Tuberculosis: Seminar

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SEMINAR

Seminar

Tuberculosis

Thomas R Frieden, Timothy R Sterling, Sonal S Munsiff, Catherine J Watt, Christopher Dye

Among communicable diseases, tuberculosis is the second leading cause of death worldwide, killing nearly 2 million
people each year. Most cases are in less-developed countries; over the past decade, tuberculosis incidence has
increased in Africa, mainly as a result of the burden of HIV infection, and in the former Soviet Union, owing to
socioeconomic change and decline of the health-care system. Definitive diagnosis of tuberculosis remains based on
culture for Mycobacterium tuberculosis, but rapid diagnosis of infectious tuberculosis by simple sputum smear for acid-
fast bacilli remains an important tool, and more rapid molecular techniques hold promise. Treatment with several
drugs for 6 months or more can cure more than 95% of patients; direct observation of treatment, a component of the
recommended five-element DOTS strategy, is judged to be the standard of care by most authorities, but currently only
a third of cases worldwide are treated under this approach. Systematic monitoring of case detection and treatment
outcomes is essential to effective service delivery. The proportion of patients diagnosed and treated effectively has
increased greatly over the past decade but is still far short of global targets. Efforts to develop more effective
tuberculosis vaccines are under way, but even if one is identified, more effective treatment systems are likely to be
required for decades. Other modes of tuberculosis control, such as treatment of latent infection, have a potentially
important role in some contexts. Until tuberculosis is controlled worldwide, it will continue to be a major killer in less-
developed countries and a constant threat in most of the more-developed countries.

Tuberculosis has probably killed 100 million people The global tuberculosis caseload appears to be growing
over the past 100 years,1 although a cure was available slowly. Case numbers have declined more or less steadily
for the second half of the 20th century. This review in western and central Europe, North and South America,
summarises the current status of tuberculosis and the Middle East. By contrast, there have been striking
epidemiology, pathophysiology, diagnosis, treatment, increases in countries of the former Soviet Union and in
and control. Although most cases of tuberculosis occur in sub-Saharan Africa (figure 2).3
less-developed countries, this review is relevant to both Tuberculosis rates have increased in the former Soviet
more-developed and less-developed countries. Union because of economic decline and the general
failure of tuberculosis control and other health services
Epidemiology since 1991.4 Periodic surveys have shown that more than
Tuberculosis is the world’s second commonest cause of 10% of new tuberculosis cases in Estonia, Latvia, and
death from infectious disease, after HIV/AIDS. There some parts of Russia are multi-drug resistant5—ie,
were an estimated 8–9 million new cases of tuberculosis resistant to at least isoniazid and rifampicin, the two most
in 2000, fewer than half of which were reported; effective antituberculosis drugs. However, resistance is a
3–4 million cases were sputum-smear positive, the most byproduct of tuberculosis resurgence in these countries,
infectious form of the disease.2 Most cases (5–6 million) not the primary cause of it.
are in people aged 15–49 years. Sub-Saharan Africa has HIV infection accounts for much of the recent increase
the highest incidence rate (290 per 100 000 population), in the global tuberculosis burden.2 Worldwide, an
but the most populous countries of Asia have the largest estimated 11% of new adult tuberculosis cases in 2000
numbers of cases: India, China, Indonesia, Bangladesh, were infected with HIV, with wide variations among
and Pakistan together account for more than half the regions: 38% in sub-Saharan Africa, 14% in more
global burden. 80% of new cases occur in 22 high-burden
countries (figure 1). Search strategy and selection criteria
We searched PubMed/MEDLINE for articles with tuberculosis
as major topic, and epidemiology, pathophysiology, diagnosis,
Lancet 2003; 362: 887–99
treatment, or control as secondary topics. The Cochrane
database was searched for reviews of tuberculosis. We also
New York City Department of Health and Mental Hygiene, examined the websites and publications of the WHO,
New York, NY, USA (T R Frieden MD, S S Munsiff MD); Center for International Union Against Tuberculosis and Lung Disease,
Tuberculosis Research, Johns Hopkins University School of British Thoracic Society, American Thoracic Society, and US
Medicine, and Baltimore City Health Department Eastern Chest Centers for Disease Control and Prevention, as well as major
Clinic, Baltimore, MD (T R Sterling MD); Centers for Disease Control
current tuberculosis textbooks. Many other papers were found
and Prevention, Atlanta, GA (S S Munsiff); and Communicable
in the reference lists of articles identified through initial
Diseases, WHO, Geneva, Switzerland (C J Watt DPhil, C Dye DPhil)
searches. The databases and publications were searched
Correspondence to: Dr Thomas R Frieden, Commissioner, New York between April, 2002, and March, 2003. We did not limit the
City Department of Health and Mental Hygiene, 125 Worth Street, search to articles published in English, nor specifically to
CN28, Room 331, New York, NY 10013, USA particular dates.
(e-mail: tfrieden@health.nyc.gov)

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Number of cases
No estimate (3)
 1000 (74)
1000–9999 (57)
10 000–99 999 (62)
100 000–999 999 (13)
 1 000 000 (2)

Figure 1: Estimated number of new tuberculosis cases by country, 2001

developed countries, and 1% in the Western Pacific positive result in the tuberculin skin test. At the cellular
Region. Rates of HIV infection among patients with level, an effective host immune response occurs as follows.
tuberculosis have so far remained below 1% in Alveolar macrophages infected with M tuberculosis interact
Bangladesh, China, and Indonesia. The increase in with T lymphocytes via several important cytokines. The
tuberculosis incidence in Africa is strongly associated with infected macrophage releases interleukins 12 and 18,
the prevalence of HIV infection.6 Rates of HIV infection which stimulate T lymphocytes (predominantly CD4-
among tuberculosis patients are correspondingly high,
exceeding 60% in Botswana, South Africa, Zambia, and Africa (high HIV prevalence)
Zimbabwe. About two million people died of tuberculosis
in 2000; about 13% of these people were also infected 3000
with HIV.2

Pathophysiology
2000
New cases of tuberculosis (thousands of cases per year)

