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Although awareness is growing, childhood tuberculosis (TB) remains a neglected disease in many resource-limited settings. In part this reflects operational difficulties, lack of visibility in official reports, as well as perceptions that children tend to develop mild disease, contribute little to disease transmission, and do not affect epidemic control. At an international level there is greater appreciation that children contribute significantly to the global TB disease burden and suffer severe TB-related morbidity and mortality, particularly in TB-endemic areas, where the disease often remains undiagnosed. However, this is not always the case at the national or local level and there remains an urgent need for feasible and implementable policies to guide clinical practice. Pediatric TB can be regarded as an emerging epidemic in areas where the adult epidemic remains out of control and Mycobacterium tuberculosis transmission is ongoing. This article reviews important concepts, challenges, and management principles related to childhood TB; it also summarizes the main priorities for future research.

Although tuberculosis (TB) has its highest burden among young adults, especially since the advent of HIV infection, two other groups with low immunity, the very young ( 65 years) with waning immunity, are vulnerable groups not to be forgotten. This review describes the epidemiology, clinical aspects, public health aspects and outcome of TB in patients at the extremes of age. The epidemiology differs therein that TB in infants occurs in developing countries with high incidences of TB and HIV, while TB in the elderly occurs in developed countries with ageing populations. The clinical presentation may be non-specific, history of contact with TB is often not known and TB is often not considered at these age extremes, and when the diagnosis is considered, disease progression may already be advanced. Anti-TB treatment regimens are the same as in other age groups, but drug dosages may need adjustment according to weight, renal function, liver function and other potentially complicating factors. Adverse events are more difficult to observe and both the young and the elderly are reliant on others for adherence to treatment. Mortality at both age extremes is higher than in the general TB population. For all the above reasons, public health measures to: prevent transmission of infection; identify those infected and providing preventive therapy; high index of suspicion in order to make an early diagnosis; and timely initiation of treatment are important in both the very young and the elderly.

There is limited literature documenting the interaction between radiologists and clinicians caring for children, especially in regions where HIV and tuberculosis (TB) are endemic. The dual burden of these diseases in resource-limited settings creates unique challenges for radiographic interpretation and utilization. This review aims to heighten awareness of issues confronting radiologists and clinicians caring for children and to encourage greater collaboration between these two disciplines in HIV- and TB-endemic regions. The Child-Friendly Healthcare Initiative is discussed, emphasizing opportunities to promote child friendliness in radiology services.

Objectives: Bacille Calmette-Guerin (BCG), a live attenuated Mycobacterium bovis vaccine, poses a risk to human immunodeficiency virus (HIV)-infected children; this risk has not been well quantified. We estimate the risk of disseminated BCG disease in HIV-infected children in a setting highly endemic for tuberculosis and HIV. Design and methods: We conducted a prospective hospital-based surveillance study in the Western Cape Province, South Africa. Clinical and laboratory-confirmed cases of disseminated BCG disease in children

Drug-resistant tuberculosis is a threat to tuberculosis control programs and community health. This growing problem mirrors the increasing incidence of tuberculosis in general. Public health problems include the absence of early diagnosis and effective treatment. The real need is to identify tuberculosis patients far earlier, particularly those with drug-resistant strains, and to begin appropriate therapy, which is of the shortest possible duration with minimal risk of acquiring further drug resistance or permitting further transmission. This article will address the epidemic of drug resistance and discuss some of the inherent difficulties in the treatment of drug-resistant tuberculosis. We highlight some of the controversies and new findings in this area, as well as future perspectives requiring more active interventions, in addition to new technology and developments.

Drug resistance among children with culture-confirmed tuberculosis (TB) provides an accurate measure of transmitted drug resistance within the community. We describe the genotype diversity in children with culture-confirmed TB and investigate the relationship between genotype and drug resistance. A prospective study was conducted from March 2003 through August 2005 at Tygerberg Children's Hospital, in the Western Cape Province of South Africa. All children (

Background: Tuberculosis (TB) is an important disease in human immunodeficiency virus (HIV) infected children living in regions where TB is endemic. There are limited data on the outcome of culture confirmed TB in HIV infected children. Aims and Methods: To describe the outcome on TB therapy and overall mortality in HIV infected children with culture confirmed TB through a retrospective cohort study. Results: Eighty seven children, median age 24 months, contributed to 93 TB episodes; six children had two confirmed episodes. Pulmonary disease (PTB) was present in 71 episodes (76.3%), extrapulmonary disease (EPTB) in 43 (46.2%), and of these, both PTB and EPTB were present in 21 (22.6%). There was cure based on bacteriological and/or radiological criteria in 54 episodes (58.1%). Eighteen children died during TB therapy and there were a total of 34 deaths (39.1%). In univariate analysis (n = 87 patients), severe malnutrition, age ⩽1 year, and a negative tuberculin skin test were significant risk factors for death during TB therapy. In multivariate survival analysis (n = 87 patients), HIV disease category, severe malnutrition at diagnosis, and lack of cure at the end of TB therapy were significantly associated with overall mortality. Conclusion: In the absence of antiretroviral therapy, HIV infected children with confirmed TB have poor outcomes on antituberculosis therapy and are at high risk of death during and after completion of antituberculosis therapy, especially due to non-TB related causes. There is an urgent need to optimise and monitor antituberculosis therapy in HIV infected children and to improve access to TB and other preventative therapy.

