of protease inhibitors. Rifabutin does not significantly affect the concentrations of ritonavir-boosted protease inhibitors and is recommended when protease inhibitors have to be used. However, the use of rifabutin in low resource settings is currently limited due to its very high cost and the widespread use of fixed-dose combination antituberculosis drugs that include rifampicin.

Between 8 and 45% of patients commencing antiretroviral therapy while being treated for tuberculosis develop paradoxical deterioration of tuberculosis, the so-called immune reconstitution inflammatory syndrome (IRIS). Paradoxical deterioration was well known in the pre-HIV era, but occurs much more frequently in HIV-infected patients starting antiretroviral therapy. The pathogenesis of IRIS is not completely understood. The most common manifestations of tuberculosis-related IRIS are focal inflammatory exacerbations of tuberculosis (lymphadenitis, serositis, or abscesses, new infiltrates), ‘unmasking’ of tuberculosis or other subclinical diseases after antiretroviral therapy initiation, etc. It typically occurs within 2 to 4 weeks after antiretroviral initiation. Risk factors associated with an increased risk of IRIS include shorter intervals between antituberculosis therapy and antiretroviral therapy initiation, low baseline CD4 counts and high baseline viral load, and vigorous CD4/viral load response to antiretroviral therapy. However, new or worsening clinical features should be attributed to IRIS only after a thorough evaluation has excluded other possible causes, notably poor adherence to antituberculosis therapy, multidrug-resistant tuberculosis, new opportunistic diseases, and systemic drug hypersensitivity reactions. The benefit of adjunctive corticosteroids in the management of patients with IRIS is suggested by results of at least one randomized controlled trial.

Duration of therapy

Despite these complications, antiretroviral therapy should not be withheld simply because the patient is being treated for tuberculosis. The optimal timing of initiation of antiretroviral therapy in relation to initiation of antituberculosis treatment is unclear. Treatment for tuberculosis should always be initiated first, and it is prudent to wait at least until it is clear that the patient is improving and tolerating the antituberculosis therapy before beginning antiretroviral therapy. While awaiting the results of ongoing controlled trials, a 2006 WHO expert opinion panel has suggested that the CD4 lymphocyte count should determine the initiation of antiretroviral therapy, unless there is other serious HIV morbidity. These WHO guidelines state that patients with CD4 counts <200 cells/µl should initiate antiretroviral therapy after 2 to 8 weeks of antituberculosis therapy and those with CD4 counts 200 to 350 cells/µl after 8 weeks. Data from recent clinical trials support initiating antiretroviral therapy for all patients with a CD4 count <500 cells/µl within two months of starting tuberculosis therapy, as this reduces mortality by >50%. Until there have been controlled studies evaluating the optimal time for starting antiretroviral therapy in patients with HIV infection and tuberculosis, this decision should be individualized. Possible factors for consideration are a patient’s initial response to treatment for tuberculosis, CD4 response to tuberculosis therapy, possible drug interactions, risk of IRIS, adherence, occurrence of side effects, and availability of antiretroviral therapy. For patients who are already receiving an antiretroviral regimen when tuberculosis is detected, antiretroviral treatment should be continued during antituberculosis therapy.

Adjunctive steroid treatment

Corticosteroids are frequently advocated with tuberculosis treatment to reduce inflammation in tuberculosis, but evidence for this practice is often lacking, particularly in HIV infection. Mortality was reduced in a small trial of patients given prednisolone for tuberculous pericarditis. Also, dexamethasone reduced mortality in a large Vietnamese study of adults with tuberculous meningitis. The HIV-infected subgroup of the latter study appeared to gain a similar benefit, but this failed to achieve statistical significance. A Ugandan study of adjunctive prednisolone in HIV-infected patients with pleural tuberculosis found faster resolution with prednisolone, but no mortality benefit. Of great concern, however, was their finding of excess cases of Kaposi’s sarcoma in the prednisolone arm. This sobering result is a reminder that the additive immunosuppressant effect of glucocorticoids can have severe consequences in HIV infection. Adjunctive glucocorticoids should only be used in HIV-infected patients when there is likely to be a mortality benefit, which may be the case for tuberculous meningitis and pericarditis, but there is still a need for definitive evidence from larger studies in both conditions.