Tuberculosis is spread by airborne droplet nuclei, which


are particles of 1–5 m in diameter that contain
Mycobacterium tuberculosis. Because of their small size, the
particles can remain airborne for minutes to hours after 1000
expectoration by people with pulmonary or laryngeal
tuberculosis during coughing, sneezing, singing, or
talking.7–9 The infectious droplet nuclei are inhaled and 0
lodge in the alveoli in the distal airways. M tuberculosis is
then taken up by alveolar macrophages, initiating a 1990 1995 2000 2005 2010
cascade of events that results in either successful
containment of the infection or progression to active Former Soviet Union
disease (primary progressive tuberculosis). Although the 800
risk of development of active disease varies according to
time since infection, age, and host immunity, the
estimated lifetime risk of disease for a newly infected 600
young child is 10%, with roughly half of that risk
occurring in the first 2 years after infection.10,11
After being ingested by alveolar macrophages, 400
M tuberculosis replicates slowly but continuously and
spreads via the lymphatic system to the hilar lymph nodes.
In most infected individuals, cell-mediated immunity 200
develops 2–8 weeks after infection. Activated
T lymphocytes and macrophages form granulomas that
limit further replication and spread of the organism.12 0
M tuberculosis is in the centre of the characteristically 1990 1995 2000 2005 2010
necrotic (caseating or cheese-like) granulomas, but it is Year
usually not viable. Unless there is a subsequent defect in Figure 2: Trends and projections in numbers of tuberculosis
cell-mediated immunity, the infection generally remains cases to 2010 for countries of eastern and southern Africa
contained and active disease may never occur. with high HIV prevalence, and in the former Soviet Union
The development of cell-mediated immunity against Broken lines indicate 95% CI. Adapted with permission from WHO global
M tuberculosis is associated with the development of a tuberculosis report 2003, based on trends in notification rates.3

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positive T lymphocytes) to release interferon .13,14 This Pleural tuberculosis occurs as a result of either primary
cytokine, in turn, stimulates the phagocytosis of progressive M tuberculosis infection or reactivation of
M tuberculosis in the macrophage. latent infection. A chest radiograph generally reveals a
Interferon  does not directly stimulate the killing of unilateral pleural effusion. Unlike other clinical
M tuberculosis by the macrophage, at least partly because manifestations of tuberculosis, pleural disease probably
the organism inhibits the cytokine’s transcriptional represents an increased, rather than diminished, immune
responses.15 Interferon  is, however, crucial for the control response. In fact, primary serofibrinous pleural effusion
of M tuberculosis infection,16 and it also stimulates the resolves without treatment in up to 90% of cases;
macrophage to release tumour necrosis factor , which is however, if untreated, nearly two-thirds of patients will
important in granuloma formation and control of the extent subsequently have relapses with tuberculosis at other
of infection.17,18 The T-lymphocyte response is antigen organ sites.41
specific and is influenced by the major histocompatibility The most serious clinical manifestation of tuberculosis
complex.12,19 Although several M tuberculosis antigens have is involvement of the central nervous system. Such
been identified, none confer protective immunity and they involvement can include inflammation of the meninges, as
are thus unsuitable for a vaccine. well as space-occupying lesions (tuberculomas) of the
When the host immune response cannot contain the brain. The clinical manifestations are due to the presence
replication of M tuberculosis associated with initial of M tuberculosis as well as the inflammatory host immune
infection, active disease occurs. This development is most response. Children under 5 years of age and HIV-infected
common in children under 5 years old and adults with individuals are at increased risk of tuberculous
advanced immunosuppression (eg, AIDS). This primary meningitis,42,43 which can present clinically as chronic
progressive disease can manifest in almost any organ meningitis, with headache, fever, and changed mental
system, but it occurs most frequently in the parenchyma status. Neurological manifestations can include cranial-
of the mid and lower lung, in the hilar lymph nodes, or as nerve palsies and motor, sensory, and cerebellar defects,
generalised lesions resulting from haematogenous according to the location of the tuberculomas; seizures
dissemination.1 can also occur. Meningitis is fatal in almost all cases
Although an effective host immune response can without chemotherapy, and prompt identification and
initially contain M tuberculosis infection, several factors treatment are essential to prevent serious neurological
can trigger subsequent development of active disease from sequelae.
reactivation of remote infection. HIV is the greatest single Tuberculosis can affect any bone or joint, but the spine
risk factor for progression to active disease in adults. (ie, Pott’s disease) is the most common bony structure
Other medical conditions that can also compromise the involved. In the spine, the most common location is the
immune system and predispose to development of active thoracic section. Vertebral-body involvement can be
disease include poorly controlled diabetes mellitus, renal followed by disease of an adjacent intervertebral disc.1
failure, underlying malignant disease, chemotherapy, Genitourinary tuberculosis (including involvement
extensive corticosteroid therapy, malnutrition, and of the renal and male and female genital tracts) is
deficiency of vitamin D or A.20–22 Defects in the production uncommon and is difficult to distinguish from other
of interferon 13,23 or tumour necrosis factor ,24,25 as well infections of the genitourinary tract. In men,
as in the interferon- receptor26 and interleukin-12 manifestations include those of prostatitis or prostate
receptor 1, have also been described.27 enlargement, epididymitis, and orchitis, but disease can
also present as a painless scrotal mass. Urine analysis may
Genetic predisposition show red or white blood cells, or both, with a negative
Several studies have suggested that some patients have urine culture for bacteria (sterile pyuria). In women,
a genetic predisposition to tuberculosis. This idea genitourinary tuberculosis is an important cause of
has arisen from studies among monozygotic and dizygotic infertility in areas with high tuberculosis incidence.44
twins28 and in an assessment of tuberculosis risk Disseminated tuberculosis is defined as involvement of
according to ancestral history.29 Population-based studies many organs simultaneously and can occur as a result of
have found an association between tuberculosis and primary progressive disease or reactivation of latent
some HLA alleles, as well as polymorphisms in the infection. The clinical manifestation of pulmonary
genes for natural resistance-associated macrophage involvement is a miliary (millet seed) pattern rather than
protein (NRAMP1), the vitamin D receptor, and an infiltrate in most cases, but not all patients with
interleukin 1.30–35 Although the functional importance disseminated disease have pulmonary involvement.
of most of these polymorphisms is unclear, NRAMP1 Mortality is high despite chemotherapy and may be
polymorphisms could influence tuberculosis susceptibility related to delays in diagnosis and other commonly present
by regulation of interleukin 10.36 Associations between underlying medical conditions.39
genetic polymorphisms and tuberculosis susceptibility
differ according to ethnic origin,37 but the extent to which Diagnosis
genetic polymorphisms contribute to the global Active disease
tuberculosis burden is unclear because of the great Criteria for the diagnosis of active tuberculosis vary
difficulty of separating lifelong environmental influences according to the setting. Patients with persistent cough
from genetic predisposition. (eg, lasting longer than 2 weeks) should be assessed
for tuberculosis.45,46 Other common symptoms include
Clinical manifestations fever, night sweats, weight loss, shortness of breath,
The most common clinical manifestation of tuberculosis is haemoptysis, and chest pain.47 Among children, important
pulmonary disease. Extrapulmonary tuberculosis accounts diagnostic clues are a history of previous exposure to an
for about 20% of disease in HIV-seronegative people but is individual with tuberculosis or evidence of tuberculosis
more common in HIV-seropositive individuals.38 Among infection (eg, a positive tuberculin skin test). To improve
people not infected with HIV, extrapulmonary disease, the diagnostic yield in children, diagnostic algorithms and
particularly lymphatic tuberculosis, is particularly common point scoring systems are often used, particularly in less-
in women and young children.39,40 developed countries.48