One of the obstacles in discussing childhood tuberculosis (TB) is the lack of standard descriptive terminology to classify the diverse spectrum of disease. Accurate disease classification is important, because the correct identification of the specific disease entity has definite prognostic significance. Accurate classification will also improve study outcome definitions and facilitate scientific communication. The aim of this paper is to provide practical guidelines for the accurate radiological classification of intra-thoracic TB in children less than 15 years of age. The proposed radiological classification is based on the underlying disease and the principles of pathological disease progression. The hope is that the proposed classification will clarify concepts and stimulate discussion that may lead to future consensus.

Setting. The Western Cape Province of South Africa, an area with a high tuberculosis (TB) incidence, where initial multidrug resistance (MDR) among adult TB cases was 1.1% during 1992–1993. Objective. To determine the long-term prevalence of TB infection and disease in children in household contact with adults with MDR pulmonary TB, and to establish the efficacy of chemoprophylaxis in preventing disease in these children. Method. Children Results. At the initial evaluation 125 children were seen, median age 27.5 months. Of these, 119 were followed up. Fourteen (12%) had disease, 61 (51%) were infected only, and 44 (37%) were noninfected. By 30-month follow-up, 29 (24%) had developed disease and 64 (54%) were infected only. Four adult-child pair Mycobacterium tuberculosis isolates were compared by DNA fingerprinting; 3 were identical. All children who developed TB disease were clinically cured. Two (5%) of 41 children who received appropriate chemoprophylaxis and 13 (20%) of 64 who did not, developed TB during follow-up (odds ratio: 4.97). Conclusion. The study confirms MDR TB transmission to childhood contacts. Seventy-eight percent of children were infected or developed disease. Appropriate chemoprophylaxis may prevent disease in these children.

Background. Moxifloxacin is currently recommended at a dose of 7.5–10 mg/kg for children with multidrug-resistant (MDR) tuberculosis, but pharmacokinetic and long-term safety data of moxifloxacin in children with tuberculosis are lacking. An area under the curve (AUC) of 40–60 µg × h/mL following an oral moxifloxacin dose of 400 mg has been reported in adults. Methods. In a prospective pharmacokinetic and safety study, children 7–15 years of age routinely receiving moxifloxacin 10 mg/kg daily as part of multidrug treatment for MDR tuberculosis in Cape Town, South Africa, for at least 2 weeks, underwent intensive pharmacokinetic sampling (predose and 1, 2, 4, 8, and either 6 or 11 hours) and were followed for safety. Assays were performed using liquid chromatography–tandem mass spectrometry, and pharmacokinetic measures calculated using noncompartmental analysis. Results. Twenty-three children were included (median age, 11.1 years; interquartile range [IQR], 9.2–12.0 years); 6 of 23 (26.1%) were human immunodeficiency virus (HIV)-infected. The median maximum serum concentration (Cmax), area under the curve from 0–8 hours (AUC0–8), time until Cmax (Tmax), and half-life for moxifloxacin were 3.08 (IQR, 2.85–3.82) µg/mL, 17.24 (IQR, 14.47–21.99) µg × h/mL, 2.0 (IQR, 1.0–8.0) h, and 4.14 (IQR, 3.45–6.11), respectively. Three children, all HIV-infected, were underweight for age. AUC0–8 was reduced by 6.85 µg × h/mL (95% confidence interval, −11.15 to −2.56) in HIV-infected children. Tmax was shorter with crushed vs whole tablets (P = .047). Except in 1 child with hepatotoxicity, all adverse effects were mild and nonpersistent. Mean corrected QT interval was 403 (standard deviation, 30) ms, and no prolongation >450 ms occurred. Conclusions. Children 7–15 years of age receiving moxifloxacin 10 mg/kg/day as part of MDR tuberculosis treatment have low serum concentrations compared with adults receiving 400 mg moxifloxacin daily. Higher moxifloxacin dosages may be required in children. Moxifloxacin was well tolerated in children treated for MDR tuberculosis.