Treatment of latent tuberculosis infection

Isoniazid chemoprophylaxis

Prevention of tuberculosis with isoniazid therapy was first documented in children in the mid-1950s. Subsequently, several controlled trials of isoniazid chemoprophylaxis were undertaken, and its efficacy firmly established. A meta-analysis of 11 placebo-controlled trials of isoniazid, involving more than 70 000 persons, found that treatment reduced tuberculosis incidence by 63%. Among patients who adhered to >80% of the isoniazid regimen, protection was 81%. These studies also showed that isoniazid chemoprophylaxis reduced tuberculosis deaths by 72%. The efficacy of isoniazid therapy to prevent tuberculosis in high-risk persons is incontrovertible.

Enthusiasm for isoniazid chemoprophylaxis was considerably dampened in the late 1960s and early 1970s when drug-related hepatotoxicity, including deaths, was observed. Several studies based on decision analysis or modelling suggested that the risks of chemoprophylaxis might outweigh the benefits, and use of preventive therapy was curtailed or ignored in many settings. Because the risk of isoniazid-related hepatotoxicity increases with age, use of chemoprophylaxis in people older than 35 years was particularly discouraged.

Preventive therapy in high-risk individuals

The resurgence of tuberculosis in the developed world, particularly HIV-related tuberculosis, and the uncontrolled global epidemic have renewed interest in the use of preventive therapy in high-risk individuals known or strongly suspected to be latently infected with M. tuberculosis. The term ‘treatment of latent tuberculosis infection’ is now preferred, emphasizing that preventive treatment is really targeted at an established infection. The ATS and the CDC published guidelines in 2000 on screening for latent tuberculosis that stress the importance of targeting efforts on populations and patients who would benefit from treatment to prevent active disease. In the past, screening for tuberculosis infection has been unfocused and often directed at patients who, if found to be infected, would have little risk of progressing to active disease. The new guidelines propose that only people with a high risk of disease or high prior probability of latent tuberculosis be tested, and that treatment be offered to infected individuals regardless of age. Individuals who should be targeted for tuberculin testing are those listed in the first two columns of Table 5, i.e. those in whom a positive test is considered equal to or exceeding 5 or equal to or exceeding 10 mm induration. People without risk factors for tuberculosis (those in whom a positive test is equal to or exceeding 15 mm) should not be tested.

Treatment regimens for latent tuberculosis are listed in Table 9, along with the rating given to the regimen by the ATS and CDC. Isoniazid remains a favoured drug for tuberculosis preventive therapy because of its well-documented efficacy, low cost, and relatively low toxicity. The optimal duration of isoniazid therapy for latent tuberculosis has been the subject of extensive debate in recent years. The International Union Against Tuberculosis and Lung Disease conducted a landmark trial in Eastern Europe in the 1970s and 1980s that compared no treatment to 3, 6, or 12 months of isoniazid in adults with fibrotic changes on radiographs. The results showed that, compared to placebo, 12 months of isoniazid reduced the incidence of tuberculosis by 75%, compared to 66% for 6 months and 20% for 3 months. In addition, patients who completed the 12 months of therapy and were judged to be compliant experienced a 92% reduction in tuberculosis risk, compared to a 69% decrease for compliant patients completing a 6-month regimen. A meta-analysis by the Cochrane Collaborative found that 12 months of isoniazid was more effective than 6 months for prevention of tuberculosis. A recent analysis of varying durations of isoniazid therapy in Alaskan natives revealed that the effectiveness of isoniazid therapy was optimal after 9 months, and that further treatment conferred no additional benefit. The new ATS/CDC statement, therefore, recommends 9 months of isoniazid as the preferred regimen, with 6 months considered an alternative, but less effective, course of treatment.

Table 9  Treatment regimens for latent tuberculosis

 

Drug regimen	Duration (months)	Interval	Rating (HIV−)	Rating (HIV+)
Isoniazid	9	Daily	A II	A II
Isoniazid	9	Twice weekly	B II	B II
Isoniazid	6	Daily	B I	C I
Isoniazid	6	Twice weekly	B II	C II
Rifampicin	4	Daily	B II	B III

A, strongly recommended; B, recommended; C, optional; I, randomized trials; II, data from other scientific studies; III, expert opinion.