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Tests for the diagnosis of tuberculosis vary in Where resources for diagnosis and treatment of drug-
sensitivity, specificity, speed, and cost. Even if additional resistant tuberculosis allow, drug-susceptibility testing
tests are done, however, culture is required for definite should ideally be done on all initial M tuberculosis
diagnosis and is essential for drug-susceptibility testing. isolates.47 Susceptibility testing should also be considered
The sputum smear is an inexpensive test that can be when cultures remain positive after 3 months of
carried out rapidly; fluorochrome, Ziehl-Neelsen, and treatment, or become positive after being previously
Kinyoun staining methods can be used. The International negative. Agar-based methods have been standard,
Union Against Tuberculosis and Lung Disease although broth-based media are faster.60 Rapid detection
(IUATLD) and WHO recommend the Ziehl-Neelsen of rifampicin resistance is particularly important, and new
method under most circumstances.46,49 Although the methods to detect this and other types of resistance are
smear is positive in only 50–80% of individuals with coming into clinical practice.61–64 Direct susceptibility
culture-confirmed pulmonary tuberculosis, cases with testing on agar plates is a highly accurate technique for
organisms on the smear are more infectious than smear- patients with heavily smear-positive tuberculosis. This
negative cases and have higher case-fatality rates.50,51 technique requires technical expertise, but it can provide
Nonetheless, smear-negative disease accounts for 15–20% first-line and second-line susceptibility results in
of M tuberculosis transmission.51,52 In countries with a high 10–14 days.65
prevalence of tuberculosis, a positive direct smear is due Nucleic-acid amplification assays can be used directly
to M tuberculosis in more than 95% of patients suspected on clinical specimens; they are most reliable in smear-
of having tuberculosis;53 routine cultures are generally positive respiratory samples from patients with previously
neither practicable nor necessary for disease control. Non- untreated tuberculosis. In such samples, the sensitivity
tuberculous mycobacteria, particularly in HIV-infected and specificity can be as high as 95% and 98%,
patients, tend to be present in much lower concentrations respectively. The sensitivity is 48–53% in smear-negative
and are therefore rarely seen on a direct sputum smear. respiratory samples, but the specificity is roughly 95%.47,66
Concentrated smears (ie, those made from samples that In areas of high tuberculosis prevalence, there is no need
have been decontaminated, liquefied, and centrifuged) to confirm a heavily positive sputum smear, which will in
may be more sensitive and are routinely used in most cases reflect M tuberculosis. However, where
laboratories that also routinely culture all specimens, concentrated smears are used and either the prevalence of
because decontaminated and concentrated specimens are HIV is high or the prevalence of tuberculosis is low,
needed for culturing.49,54 In less-developed countries, a amplification techniques can be useful in distinguishing
diagnostic algorithm for sputum-smear-negative patients positive smears due to M tuberculosis from positive smears
is commonly used, based on response to antibiotics and with other mycobacteria.
results of chest radiography. Widespread implementation of nucleic-acid
Although the organism can take 6 weeks or longer amplification assays has been limited by high cost and
to grow on solid culture media (eg, the egg-based potential for poor performance under field conditions.
Lowenstein-Jensen medium or the agar-based Amplification tests do not replace the sputum smear
Middlebrook 7H10 or 7H11), growth generally occurs (which provides a gauge of infectiousness) or culture
within 7–21 days with liquid culture media.55 Ideally, when (which is necessary for drug-susceptibility testing). The
cultures are done, both solid and liquid culture media assays can still give positive results after effective
should be used, because the former allow examination of treatment (because of detection of residual genetic
colony morphology and the identification of mixed material), so they may not be as useful in people with
cultures, and the latter enable more rapid diagnosis. previous disease or in monitoring response to therapy.
Radiographic findings suggesting tuberculosis include In addition to advances in clinical laboratory tests,
upper-lobe infiltrates, cavitary infiltrates, and hilar or research methods of DNA fingerprinting can be useful to
paratracheal adenopathy. In many patients with primary identify laboratory cross-contamination and elucidate the
progressive disease and those with HIV infection, epidemiology of tuberculosis.67
radiographic findings are more subtle and can include
lower-lobe infiltrates or a miliary pattern. HIV-infected Latent infection
patients, particularly those late in the course of HIV The intradermal administration of tuberculin has been
infection, generally experience greater weight loss and used as a diagnostic test for tuberculosis infection since
fever but are less likely to have cavitary disease and positive the early 1900s;68 the more consistent form of tuberculin,
smears for acid-fast bacilli56 than those not infected with standardised purified protein derivative (PPD-S), has
HIV, and in one study, 8% of HIV-infected patients with been used to assess latent M tuberculosis infection since
pulmonary tuberculosis had normal chest radiographs.57 1939.69,70 Although the tuberculin skin test is the best
About 15–20% of adults with tuberculosis (on the basis available way to diagnose latent M tuberculosis infection, it
of clinical, radiographic, and histopathological findings, has limitations, including low sensitivity in immuno-
as well as response to antituberculosis treatment)47 compromised patients, cross-reactivity with bacille
have negative sputum cultures. Among children, the Calmette-Guerin (BCG) vaccine and environmental
proportion of culture-negative cases is much higher. mycobacteria (resulting in decreased specificity), and a
False-positive cultures can also occur; in a review of requirement that patients must return 48–72 h after the
12 studies that assessed more than 100 patients and used test is done to have the result read.71 The criteria for a
DNA fingerprinting, the median false-positive rate was positive test vary according to the population group being
2·9% (range 0–33%).58 False-positive results can be due to tested; they are influenced by the likelihood of being
laboratory cross-contamination, contamination of clinical infected with M tuberculosis and the risk of developing
devices, or clerical errors, and are more common with active disease if infected.20
liquid culture media.59 Where resources permit, there A whole-blood interferon- release assay (IGRA), like
should be close scrutiny of cases with no positive smear, the tuberculin skin test, assesses cell-mediated immunity
only one positive culture, and several negative cultures; to tuberculin.72 The correlation between the IGRA and
selective use of DNA fingerprinting should be considered the tuberculin skin test has been low.73,74 IGRA responses
to rule out a false-positive culture. are diminished in HIV-infected individuals, resulting in