Background While the prevalence of multidrug-resistant (MDR) tuberculosis (TB) is high among children in the Western Cape of South Africa, the psychosocial implications of treatment for children with MDR-TB remain poorly understood. We sought to explore how MDR-TB and its treatment impact children on an individual, familial, and social level. Methods Semi-structured interviews were conducted with 20 children and caregivers purposively sampled from a prospective clinical cohort of children. The sample was stratified by age at the start of treatment (children >10 years, and 5-10 years). Caregiver proxy interviews were conducted with younger children, supplemented with child interviews; older children were interviewed directly, supplemented with caregiver proxy interviews. Data were analysed using grounded theory. Results Findings revealed pill volume and adverse effects produced significant physical, psychological and academic disturbances in children. Adverse effects related to the medication were important obstacles to treatment adherence. While there appear to be no long-lasting effects in younger children, a few older children showed evidence of persisting internalised stigma. Caregivers suffered important treatment-related financial and psychological costs. Community support, notably through the continued involvement of children in strong social networks, promoted resilience among children and their families. Conclusions We found that the current treatment regimen for childhood MDR-TB has significant psychological, academic, and financial impacts on children and their families. There is a need for psychosocial support of children and caregivers to mitigate the negative effects of community stigma, and to manage the stressors associated with chronic illness. Electronic supplementary material The online version of this article (doi:10.1186/1471-2334-14-426) contains supplementary material, which is available to authorized users.

Transcranial Doppler imaging (TCDI) is potentially a valuable investigational tool in children with tuberculous meningitis (TBM), a condition often complicated by pathology relevant to Doppler imaging such as raised intracranial pressure (ICP) and cerebral vasculopathies.Serial TCDI was performed on 20 TBM children with the aim of investigating cerebrovascular haemodynamics and the relationship between pulsatility index (PI) and ICP.We observed a poor correlation between ICP and PI in children with communicating hydrocephalus (p = 0.72). No decline in PI was noted following 7 days of medical therapy for communicating hydrocephalus (p = 0.78) despite a concomitant decline in ICP. Conversely, a decline in PI was noted in all four children with non-communicating hydrocephalus who underwent cerebrospinal fluid diversion. High blood flow velocities (BFV) in all the basal cerebral arteries were observed in 14 children (70 %). The high BFV persisted for 7 days suggesting stenosis due to vasculitis rather than functional vasospasm. Complete middle cerebral artery (MCA) occlusion, subnormal mean MCA velocities (40 cm/s) and PIs (0.4) correlated with radiologically proven large cerebral infarcts.TCDI-derived PI is not a reliable indicator of raised ICP in children with tuberculous hydrocephalus. This may be attributed to individual variation of tuberculous vascular disease, possibly compromising cerebral vascular compliance and resistance. Basal artery stenosis secondary to vasculitis is observed during the acute stage of TBM in the majority of children.

BACKGROUND: Young children exposed to Mycobacterium tuberculosis have a high risk of disease progression following infection. This study aimed to determine risk factors for M. tuberculosis infection and disease in children following exposure to adults with multidrug-resistant (MDR) tuberculosis (TB). METHODS: Cross-sectional study; all children aged

Options for the treatment of children with drug-resistant tuberculosis (DR-TB) are limited. Emerging evidence in adults from systematic reviews and a randomized trial has shown good efficacy of linezolid in difficult cases of DR-TB but with frequent serious adverse effects. Published data in children are limited and we are unaware of formal guidelines for linezolid in treatment of paediatric DR-TB, though it will likely be an important component of DR-TB treatment for a growing number of children. We performed a structured review of existing literature on the efficacy, adverse effects, pharmacokinetics and pharmacodynamics of linezolid in DR-TB, highlighting the key evidence from the adult literature and systematically evaluating published paediatric data. Our search identified 8 reports of 18 children receiving linezolid for difficult to treat DR-TB. All 18 had culture conversion and 15 of 18 had successful long-term treatment outcomes. Adverse events were reported in 9 of 18; a linezolid dose reduction was required in 5 of 18, and 2 of 18 permanently discontinued linezolid because of adverse events. We make specific recommendations for the use of linezolid in children with DR-TB, and identify priority questions for future research. For children with multidrug-resistant (MDR)-TB with additional resistance or with extensively drug-resistant (XDR)-TB, linezolid may make the difference between a successful or poor outcome, and until newer antituberculosis agents with better efficacy and safety become available in children, linezolid will be an important component of treatment for children with the worst forms of DR-TB.