Isoniazid hepatotoxicity

Although isoniazid is a well-tolerated drug, serious hepatotoxicity can occur in a small proportion of patients. Isoniazid may result in asymptomatic elevations in hepatic aminotransferase levels, but this does not always signal impending clinical toxicity. Hepatotoxicity is of concern when symptoms of hepatitis develop, including pain, nausea, vomiting, and jaundice. Continuing isoniazid in the presence of symptoms may lead to death from fulminant hepatic necrosis and liver failure, with a case fatality rate of 10 to 15%. Studies in the 1960s and 1970s found evidence of hepatotoxicity in 1 to 5% of recipients of isoniazid, with higher rates among older patients. More recent experience with isoniazid therapy that is closely monitored shows a risk of hepatotoxicity in the range of 0.1 to 0.3%. Thus, appropriate patient screening and follow-up makes the use of isoniazid for treating latent infection markedly safer.

Alternative regimens

One of the most important new developments in the treatment of latent tuberculosis is the development of alternative regimens that shorten the duration of treatment. A 3-month regimen of rifampicin alone was found to reduce the incidence of tuberculosis by about 65% in men with silicosis, and was more effective than 6 months of isoniazid. The combination of rifampicin and isoniazid given for three to four months is widely used for treatment of latent tuberculosis in children and improves completion rates. This regimen has also been found to be equally effective as isoniazid in studies in adults.

The use of rifampicin does pose the risk of important drug interactions. For example, reduction in methadone concentrations caused by rifampicin can precipitate narcotic withdrawal. Moreover, rifampicin can lower levels of protease inhibitors and non-nucleoside reverse transcriptase inhibitors used to treat HIV infection. Substitution of rifabutin for rifampicin in patients receiving HIV drugs provides equally efficacious treatment of active tuberculosis and less effect on antiretroviral drugs. If multidrug-resistant tuberculosis is suspected, the recommended preventive therapy is pyrazinamide and ethambutol or pyrazinamide and a fluoroquinolone (e.g. moxifloxacin) for 6 to 12 months. Treatment for suspected exposure to multidrug-resistant tuberculosis should be routinely extended to 12 months in HIV-infected individuals.

Candidates for treatment of latent tuberculosis are listed in Table 5. Criteria for treatment include a positive tuberculin test according to the categories in Table 5, elevated risk for developing active tuberculosis if untreated, and exclusion of active tuberculosis by clinical evaluation and chest radiograph. In addition, HIV-infected and other severely immunocompromised persons who are contacts to an infectious tuberculosis patient should be treated for latent tuberculosis regardless of tuberculin skin test results.

Monitoring treatment

Patients receiving treatment for latent tuberculosis should be monitored for drug toxicity, as well as to promote adherence to therapy. As in treatment of active tuberculosis, patients receiving isoniazid should be warned about signs and symptoms of hepatotoxicity and advised to discontinue therapy and seek care if any of these occur. Patients with or at risk of chronic liver disease should have baseline liver enzymes obtained, with monthly monitoring if the results are abnormal. All patients should be clinically evaluated at least monthly to assess. Treatment using other preventive regimens (i.e. isoniazid) and treatment of patients with mild transaminase elevations (3 times upper limits of normal or less) can proceed with regular clinical and laboratory monitoring. Higher elevations of transaminases, or the development of symptoms or signs of hepatitis should be managed with discontinuation of therapy at least temporarily. Patients who complete therapy for latent tuberculosis do not need periodic monitoring for tuberculosis subsequently.