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Treatment Patients Tuberculosis treatment*


category
Initial phase (daily or three times per Continuation phase
week) (daily or three times per week)
I New cases of smear-positive pulmonary tuberculosis or severe 2 months H3R3Z3E3 or 2 months H3R3Z3S3 4 months H3R3
extrapulmonary tuberculosis or severe smear-negative pulmonary 2 months HRZE or 2 months HRZS 4 months HR
tuberculosis or severe concomitant HIV disease 6 months HE†
II‡ Previously treated smear-positive pulmonary tuberculosis; 2 months H3R3Z3E3S3/1 month H3R3Z3E3 5 months H3R3E3
relapse; treatment failure; treatment after default 2 months HRZES/1 month HRZE 5 months HRE
III§ New cases of smear-negative pulmonary tuberculosis or 2 months H3R3Z3E3 4 months H3R3
with less severe forms of extrapulmonary tuberculosis 2 months HRZE 4 months HR
6 months HE†
*Subscript after letters refers to the number of doses per week; daily has no subscript. H=isoniazid; R=rifampicin; Z=pyrazinamide; S=streptomycin, E=ethambutol.
†A continuation phase of 6 months of HE has a higher failure and relapse rate than a continuation phase of 4 months of HR but can be used for mobile patients and
those with limited access to health services; the HE regimen can also be used concomitantly with antiretroviral treatment of HIV-infected patients. ‡CDC/ATS and BTS
recommend treatment for such patients based on susceptibility testing, with regimens tailored to the susceptibility profile. WHO recommends susceptibility testing
whenever possible for patients with treatment failure. §WHO indicates that ethambutol need not be given in the initial phase of category III treatment if patients have
non-cavitary, smear-negative pulmonary tuberculosis, or if patients are known to have a drug-susceptible organism, or for young children with primary tuberculosis.
Table 1: WHO-recommended treatment regimens

low sensitivity in this important population,75 but they direct observation.89 Randomised controlled trials have
may aid in detecting latent infection among certain not shown a benefit from treatment observation; however,
populations who are at increased risk (eg, recent migrants these trials have had a common shortcoming of less than
from countries with high incidence of tuberculosis).72 optimum implementation of treatment observation, with
Although the IGRA is less sensitive and specific than the rates of treatment success significantly below those of
tuberculin skin test,74 responses are less affected by worldwide programmes of DOTS.90 Direct observation by
previous BCG vaccination.76 An enzyme-linked trained individuals is the standard of practice in most
immunospot (ELISPOT) assay has recently been countries3 and is a component of the five-point DOTS
developed that is relatively sensitive and specific in strategy recommended by WHO and IUATLD.45,46,81
detecting latent M tuberculosis infection.77 Family members should not be relied on to ensure
treatment completion.91,92 However, direct observation is
Treatment only one feature of comprehensive tuberculosis care;
The goals of treatment are to ensure cure without relapse, sensitive, patient-centred treatment that includes direct
to prevent death, to stop transmission, and to prevent the observation is crucial for cure of patients and success of
emergence of drug resistance. M tuberculosis can remain the programme.
dormant for long periods. The number of tubercle bacilli The initial phase of regimens including rifampicin
varies widely with the type of lesion, and the larger the should always be directly observed to ensure adherence
bacterial population, the higher the probability that and prevent emergence of resistance to rifampicin. The
naturally resistant mutants are present even before continuation phase eliminates most residual bacilli and
treatment is started.78 Long-term treatment with a reduces numbers of failures and relapses. At the start of
combination of drugs is required.79 Treatment of active the continuation phase there are low numbers of bacilli
tuberculosis with a single drug should never be attempted, and less chance that drug-resistant mutants will be
and a single drug should never be added to a failing selected, and therefore fewer drugs are needed.83,89
regimen.1,80
Almost all recommended treatment regimens have two Standard treatment regimens
phases,81,82 on the basis of extensive evidence from WHO-recommended treatment regimens are shown in
controlled clinical trials. There is an initial intensive phase table 1. For each patient, the recommended regimen
designed to kill actively growing and semidormant bacilli. depends on the treatment category, which is based on
This action shortens the duration of infectiousness with severity of disease and history of previous treatment. For
rapid smear and culture conversion after 2–3 months of some forms of disease, such as tuberculous meningitis,
treatment, in most cases (80–90%).83 At least two disseminated tuberculosis, and spinal tuberculosis with
bactericidal drugs, isoniazid and rifampicin, are necessary neurological involvement, a 7–10-month continuation
in the initial phase. Pyrazinamide given in the initial phase with isoniazid and rifampicin is often recommended.45
intensive phase allows the duration of treatment to be There are slight differences in the recommendations of
reduced from 9 to 6 months, but it offers no benefit if the US Centers for Disease Control and Prevention and
given past the second month to patients with drug- the American Thoracic Society (CDC/ATS), and the UK
susceptible tuberculosis.84 The addition of ethambutol Joint Tuberculosis Committee of the British Thoracic
benefits the regimen when initial drug resistance may be Society (BTS) and WHO and IUATLD.45,46,81,82 WHO,
present or the burden of organisms is high. IUATLD, and the BTS do not recommend twice-weekly
Several studies have shown that reliable prediction of dosing, although this is one recommendation in the USA.
which patients will take all prescribed medication by The 8-month regimen (2 months of HRZE/6 months of
themselves is not possible;85 only direct observation can HE) is not recommended in the USA or the UK. The UK
ensure that all drugs are taken. Directly observed and US guidelines recommend use of the same 6-month
treatment, in which a trained observer personally observes rifampicin-based regimens for both smear-positive and
each dose of medication being swallowed by the patient, smear-negative pulmonary tuberculosis.
can ensure high rates of treatment completion, reduce The recommended drug doses differ also; WHO
development of acquired drug resistance, and prevent recommends doses that are generally lower than those
relapse.86–88 Non-adherence to tuberculosis treatment is recommended by other authorities and which are supported
known to have been common ever since the advent of by clinical trials, although the lower doses appear to have
chemotherapy in the 1950s.85 Thus, most tuberculosis been safe and effective in large-scale treatment. Tables 2
treatment trials since that time have been carried out with and 3 give recommendations on dosing and monitoring,