Background Accurate identification of Mycobacterium tuberculosis infection in young and HIV-infected children could guide delivery of preventive therapy, improve resource utilization and help prevent tuberculosis. Methods We assessed the performance of the tuberculin skin test (TST) and interferon-γ release assays (IGRAs) for identifying M. tuberculosis infection in South African children presenting for outpatient care. Tuberculosis contact was quantified using a standardized measure of M. tuberculosis exposure. Logistic regression assessed the association among test positivity, age, nutritional and HIV status, while controlling for M. tuberculosis exposure, bacille Calmette-Guerin vaccination and prior tuberculosis treatment. Results Among 250 (130 HIV infected) children (age 0.25-14.6 years, median 39 months), the proportion positive for each test varied: 34% (TST), 21% (T-SPOT.TB) and 25% (QuantiFERON-TB Gold In-Tube). IGRAs were more likely to be positive in HIV-uninfected compared with HIV-infected children; TST positivity did not differ between these groups. Agreement between tests was good-to-excellent in HIV-uninfected children and poor-to-good in HIV-infected children. In adjusted models, TST and T-SPOT.TB were positively associated with age; this effect varied by HIV status. The QuantiFERON-TB Gold In-Tube was negatively associated with chronic malnutrition; this effect varied by HIV status. Because 93% of children had received bacille Calmette-Guerin, we could not assess the contribution of bacille Calmette-Guerin to false-positive TST results. Conclusions Our findings indicate that the TST and IGRAs perform similarly for the detection of M. tuberculosis infection in well-nourished HIV-uninfected children, but test performance is differentially affected by chronic malnutrition, HIV infection and age. Similar to TST interpretation, clinicians and researchers should interpret IGRAs in children with caution taking age, nutritional and HIV status into consideration.

The management of children with drug-resistant tuberculosis (DR-TB) is challenging, and it is likely that in many places, the roll-out of molecular diagnostic testing will lead to more children being diagnosed. There is a limited evidence base to guide optimal treatment and follow-up in the pediatric population; in existing DR-TB guidelines, the care of children is often relegated to small "special populations" sections. This article seeks to address this gap by providing clinicians with practical advice and guidance. This is achieved through review of the available literature on pediatric DR-TB, including research studies and international guidelines, combined with consensus opinion from a team of experts who have extensive experience in the care of children with DR-TB in a wide variety of contexts and with varying resources. The review covers treatment initiation, regimen design and treatment duration, management of comorbid conditions, treatment monitoring, adverse events, adherence promotion, and infection control, all within a multidisciplinary environment.

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis., Background Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. Methods and Findings Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1–6.0]), ofloxacin (aOR: 2.5 [1.6–3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3–2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7–4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7–4.3]), ofloxacin (aOR: 2.3 [1.3–3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4–2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4–6.0]). Conclusions In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary., Editors' Summary Background In 2010, 8.8 million people developed tuberculosis—a contagious bacterial infection—and 1.4 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs (pulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months. The standard treatment for tuberculosis comprises an initial intensive phase lasting 2 months during which four antibiotics are taken daily followed by a 4-month continuation phase during which two antibiotics are taken. However, global efforts to control tuberculosis are now being thwarted by the emergence of M. tuberculosis strains that are resistant to several antibiotics, including isoniazid and rifampicin, the two most powerful, first-line (standard) anti-tuberculosis drugs. Why Was This Study Done? Although multi-drug resistant tuberculosis (MDR-TB) can be cured using second-line anti-tuberculosis drugs, these are more expensive and more toxic than first-line drugs and optimal treatment regimens for MDR-TB have not been determined. Notably, there have been no randomized controlled trials of treatments for MDR-TB. Such trials, which compare outcomes (cure, treatment failure, relapse, and death) among patients who have been randomly assigned to receive different treatments, are the best way to compare different anti-tuberculosis drug regimens. It is possible, however, to get useful information about the association of various treatments for MDR-TB with outcomes from observational studies using a statistical approach called “individual patient data meta-analysis.” In observational studies, because patients are not randomly assigned to different treatments, differences in outcomes between treatment groups may not be caused by the different drugs they receive but may be due to other differences between the groups. An individual patient data meta-analysis uses statistical methods to combine original patient data from several different studies. Here, the researchers use this approach to investigate the association of specific drugs, numbers of drugs and treatment duration with the clinical outcomes of patients with pulmonary MDR-TB. What Did the Researchers Do and Find? The researchers used three recent systematic reviews (studies that use predefined criteria to identify all the research on a given topic) to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. They obtained individual patient data from the authors of these studies and estimated adjusted odds (chances) of treatment success from the treatment and outcome data of 9,153 patients with MDR-TB provided by 32 centers. The use of later generation quinolones, ofloxacin, and ethionamide/prothionamide as part of multi-drug regimens were all associated with treatment success compared to failure, relapse or death, as were the use of four or more likely effective drugs (based on drug susceptibility testing of mycobacteria isolated from study participants) during the initial intensive treatment phase and the use of three or more likely effective drugs during the continuation phase. The researchers also report that among patients who did not die or stop treatment, the chances of treatment success increased with the duration of the initial treatment phase up to 7.1–8.5 months and with the total duration of treatment up to 18.6–21.5 months. What Do These Findings Mean? These findings suggest that the use of specific drugs, the use of a greater number of effective drugs, and longer treatments may be associated with treatment success and the survival of patients with MDR-TR. However, these findings need to be interpreted with caution because of limitations in this study that may have affected the accuracy of its findings. For example, the researchers did not include all the studies they found through the systematic reviews in their meta-analysis (some authors did not respond to requests for individual patient data, for example), which may have introduced bias. Moreover, because the patients included in the meta-analysis were treated at 32 centers, there were many differences in their management, some of which may have affected the accuracy of the findings. Because of these and other limitations, the researchers note that, although their findings highlight several important questions about the treatment of MDR-TB, randomized controlled trials are urgently needed to determine the optimal treatment for MDR-TB. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001300. The World Health Organization provides information on all aspects of tuberculosis, including MDR-TB; its guidelines for the programmatic management of drug-resistant tuberculosis are available The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the treatment of tuberculosis and on MDR-TB The US National Institute of Allergy and Infectious Diseases also has information on all aspects of tuberculosis, including a drug-resistant tuberculosis visual tour MedlinePlus has links to further information about tuberculosis (in English and Spanish) TB & ME, a collaborative blogging project run by patients being treated for multidrug-resistant tuberculosis and Medecins sans Frontieres, provides information about MDR-TB and patient stories about treatment for MDR-TB The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, also provides personal stories about treatment for tuberculosis