Prevention of tuberculosis

Strategies to control tuberculosis are aimed at the prevention of the spread of M. tuberculosis infection and the development of clinical tuberculosis. The principal approaches employed toward this end are:

• ◆ identification and treatment of infectious tuberculosis cases
• ◆ treatment of latent tuberculosis infection
• ◆ prevention of exposure to infectious particles in air, especially in hospitals and other institutions
• ◆ vaccination

Identification and treatment of infectious tuberculosis cases

Case identification and treatment reduces transmission by rendering patients with communicable tuberculosis noninfectious. Patients with pulmonary tuberculosis produce infectious aerosols that may transmit tubercle bacilli to contacts breathing the same air. When cases are identified and treated, infectiousness is rapidly eliminated. The duration of treatment required to prevent further transmission of infection is not known precisely, but experimental, clinical, and microbiological data suggest that the level of infectiousness is reduced enormously within several days of beginning effective treatment. The number of secondary infections generated by an infectious tuberculosis patient varies greatly depending on the duration of illness, the extent of pulmonary pathology, the amount of patient coughing, and the environment into which the patient expels infectious aerosols. Early diagnosis and treatment reduces the number of secondary infections, while delays can result in ongoing transmission to large numbers of contacts. Failure to retain patients in treatment until they are cured also contributes to spread of infection.

Treatment of latent tuberculosis infection

This is discussed above. The benefit of treating latent infection is not only to the individual patient who does not fall ill with tuberculosis, but also accrues to the potential contacts of that patient, who might become secondarily infected were disease to develop. Targeting of high-risk groups for screening and treatment of latent tuberculosis thereby reduces tuberculosis incidence within communities. Groups that should be targeted for screening are listed in the first two columns of Table 5.

Prevention of exposure especially in hospitals and other institutions

Control of exposure to infectious aerosols can have a major impact on the spread of tuberculosis. In the late 1980s and early 1990s, transmission of tuberculosis, including multidrug-resistant tuberculosis, was widespread in hospitals, homeless shelters, and correctional facilities in New York City. More recently, the outbreak of extensively drug-resistant tuberculosis in the KwaZulu-Natal province of South Africa is a tragic reminder of the importance of infection control measures in institutions. The congregation of large numbers of highly susceptible people, especially HIV-infected persons, in closed environments with untreated tuberculosis patients has resulted in numerous microepidemics of both drug-susceptible and drug-resistant tuberculosis. Reversal of the resurgence of tuberculosis in New York at that time was attributable in large part to strengthening of infection control practices.

Identification and isolation of infected patients

Tuberculosis infection control involves prompt identification and isolation of patients with suspected tuberculosis. The decision to isolate a patient in a hospital setting is a function of epidemiological and clinical factors. Patients with known tuberculosis risk factors who present with symptoms and signs characteristic of pulmonary tuberculosis should be placed in respiratory isolation. Local epidemiological data should influence isolation practices. In settings where tuberculosis is prevalent, all HIV-infected patients with pneumonia may require isolation, whereas isolation can be more selective and based on individual patient features in low prevalence settings.

Respiratory isolation requires placement of the patient in a room with negative air pressure relative to adjoining areas, ventilation to the room should provide at least six complete air changes per hour, and air should not be recirculated without filtering or irradiation. Patients should be instructed to cover their coughs at all times, and should wear surgical face masks when outside the room to reduce aerosol generation. Anyone entering the patient’s room should wear an appropriate face mask or respirator to prevent inhalation of droplet nuclei with tubercle bacilli. A considerable amount of debate has occurred in recent years in the United States of America regarding what constitutes appropriate protection for health care workers exposed to infectious tuberculosis. This debate is influenced as much by philosophy as by science, and will not be detailed here. Use of surgical masks for the protection against tuberculosis is clearly inappropriate, even though these masks are useful when placed on patients to prevent creation of infectious aerosols. Tightly fitting face masks that filter out more than 99.7% of particles less than 0.5 µm in size (high-efficiency particle air (HEPA) filters) are effective. Other devices, including positive air pressure respirators (PAPRs), are also effective.

Bullet list 1 Criteria for discontinuing respiratory isolation for tuberculosis in hospital inpatients

Use of ultraviolet germicidal irradiation can be useful for reducing the number of infectious particles in ambient air in settings where ventilation alone is not sufficient. Ultraviolet light must be concentrated in areas of rooms where exposure to people will not occur, such as upper air zones, in order to prevent skin and ocular toxicity. Areas where ultraviolet lights are often used include bronchoscopy suites, inside air circulation ducts, in emergency rooms, and in homeless shelters.