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Drug Route Mode of Daily dose Twice-weekly dose Thrice-weekly dose


action
Children Adults Maximum Children Adults Maximum Children Adults Maximum
Isoniazid Oral or Bactericidal 5–10 5 mg/kg 300 mg 15 mg/kg 15 mg/kg 900 mg 10 mg/kg 10 mg/kg 900 mg
IM* mg/kg† (range 13–17) (range 8–12)
Rifampicin Oral or Bactericidal 10–20 600 mg 600 mg 10–20 600 mg 600 mg 10–20 600 mg 600 mg
IV mg/kg‡ (range 8– mg/kg‡ (range 8– mg/kg‡ (range 8–
12 mg/kg) 12 mg/kg) 12 mg/kg)
Pyrazinamide§ Oral Bactericidal 20–30 1·5 g (<50 kg) ·· 50 mg/kg 2·5 g (<50 kg) ·· 35 mg/kg 2·0g (<50 kg) ··
mg/kg 2·0 g (range 40– 3·0g (range 30– 2·5 g
(51–74 kg) 60 mg/kg) (51–74 kg) 40 mg/kg) (51–74 kg)
2·5 g (75 kg) 3·5g (75 kg) 3·0 g (7 5 kg)
Ethambutol¶ Oral Bacteriostatic 15–25 15–25 2·5 g 30–50 45 mg/kg ·· 30–50 30 mg/kg ··
mg/kg mg/kg mg/kg mg/kg
Streptomycin IM, IV Bactericidal 15–30 15 mg/kg 1000 mg 15 mg/kg 15 mg/kg 1000 mg 15 mg/kg 15 mg/kg 1000 mg
mg/kg
Thioacetazone Oral Bacteriostatic 2 mg/kg 150 mg ·· NR NR NR NR NR NR
Adapted with permission from the New York City Department of Health. Tuberculosis treatment, 3rd edn. City Health Information: 1999, 18 number 2 (available at
http://www.nyc.gov/html/doh/pdf/chi/chi18-2.pdf). IM=intramuscular; IV=intravenous; NR=not recommended. *Intravenous and suppository forms are available in some
countries. †WHO, IUATLD, and BTS recommend 5 mg/kg in children; CDC/ATS and the American Academy of Pediatrics recommend 10 mg/kg. ‡WHO, IUATLD, and BTS
recommend 10 mg/kg in children; CDC/ATS and the American Academy of Pediatrics recommend 10–20 mg/kg. §WHO and CDC/ATS recommend dosing of pyrazinamide
in adults on a weight basis, but dosing based on weight categories as recommended by BTS and by tuberculosis programmes is more useful in practice. Recommendations
of dosing for this drug vary widely. Adults weighing <45 kg can have paediatric doses. The doses given here are based on the New York City Tuberculosis Control Program.
¶WHO, IUATLD, and BTS recommend 15 mg/kg ethambutol for daily administration in adults and children and 30 mg/kg for thrice-weekly dosing.
Table 2: Doses, route of administration, and mode of action of primary drugs used in the treatment of tuberculosis

along with information on common and major adverse I regimens for severe forms and category III regimens for
events for the standard drugs. Detailed information on non-severe forms.45 All major organisations agree that
adverse effects and their management is available from some forms of disease, such as meningitis, may benefit
several excellent resources.45,93–96 from a longer treatment course.45,81,82 Steroids should be
used for patients with large pleural effusions, pericardial
Extrapulmonary tuberculosis disease, and meningitis, particularly with neurological
In most cases of extrapulmonary tuberculosis there are impairment, since these drugs are likely to decrease
many fewer organisms present.97 In general, regimens morbidity and mortality in such cases.103–110
used for pulmonary tuberculosis are effective in the
treatment of extrapulmonary tuberculosis.98–102 WHO Treatment in pregnant and breastfeeding women
recommends classification of the disease into severe and Isoniazid, rifampicin, pyrazinamide, and ethambutol are
non-severe forms. Severe forms include meningeal and not teratogenic,111 and WHO recommends their use in
central-nervous-system tuberculosis, spinal tuberculosis, women who are pregnant.45 In the USA, pyrazinamide is
abdominal tuberculosis, bilateral pleural effusion, not recommended for use during pregnancy except when
pericardial effusion, and bone and joint tuberculosis alternative drugs are not available or are less effective.81
involving more than one site. WHO recommends category Active tuberculosis in pregnancy must be treated, because

Drug Major adverse reactions Recommended regular monitoring Comments


Isoniazid Increases in hepatic enzymes; hepatitis; peripheral Hepatic function tests (if baseline Aluminum-containing antacids reduce
neuropathy; CNS effects; increased phenytoin abnormal) absorption. Pyridoxine (vitamin B6) can
concentrations; interaction with disulfiram decrease peripheral neuritis and CNS
effects, and should be used in alcoholic,
pregnant, and malnourished patients.
Rifampicin Hepatitis, fever, thrombocytopenia, flu-like syndrome. Hepatic function tests (if baseline Orange discolouration of secretions, urine,
Lowers concentrations of many drugs, including abnormal) tears, and contact lenses. Patients on
methadone, warfarin, oral contraceptives, oral methadone need a higher dose (average
hypoglycaemic agents, theophylline, dapsone, 50%) to avoid opioid withdrawal.
ketoconazole, protease inhibitors, and non- Interaction with many drugs leads to low
nucleoside reverse transcriptase inhibitors. concentrations of one or both. May make
glucose control more difficult in diabetes.
Women should be advised to use barrier
contraceptives during treatment.
Contraindicated for patients taking most
protease inhibitors and non-nucleoside
reverse transcriptase inhibitors.
Pyrazinamide Gastrointestinal upset; hepatotoxicity; Hepatic function tests (if baseline May complicate management of diabetes
hyperuricaemia; arthralgias; gout, rarely; rash abnormal mellitus. Hyperuricaemia can be used as
indicator of compliance. Treat raised uric
acid only if symptomatic.
Ethambutol Diminished red-green colour discrimination; Check colour vision and visual acuity Optic neuritis may be unilateral; check
decreased visual acuity; rash monthly each eye separately. If possible avoid in
children too young to undergo vision
testing.
Streptomycin Auditory and renal toxicity; hypokalaemia; Audiometry, renal function, and Ultrasound and warm compresses on
hypomagnesaemia electrolytes injection site may reduce pain and
induration.
Thioacetazone Rash and hypersensitivity reactions such as Close observation for skin reactions Do not use in HIV-infected patients. If
erythema multiforme and Stevens-Johnson rash develops, do not rechallenge.
syndrome; gastrointestinal upset, hepatitis
Not all toxicities are listed here. Full prescribing information should be checked in the package insert or pharmacology texts.
Table 3: Major adverse reactions and recommended regular monitoring of primary drugs used in the treatment of tuberculosis