Children with presumed tuberculosis who are in contact with a multidrug-resistant source case should be treated according to the drug susceptibility of the source case's isolate. However, it is important to obtain a microbiologic diagnosis as it is possible for the child to have a different susceptibility profile to the source case. We present 2 such cases.

Summary Background Paediatric multidrug-resistant (MDR) tuberculosis is a public health challenge of growing concern, accounting for an estimated 15% of all global cases of MDR tuberculosis. Clinical management is especially challenging, and recommendations are based on restricted evidence. We aimed to assess existing evidence for the treatment of MDR tuberculosis in children. Methods We did a systematic review and meta-analysis of published and unpublished studies reporting treatment outcomes for children with MDR tuberculosis. We searched PubMed, Ovid, Embase, Cochrane Library, PsychINFO, and BioMedCentral databases up to Oct 31, 2011. Eligible studies included five or more children (aged ≤16 years) with MDR tuberculosis within a defined treatment cohort. The primary outcome was treatment success, defined as a composite of cure and treatment completion. Results We identified eight studies, which reported treatment outcomes for a total of 315 patients. We recorded much variation in the characteristics of patients and programmes. Time to appropriate treatment varied from 2 days to 46 months. Average duration of treatment ranged from 6 months to 34 months, and duration of follow-up ranged from 12 months to 37 months. The pooled estimate for treatment success was 81·67% (95% CI 72·54–90·80). Across all studies, 5·9% (95% CI 1·3–10·5) died, 6·2% (2·3–10·2) defaulted, and 39·1% (28·7–49·4) had an adverse event. The most common drug-related adverse events were nausea and vomiting. Other serious adverse events were hearing loss, psychiatric effects, and hypothyroidism. Interpretation The treatment of paediatric MDR tuberculosis has been neglected, but when children are treated outcomes can be achieved that are at least as good as those reported for adults. Programmes should be encouraged to report outcomes in children to improve the knowledge base for care, especially as new drugs become available. Funding None.

Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the imminent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and require treatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely on second-line medications which are less effective and often associated with more pronounced adverse effects than first-line therapy. Despite the fact that most of these agents were discovered many years ago, robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties, adverse effects and drug interactions, especially in children. Children differ from adults in the way that drugs are administered, the manner in which they are metabolised and in the adverse effects experienced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviral therapy is also poorly documented. This article reviews the available second-line drugs currently used in the treatment of MDR-TB in children and discusses medication properties and adverse effects while potential interactions with antiretroviral therapy are explored.

Background. Ototoxicity following aminoglycoside treatment for multidrug-resistant tuberculosis (MDR-TB), is a significant problem. This study documents the incidence of ototoxicity in HIV-positive and HIV-negative patients with MDR-TB and presents clinical guidelines relating to ototoxicity.Methods. A prospective cohort study of 153 MDR-TB patients with normal hearing and middle ear status at baseline controlling for 6 mitochondrial mutations associated with aminoglycoside-related ototoxicity, at Brooklyn Chest Hospital in Cape Town. Pure tone audiometry was performed monthly for 3 months to determine hearing loss. HIV status was recorded, as was the presence of 6 mutations in the MT-RNR1 gene.Results. Fifty-seven per cent developed high-frequency hearing loss. HIV-positive patients (70%) were more likely to develop hearing loss than HIV-negative patients (42%). Of 115 patients who were genetically screened, none had MT-RNR1 mutations.Conclusion. Ototoxic hearing loss is common in MDR-TB patients treated with aminoglycosides. HIV-positive patients are at increased risk of ototoxicity. Auditory monitoring and auditory rehabilitation should be an integral part of the package of care of MDR-TB patients.S Afr Med J 2012;102(6):363-366