Criteria for discontinuation of respiratory isolation are listed in Bullet list 1. Guidelines for taking patients out of isolation in the hospital are strict and are intended to protect other vulnerable patients and hospital staff from any exposure to the disease. Respiratory isolation is not usually required or practical in the home setting, and patients with infectious tuberculosis do not need to be hospitalized solely for respiratory isolation. It is assumed that contacts in the home environment will already have had significant exposure to tuberculosis by the time a diagnosis is made, and isolation of the patient affords no measurable benefit. Exceptions to this may include patients living in congregate living facilities or other special situations. The primary protective measures for contacts of cases are a clinical evaluation to identify and evaluate symptoms of tuberculosis and tuberculin skin testing with treatment of latent infection, if present. Instituting infection control measures is likely to be challenging in developing countries where the health care system is already overburdened and where facilities often lack negative pressure isolation rooms and air filtration systems. In such settings, work practice and administrative control measures have been emphasized and are considered to be more effective and less expensive. These measures consist of policies and procedures intended to promptly identify infectious tuberculosis cases so that additional precautions and health care steps can be taken.

BCG vaccination

Vaccination against tuberculosis with the bacille Calmette-Guérin (BCG) vaccine is widely administered throughout the world but is a practice mired in controversy. BCG is an attenuated live bacterial vaccine developed in the early 20th century by Calmette and Guérin at the Institut Pasteur in Paris. After a series of uncontrolled and anecdotal assessments of the vaccine, a series of controlled trials of BCG was begun in the 1930s and continued through to the 1990s. The efficacy of BCG has varied greatly in these studies, ranging from more than 80% protection to complete lack of protection, with possibly increased risk in vaccine recipients. A meta-analysis of BCG trials performed in the early 1990s found that the weighted protective benefit of BCG was about 50% for both the prevention of active tuberculosis disease and death.

In addition to the protective efficacy observed in trials of BCG, there is evidence that BCG diminishes haematogenous dissemination of primary tuberculosis infection and thereby reduces the incidence of miliary tuberculosis and tuberculous meningitis in children. It is primarily for this reason that BCG is included in the Expanded Programme on Immunization of the WHO.

The current efficacy of BCG for preventing pulmonary tuberculosis is debated on the basis of several recent trials which have failed to show protection. Several hypotheses have been proposed for the variation in efficacy reported in various studies, including differences in susceptibility within populations, environmental exposure to mycobacteria which masks vaccine effect, and attenuation of vaccine immunogenicity. This last explanation is very compelling and fits well with clinical trial data. Unlike most vaccines, BCG is not standardized and there is no seedlot of vaccine from which new batches are derived. BCG is grown in several laboratories around the world and has not been re-passaged in animals since it was derived from cattle a century ago. Multiple commercial and noncommercial BCG products are in use presently, and comparative genomic analysis demonstrates considerable genetic heterogeneity in these strains, with many gene deletions and polymorphisms. One analysis of BCG trials found that protective efficacy was reduced in studies using multiply-passaged vaccine strains. The evidence supports the hypothesis that BCG has become further attenuated over time and no longer promotes immunity to M. tuberculosis infection and disease in adults. This position has not been universally accepted, however, and BCG remains one of the most widely administered vaccines in the world, largely for its perceived effects on paediatric tuberculosis.

Areas for further research

Effective global tuberculosis control will require a coordinated set of clinical and public health strategies that are based on a thorough understanding of the epidemiology, pathogenesis, and therapy of infection with M. tuberculosis. It appears that the WHO’s DOTS strategy, which focuses on finding and effectively treating cases, is not sufficient to control or eliminate tuberculosis, particularly in countries with large HIV epidemics. Improved methods for the diagnosis and treatment of tuberculosis infection and disease, particularly drug-resistant tuberculosis, are urgently needed. Effective regimens for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis, with both existing and new agents, need to be developed. A better understanding of the pathogenesis of and natural immunity to tuberculosis may contribute to the development of a more effective vaccine. The sequencing of the genome of M. tuberculosis promises to open the door to a new generation of research on tuberculosis and its control. Scientific progress alone, however, will be insufficient to combat tuberculosis worldwide. The willingness of societies and nations to pay for the deployment of the fruits of biomedical research, both past and future, to combat the disease where it is prevalent will be required for the conquest of tuberculosis.

Further reading