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Drug Route Mode of action Daily dose Major adverse reactions* Recommended Comments
regular monitoring
Capreomycin IV, IM Bactericidal Children 15–30 mg/kg Auditory, vestibular, renal toxicity; Audiometry, renal Ultrasound and warm
Adults 15 mg/kg eosinophilia; hypokalaemia; function, compresses on injection
Maximum 1000 mg hypomagnesaemia electrolytes site may reduce pain and
induration.
Ciprofloxacin Oral or IV Bacteriostatic Adults 750–1500 mg Abdominal cramps; .. Antacids containing
gastrointestinal upset; aluminum, magnesium,
restlessness; insomnia; or calcium, and
headache; interactions with sucralfate reduce
warfarin and theophylline absorption and should
not be given within 2 h of
dose. Caffeine effects
may be increased. Not
approved for use in
children yet.
Cycloserine† Oral Bacteriostatic Children 15–20 mg/kg Psychosis; seizures; headache; Assessment of Increase gradually,
Adults 500–1000 mg depression; suicide; other CNS mental status checking serum
Divided doses effects; rash; increased phenytoin concentrations.
concentrations Pyridoxine (vitamin B6),
50 mg with each
250 mg, may reduce
CNS effects.
Ethionamide Oral Bacteriostatic Children 15–20 mg/kg Gastrointestinal upset; bloating; Hepatic function Antacids/antiemetics and
Protionamide† Adults 500–1000 mg hepatotoxicity; hypothyroidism tests (if baseline lying flat for 20 min after
Divided doses (especially with aminosalicylic abnormal); thyroid doses may help tolerance.
acid); metallic taste function Start with 250 mg daily
and increase as tolerated.
Kanamycin IM, IV Bactericidal Children 15–30 mg/kg Auditory and renal toxicity; rare Audiometry, renal Ultrasound and warm
Amikacin Adults 15 mg/kg vestibular toxicity; hypokalaemia; function, compresses on injection
Maximum 1000 mg hypomagnesaemia electrolytes site may reduce pain and
induration.
Levofloxacin Oral or IV Bacteriostatic, Adults 500–1000 mg Similar to ciprofloxacin but many ·· Similar to ciprofloxacin.
possibly fewer side-effects and drug More active than
bactericidal interactions ciprofloxacin and
ofloxacin.
Moxifloxacin Oral or IV Bactericidal Adults 400 mg Similar to ciprofloxacin but fewer ·· Similar to ciprofloxacin.
drug interactions Data on long-term use
are limited at present.
Avoid in patients with
prolonged QT interval,
and those receiving class
Ia or III antiarrhythmic
agents.112
Ofloxacin Oral or IV Bacteriostatic Adults 600–800 mg Probably similar to ciprofloxacin; .. Similar to ciprofloxacin.
possibly fewer drug interactions
Aminosalicylic acid Oral Bacteriostatic Children 150 mg/kg Gastrointestinal upset; Thyroid function Begin gradually and
Adults 4 g every 12 h hypersensitivity; hepatotoxicity; increase dose as
Maximum 12 g hypothyroidism; low digoxin, high tolerated. May cause
phenytoin concentrations; haemolytic anaemia in
concentrations decreased by patients with deficiency
diphenhydramine of glucose-6-phosphate
dehydrogenase.
Rifabutin Oral Bactericidal Children 10–20 mg/kg Rash; hepatitis; fever; Complete blood- Orange discolouration of
Adults 5 mg/kg neutropenia; thrombocytopenia; cell count with secretions, urine, tears
Maximum 300 mg low concentrations of many platelets; and contact lenses. Can
drugs;‡ uveitis with high doses hepatic function be used in daily, twice-
tests (if baseline weekly, or thrice-weekly
abnormal) dosing. See text for
dosing in HIV infection.§
Methadone dose
generally does not need
to be increased. Patients
should be advised to use
barrier contraceptives
during treatment.
Adapted with permission from the New York City Department of Health. Tuberculosis treatment, 3rd edn. City Health Information: 1999, 18 number 2 (available at
http://www.nyc.gov/html/doh/pdf/chi/chi18-2.pdf). *Not all toxicities are listed here. Full prescribing information should be checked in the package insert or
pharmacology texts.†WHO-recommended daily maximum doses are 750 mg for cycloserine, ethionamide, and protionamide. ‡Including protease inhibitors, non-
nucleoside reverse transcriptase inhibitors, dapsone, ketoconazole, and oral contraceptives. §Contraindicated with saquinavir or delavirdine. See drug reference
manuals for details on individual drugs.
Table 4: Reserve drugs used in the treatment of tuberculosis: doses, major adverse reactions, and recommended regular monitoring

untreated disease will harm the mother and the unborn Most antituberculosis drugs can be used during
child more than standard drugs would. However, some breastfeeding.113 No data are available for ethionamide.
reserve drugs may be more toxic (table 4); the risks and Although data are lacking on amikacin and capreomycin,
benefits of these drugs must be assessed for each woman they are likely to be safe given their structural
separately, and in some instances treatment with reserve similarity to streptomycin and kanamycin (which
drugs should be deferred. are considered safe). Concentrations of antituberculosis

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Drug Safety in pregnancy* CNS penetration† Dose in renal insufficiency‡ Dose in hepatic insufficiency
Isoniazid Has been used safely§ Good (20–100%) No change No change but use with caution
Rifampicin Has been used safely (isolated Fair; inflamed meninges No change No change but use with caution
reports of malformations) (10–20%)
Rifabutin Use with caution (limited Good (30–70%) No change No change but use with caution
data on safety)
Pyrazinamide Recommended by WHO, not Good (75–100%) Increase interval No change but use with caution
by US FDA (limited data on safety) (use with caution)
Ethambutol Has been used safely Inflamed meninges only Decrease dose/increase No change
(4–64%) interval
Aminoglycosides Avoid¶ (associated with Poor|| Decrease dose/increase No change
(streptomycin, hearing impairment in fetus) interval**
kanamycin,
amikacin)
Capreomycin Avoid (limited data on safety) Poor Decrease dose/increase No change
interval**
Ciprofloxacin, Do not use (teratogenic in Fair (5–10%); inflamed Decrease dose/increase No change
levofloxacin, animals) meninges 50–90% interval
ofloxacin
Ethionamide, Do not use (premature labour, Good (100%) No change No change, but use with caution
protionamide congenital malformations)
Cycloserine Use with caution (limited data Good (50–100%) Decrease dose/increase No change
on safety) interval
Aminosalicylic acid Has been used safely Inflamed meninges only Probably no change No change
(limited data)
Thioacetazone Has been used safely Unknown Avoid Avoid
*As with all medications given during pregnancy, antituberculosis medications should be used with extreme caution. The risk of tuberculosis to the fetus far outweighs
the risk of most medications. Data are limited on the safety of antituberculosis medications during pregnancy. This table presents a consensus of published data and
recommendations. †Steroid treatment seems to improve outcome in tuberculous meningitis, particularly in patients with altered mental status. ‡If possible, monitor
serum drug concentrations of patients with renal insufficiency. §Supplement with pyridoxine (vitamin B6). ¶If an injectable medication must be used during pregnancy,
streptomycin is preferred. ||Has been used intrathecally; efficacy not documented. **Avoid aminoglycosides and capreomycin in patients with reversible renal damage,
if possible.
Table 5: Use of antituberculosis drugs during pregnancy, tuberculous meningitis, and renal and hepatic failure