Isoniazid (INH), nearly 60 years after its discovery, remains an essential drug in tuberculosis regimens. Recent studies confirm its excellent bactericidal activity; the rapid killing of approximately 90% of bacilli in microscopy smear-positive sputum within 48 h explains its great efficacy in preventing drug resistance in companion drugs. Studies of the pharmacokinetics and pharmacodynamics of INH suggest that INH dosages giving serum concentrations 2 h after dosing of 3 µg/ml will suffice for the killing of fully drug-sensitive Mycobacterium tuberculosis isolates; concentrations of 5 µg/ml will aid the suppression of a significant proportion of isolates resistant to lower INH concentrations. Hepatotoxicity is one of the most important complications of INH therapy; increases in the values of the hepatic enzymes aspartate aminotransferase and alanine aminotransferase have been shown to be more common in slow acetylators of INH than in faster acetylators of INH. N-acetyltransferase genotyping may make it possible to treat slow acetylators with lower doses of INH and thus achieve optimal efficacy without increasing the risk of hepatotoxicity. Recent studies suggest that children under the age of approximately 10 years should receive INH doses of 10–15 mg/kg to reach serum concentrations equivalent to those of adults receiving 4–6 mg/kg INH.

We report a case of rapidly progressive miliary tuberculosis in a 21-month old HIV-infected girl exposed to tuberculosis, despite early access to highly active antiretroviral therapy and proven adherence to isoniazid chemoprophylaxis. Post mortem revealed multidrug-resistant tuberculosis. This case report illustrates the consequences of inadequate programmatic management of children exposed to an adult case of sputum smear-positive multidrug-resistant tuberculosis. Drug susceptibility testing of the adult source case should become standard of care for all children who have been in close contact with a case of sputum smear-positive tuberculosis, and the choice of chemoprophylactic agents should be based on the sensitivities of the source case organism.

Although tuberculosis (TB) has its highest burden among young adults, especially since the advent of HIV infection, two other groups with low immunity, the very young (1 year) with immature immunity and the elderly (65 years) with waning immunity, are vulnerable groups not to be forgotten. This review describes the epidemiology, clinical aspects, public health aspects and outcome of TB in patients at the extremes of age. The epidemiology differs therein that TB in infants occurs in developing countries with high incidences of TB and HIV, while TB in the elderly occurs in developed countries with ageing populations. The clinical presentation may be non-specific, history of contact with TB is often not known and TB is often not considered at these age extremes, and when the diagnosis is considered, disease progression may already be advanced. Anti-TB treatment regimens are the same as in other age groups, but drug dosages may need adjustment according to weight, renal function, liver function and other potentially complicating factors. Adverse events are more difficult to observe and both the young and the elderly are reliant on others for adherence to treatment. Mortality at both age extremes is higher than in the general TB population. For all the above reasons, public health measures to: prevent transmission of infection; identify those infected and providing preventive therapy; high index of suspicion in order to make an early diagnosis; and timely initiation of treatment are important in both the very young and the elderly.

Item does not contain fulltext Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of the estimated 440,000 cases of MDR tuberculosis that occurred in 2008, only 7% were identified and reported to WHO. Of these cases, only a fifth were treated according to WHO standards. Although treatment of MDR and XDR tuberculosis is possible with currently available diagnostic techniques and drugs, the treatment course is substantially more costly and laborious than for drug-susceptible tuberculosis, with higher rates of treatment failure and mortality. Nonetheless, a few countries provide examples of how existing technologies can be used to reverse the epidemic of MDR tuberculosis within a decade. Major improvements in laboratory capacity, infection control, performance of tuberculosis control programmes, and treatment regimens for both drug-susceptible and drug-resistant disease will be needed, together with a massive scale-up in diagnosis and treatment of MDR and XDR tuberculosis to prevent drug-resistant strains from becoming the dominant form of tuberculosis. New diagnostic tests and drugs are likely to become available during the next few years and should accelerate control of MDR and XDR tuberculosis. Equally important, especially in the highest-burden countries of India, China, and Russia, will be a commitment to tuberculosis control including improvements in national policies and health systems that remove financial barriers to treatment, encourage rational drug use, and create the infrastructure necessary to manage MDR tuberculosis on a national scale.

Background. In most countries with a high burden of tuberculosis, children with tuberculosis are prescribed isoniazid at dosages of 4-6 mg/kg/day, as recommended by international authorities. Methods. We studied isoniazid concentrations in 56 hospitalized children (median age, 3.22 years; interquartile range [IQR], 1.58-5.38 years) who received isoniazid daily (median dosage, 5.01 mg/kg/day; range, 2.94-15.58 mg/kg/day) as part of antituberculosis treatment. At 1 and 4 months after initiation of treatment, isoniazid concentrations were measured in plasma samples at 0.75, 1.5, 3, 4, and 6 h after a treatment dose, to describe pharmacokinetic measures by using noncompartmental analysis. The effects of dose in milogram per kilogram, acetylator genotype, age, sex, and clinical diagnosis of kwashiorkor and human immunodeficiency virus (HIV) infection on isoniazid concentrations were evaluated. Results. Median peak concentrations of isoniazid in children prescribed a dose of 4-6 mg/kg were 58% lower than those in children prescribed a dose of 8-10 mg/kg (2.39 mg/L [IQR, 1.59-3.40] vs. 5.71 mg/L [IQR, 4.74-7.62]). Peak concentrations were

Background South Africa has one of the highest incidences of multidrug-resistant tuberculosis (MDR-TB) in the world. Concomitantly, aminoglycosides are commonly used in this country as a treatment against MDR-TB. To date, at least five mutations are known to confer susceptibility to aminoglycoside-induced hearing loss. The aim of the present study was to develop a rapid screening method to determine whether these mutations are present in the South African population. Methods A multiplex method using the SNaPshot technique was used to screen for five mutations in the MT-RNR1 gene: A1555G, C1494T, T1095C, 961delT+C(n) and A827G. A total of 204 South African control samples, comprising 98 Mixed ancestry and 106 Black individuals were screened for the presence of the five mutations. Results A robust, cost-effective method was developed that detected the presence of all five sequence variants simultaneously. In this pilot study, the A1555G mutation was identified at a frequency of 0.9% in the Black control samples. The 961delT+C(n) variant was present in 6.6% of the Black controls and 2% of the Mixed ancestry controls. The T1095C, C1494T and A827G variants were not identified in any of the study participants. Conclusion The frequency of 0.9% for the A1555G mutation in the Black population in South Africa is of concern given the high incidence of MDR-TB in this particular ethnic group. Future larger studies are warranted to determine the true frequencies of the aminoglycoside deafness mutations in the general South African population. The high frequencies of the 961delT+C(n) variant observed in the controls suggest that this change is a common non-pathogenic polymorphism. This genetic method facilitates the identification of individuals at high risk of developing hearing loss prior to the start of aminoglycoside therapy. This is important in a low-resource country like South Africa where, despite their adverse side-effects, aminoglycosides will continue to be used routinely and are accompanied with very limited or no audiological monitoring.

OBJECTIVE. National tuberculosis programs in tuberculosis-endemic countries rarely implement active tracing and screening of child tuberculosis contacts, mainly because of resource constraints. We aimed to evaluate the safety and feasibility of applying a simple symptom-based approach to screen child tuberculosis contacts for active disease. METHODS. We conducted a prospective observational study from January through December 2004 at 3 clinics in Cape Town, South Africa. All of the children RESULTS. During the study period, 357 adult tuberculosis cases were identified; 195 cases (54.6%) had sputum smear and/or culture positive results and were in household contact with children aged CONCLUSIONS. Our findings support current World Health Organization recommendations, demonstrating that symptom-based screening of child tuberculosis contacts should improve feasibility in resource-limited settings and seems to be safe.

Background The tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics are poorly controlled in sub-Saharan Africa, where highly active antiretroviral treatment (HAART) has become more freely available. Little is known about the clinical presentation and outcome of TB in HIV-infected children on HAART. Methods We performed a comprehensive file review of all children who commenced HAART at Tygerberg Children's Hospital from January 2003 through December 2005. Results Data from 290 children were analyzed; 137 TB episodes were recorded in 136 children; 116 episodes occurred before and 21 after HAART initiation; 10 episodes were probably related to immune reconstitution inflammatory syndrome (IRIS). The number of TB cases per 100 patient years were 53.3 during the 9 months prior to HAART initiation, and 6.4 during post HAART follow-up [odds ratio (OR) 16.6; 95% confidence interval (CI) 12.5–22.4]. A positive outcome was achieved in 97/137 (71%) episodes, 6 (4%) cases experienced no improvement, 16 (12%) died and the outcome could not be established in 18 (13%). Mortality was less in children on HAART (1/21; 4.8%) compared to those not on HAART (15/116; 12.9%). Conclusion We recorded an extremely high incidence of TB among HIV-infected children, especially prior to HAART initiation. Starting HAART at an earlier stage is likely to reduce morbidity and mortality related to TB, particularly in TB-endemic areas. Management frequently deviated from standard guidelines, but outcomes in general were good.