drugs in breastmilk are too low to prevent or treat The clinical, radiographic, and microbiological
tuberculosis in infants. If tuberculosis is suspected in the responses to short-course treatment are similar
child, he or she should be treated. irrespective of HIV status, although death during
antituberculosis treatment is much more common in
Treatment in patients with liver disease HIV-infected individuals.120–122 There is evidence that
Drug-induced hepatitis can be fatal.93,94 WHO direct observation of treatment is even more important for
recommends that pyrazinamide should not be used in HIV-infected patients, and it is considered the standard of
patients with known chronic liver disease. In care.121,123 Several studies have found that, although relapse
decompensated liver disease, a regimen without rates are low, they are higher than in HIV-negative
rifampicin can be used.45 Streptomycin, ethambutol, and a individuals,124–126 whereas other studies have found similar
reserve drug such as a fluoroquinolone can be used if relapse rates in HIV-infected and HIV-negative
treatment is necessary in patients with fulminant liver individuals.127,128 Others have identified reinfection rather
disease.81 than relapse as a common cause of recurrence of
tuberculosis in HIV-infected patients in areas with high
Treatment of patients with renal failure incidence of tuberculosis.129 Clinical suspicion of
Normal doses of isoniazid, rifampicin, and pyrazinamide recurrence of disease, due to relapse or reinfection, should
can be given in renal failure, since these drugs are be high in HIV-infected patients who have completed
eliminated almost entirely by biliary excretion or treatment.
are metabolised into non-toxic compounds.114 In severe Several antiretroviral drugs (ie, most protease inhibitors
renal failure, patients receiving isoniazid should and non-nucleoside reverse transcriptase inhibitors except
also receive pyridoxine to prevent peripheral neuropathy. efavirenz) should not be used with rifampicin.130 Rifabutin
Ethambutol can accumulate and cause optic has similar activity against M tuberculosis,131–133 has less effect
neuropathy.112 Recommendations on the use of the other on the pharmacokinetics of some antiretroviral drugs,
drugs in patients with renal failure are given in table 5. and is recommended in the USA as an equivalent
Individuals on haemodialysis should receive primary drug alternative agent for HIV-infected patients receiving certain
treatment by direct observation after dialysis; several of antiretroviral drugs.134–136 There are concerns that patients
the drugs are eliminated during dialysis.115,116 with less than 100 CD4-positive cells per L who are
treated with highly intermittent regimens may have a higher
Treatment of HIV-infected patients risk of relapsing with acquired rifampicin resistance.
Recommended treatment regimens are similar for Therefore, twice-weekly therapy with any rifamycin-based
HIV-infected and HIV-negative tuberculosis patients. regimen is not recommended for HIV-infected individuals
However, thioacetazone should never be used, because with less than 100 CD4-positive cells per L.137
it is associated with an increased risk of severe and in Rifapentine is a rifamycin derivative with a long half-life
some cases fatal skin reactions in HIV-infected and its activity against M tuberculosis is similar to that
individuals.117,118 In addition, response to treatment and of rifampicin. It is not recommended in HIV-infected
survival are better in HIV-infected patients treated with patients because of increased risk of acquired rifampicin
short-course treatment including rifampicin than with resistance.138 It has not been studied in patients
other regimens that do not include rifampicin.118,119 with extrapulmonary tuberculosis. Rifapentine is
Therefore, all attempts should be made to use directly recommended in the USA in the continuation-phase
observed rifamycin-based regimens. treatment of HIV-negative patients with non-cavitary

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SEMINAR

pulmonary disease.81 Most but not all strains resistant to 80

Smear-positive case detection (%)


rifampicin are resistant to rifabutin and rifapentine. 70% target case detection
70
Paradoxical worsening of tuberculosis (defined as
increased fever, worsening of pulmonary infiltrates, or 60
new clinical manifestations of disease) can occur in 50
patients on effective treatment. Although described in All notifications
both HIV-seronegative and HIV-seropositive patients, it 40
may be more common in the latter.139–141 The underlying 30
pathophysiology of paradoxical worsening is not well
understood, but it probably involves increased recognition 20
Notifications under DOTS
of mycobacterial antigens resulting from improved 10
immune function.142 Other possible causes of the signs and
symptoms should be excluded; these include drug failure, 0
drug resistance, non-adherence, and other diseases such 2000 20051990 1995
2010 2015
as lymphoma. Paradoxical worsening can occur after Year
initiation of tuberculosis treatment or can be associated Figure 3: Observed and projected rate of detection of smear-
with the initiation of antiretroviral therapy in HIV- positive cases compared with the 70% global target
The lower set of points is derived from case notifications submitted to
infected patients with tuberculosis.139,143 WHO by DOTS programmes divided by the estimated incidence rate for
these countries. Linear projection of the trend observed from 1995 to
Management of drug-resistant cases 2001 (blue line) indicates that, if the trend is maintained, 70% case
The treatment of patients whose organisms are resistant detection will be reached in 2012. To reach 70% case detection by 2005,
case finding must be significantly accelerated (red line). The upper set of
to standard drugs or who do not tolerate them is difficult. points represent all smear-positive cases notified to WHO from all
Reserve drugs are generally less effective and more toxic sources, including DOTS and non-DOTS programmes. Observations on the
than standard therapy; they must be given daily, and some implementation of DOTS suggest that case-detection rates may reach a
need to be taken several times a day.45,80 maximum of less than 50%, indicated by the broken line, unless case
detection improves. Adapted with permission from Dye et al.147
When devising a regimen for suspected or confirmed
drug-resistant disease, several important principles must
be followed. The initial regimen should include at least complex tuberculosis-control strategies where rates of
three drugs to which the bacilli are likely to be fully drug resistance or HIV infection are high. The
susceptible. Drugs should not be kept in reserve; the international targets for tuberculosis control by 2005 are
regimen most likely to be effective should be prescribed. to detect 70% of new pulmonary smear-positive cases
Second-line drugs should be given daily under direct annually, and to treat 85% of detected cases
observation. Bacteriological results (smear and, if successfully.146
possible, culture) should be monitored.45,80 Many of the 155 national DOTS programmes in
If susceptibility test results are available, a regimen can existence by the end of 2001 have shown that they can
be chosen, based on the drugs to which the strain of achieve high cure rates: average treatment success was
M tuberculosis is susceptible. Most authorities recommend 82%, not far below the 85% target,3 with lower rates in
three or four oral drugs plus one injectable drug (such as Africa (72%) and some countries of the former Soviet
capreomycin, amikacin, or kanamycin) to which the Union (eg, 68% in the Russian Federation). However,
isolate is susceptible for 3–6 months, and then at least only 32% of all estimated new smear-positive cases were
three effective oral drugs for 15–18 months, for a total of treated under DOTS programmes in 2001.3 The increase
12–18 months after culture conversion to negative.45,80 in case notifications under DOTS has been steady since
All efforts should be pursued to obtain an accurate 1995 (figure 3); if the current rate of progress in DOTS
susceptibility profile in patients for whom a standard expansion is maintained, the target of 70% case detection
regimen with first-line drugs fails, particularly if the will not be reached until after 2010. However, there is a
treatment was given under direct observation. If drug- risk that progress will be slower: if DOTS programmes fail
susceptibility testing is not available, standard retreatment to reach beyond traditional public-health systems, they
regimens can be used. Decisions must take into account may never be able to detect more than the 50% of cases
the regimens the patient has received before, and whether currently notified to WHO (figure 3).147
the previous regimens were fully administered under Both mathematical modelling and practical experience
direct observation and for how long. Longer use of suggest that, if case-detection and cure rates can be
injectable drugs is associated with improved outcomes,144 increased to 70% and 85%, respectively, tuberculosis
but long-term administration is commonly complicated incidence will decline at 5–10% per year in areas of high
by ototoxicity, nephrotoxicity, and local adverse reactions incidence and in the absence of HIV.148,149 At a 7% annual
(eg, pain, induration, abscess formation). Details on the decline, incidence would be halved in 10 years. In Peru,
doses and major common adverse effects for the reserve where DOTS was introduced in 1990, high rates of
drugs are given in table 4. case detection and cure have decreased the incidence
of pulmonary tuberculosis by at least 6% per
Control year (figure 4).150
To control tuberculosis, WHO and IUATLD recommend With effective treatment, tuberculosis mortality
the DOTS strategy,145 which has five elements: political typically falls faster than case numbers. Thus, incidence in
commitment, diagnosis primarily by sputum-smear the Netherlands decreased at an average of 7% per year
microscopy among patients attending health facilities, between 1950 and 1995, but the death rate fell more than
short-course treatment with effective case management 12% annually.149 Indirect assessments of the effect of
(ie, direct observation), regular drug supply, and DOTS suggest that hundreds of thousands of lives have
systematic monitoring to assess outcomes of every patient been saved in China and India.151,152
started on treatment. Standard short-course regimens can Where the prevalence of HIV infection is high, as in
cure more than 95% of cases of new, drug-susceptible eastern and southern Africa, tuberculosis treatment alone
tuberculosis. DOTS should be used as the basis for more will not be able to reverse the rise in incidence of

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SEMINAR

220 more frequently to prevent tuberculosis among HIV-


Pulmonary tuberculosis cases

DOTS begins 1990


infected individuals even though, in areas of high
(per 100 000 population)

200
Case finding transmission, protection may not extend for more than
180 2–3 years beyond the end of treatment, and there is at
most a short prolongation of life.163–165
160
Conclusion
140 The current state of tuberculosis diagnosis, treatment,
Incidence falling and control reveals striking contrasts. On the one hand,
120 new diagnostic methods have been developed, and
at 6% per year
widespread application of control strategies has increased
100
the number of patients effectively diagnosed and treated
1980
1990 1985
1995 2000 annually from 696 000 in 1995 to 2·4 million in 2001 (all
Year forms of tuberculosis treated under DOTS), with more
Figure 4: Notified pulmonary tuberculosis cases per 100 000 than 10 million patients treated in the past 10 years.
population, Peru, 1980–2000 Effective tuberculosis control is both inexpensive and
The DOTS strategy was introduced in 1990, and the incidence of
pulmonary tuberculosis has been falling at an average of 6% per year
cost-effective.166 On the other hand, the mainstays of
since 1996. Adapted with permission from Suárez et al.150 diagnosis remain the sputum smear and culture, both
100 years old. No new first-line drugs have been
tuberculosis. At present, the most effective way to address discovered for several decades, and two-thirds of patients
HIV-associated tuberculosis is via a sound DOTS who develop tuberculosis are not effectively diagnosed,
programme coupled with comprehensive, effective HIV treated, or monitored. The influence of HIV infection on
prevention and care.153,154 the tuberculosis burden in eastern and southern Africa
will be difficult to reverse without more effective HIV
BCG vaccination prevention and more widely available antiretroviral
Randomised and case-control trials have shown therapy in the less-developed countries. Further progress
consistently high protective efficacy (mostly above 70%) will require continued rigorous and dedicated application
of BCG against serious forms of disease in children of current technology and will be greatly facilitated by the
(meningitis and miliary tuberculosis), but variable efficacy discovery and widespread application of new diagnostic
against pulmonary tuberculosis in adults.155 Thus, in high- techniques, drugs, and prevention strategies, such as an
prevalence areas, vaccination is recommended for effective vaccine.
children at birth or at first contact with health services,
except for children with symptomatic HIV infection.156 Conflict of interest statement
Even with high coverage, BCG has not had any None declared.
substantial effect on transmission or incidence, because its
main action is to prevent serious (but non-infectious) Acknowledgments
We thank William Harris, senior consultant to the Bureau of Tuberculosis
disease in children.157 Adverse events from BCG Control of the New York City Department of Health and Mental
vaccination can occur, including local subcutaneous Hygiene, Mark Perkins of the UNDP-World Bank-WHO Special
abscess and ulcers, suppurative lymphadenitis, and, more Programme for Research and Training in Tropical Diseases, and
rarely, disseminated disease.158 John A Jereb and Kenneth G Castro of the Centers for Disease Control
and Prevention for their insights in reviewing this document, and
Despite continuing efforts to develop more effective Drew Blakeman for editorial preparation.
tuberculosis vaccines, none have been identified to date.
Even if one were to be developed, it might not prevent Role of the funding source
progression to active disease among the more than TRS received funding from the National Institutes of Allergy and
2 billion people already infected with M tuberculosis. Infectious Diseases (k23 AIO1654). No other person or organisation
provided any of the authors with funding related to the preparation of this
Therefore, even if a new vaccine were to be implemented article.
worldwide, more effective treatment systems would be
required for decades.
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