Animal studies point to increased virulence of certain mycobacterial strains notably those of the Beijing genotype. There are limited data on mycobacterial genotypic diversity in children with tuberculous meningitis (TBM). We investigated mycobacterial genotypic diversity in children with TBM and analyzed the relationship among genotype clinical presentation and outcome. Data were extracted from an ongoing prospective study on children with confirmed TBM from 1992 through 2003 at a referral hospital in the Western Cape Province South Africa. Mycobacterial isolates were genotyped by standardized restriction fragment length polymorphism methodology. Clinical data at diagnosis inflammatory progression during the first month of antituberculosis therapy and neurologic outcomes after 6 months of therapy were analyzed according to the principal genetic group of the strain and the presence of the Beijing strain respectively. Fifty-nine children were included (median age at diagnosis 23 months); 37 presented with stage II and 22 with stage III presented with TBM. At completion of antituberculosis therapy 6 children were neurologically normal 22 were moderately neurologically impaired 23 were severely neurologically impaired and 6 children died; detailed outcomes were not available in 2 children. All 3 principal genetic groups were represented (group 1 27.1%; group 2 59.3%; group 3 13.6%); the most prevalent strains were of the Beijing genotype (family 29; 25.4%) followed by family 28 (10.2%) and family 11 (8.5%). Predictors of poor neurologic outcome included advanced disease at diagnosis and male gender. There was no association between the principal genetic group of the strain or the presence of the Beijing genotype and clinical presentation or outcome. We found no association between Mycobacterium tuberculosis genotypes and clinical presentation or outcome. (authors)

Background The clinical, radiological and microbiological features of culture-confirmed childhood tuberculosis diagnosed at two referral hospitals are described. Methods Cultures of Mycobacterium tuberculosis from children less than 13 years of age at Tygerberg and Red Cross Children's Hospitals, Cape Town, South Africa, were collected from March 2003 through February 2005. Folder review and chest radiography were performed and drug susceptibility tests done. Results Of 596 children (median age 31 months), 330 (55.4%) were males. Of all children, 281 (47.1%) were HIV-uninfected, 133 (22.3%) HIV-infected and 182 (30.5%) not tested. Contact with infectious tuberculosis adults was recorded in 295 (49.5%) children. Missed opportunities for chemoprophylaxis were present in 117/182 (64.3%) children less than 5 years of age. Extrathoracic TB was less common in HIV-infected than in HIV-uninfected children (49/133 vs. 156/281; odds ratio 0.50, 95% confidence interval 0.32–0.78). Alveolar opacification (84/126 vs. 128/274; OR 1.85, 95%CI 1.08–3.19) and cavitation (33/126 vs. 44/274; OR 2.28, 95%CI 1.44–3.63) were more common in HIV-infected than in HIV-uninfected children. Microscopy for acid-fast bacilli on gastric aspirates and sputum was positive in 29/142 (20.4%) and 40/125 (32.0%) children, respectively. Sixty-seven of 592 (11.3%) children's isolates showed resistance to isoniazid and/or rifampicin; 43 (7.3%) were isoniazid-monoresistant, 2 (0.3%) rifampicin-monoresistant and 22 (3.7%) multidrug-resistant. Death in 41 children (6.9%) was more common in HIV-infected children and very young infants. Conclusion HIV infection and missed opportunities for chemoprophylaxis were common in children with culture-confirmed TB. With cavitating disease and sputum or gastric aspirates positive for acid-fast bacilli, children may be infectious. Transmission of drug-resistant TB is high in this setting.

Objectives To investigate the impact of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV. Design Two centre prospective double blind placebo controlled trial. Participants Children aged ≥8 weeks with HIV. Interventions Isoniazid or placebo given with co-trimoxazole either daily or three times a week. Setting Two tertiary healthcare centres in South Africa. Main outcome measures Mortality, incidence of tuberculosis, and adverse events. Results Data on 263 children (median age 24.7 months) were available when the data safety monitoring board recommended discontinuing the placebo arm; 132 (50%) were taking isoniazid. Median follow-up was 5.7 (interquartile range 2.0-9.7) months. Mortality was lower in the isoniazid group than in the placebo group (11 (8%) v 21 (16%), hazard ratio 0.46, 95% confidence interval 0.22 to 0.95, P=0.015) by intention to treat analysis. The benefit applied across Centers for Disease Control clinical categories and in all ages. The reduction in mortality was similar in children on three times a week or daily isoniazid. The incidence of tuberculosis was lower in the isoniazid group (5 cases, 3.8%) than in the placebo group (13 cases, 9.9%) (hazard ratio 0.28, 0.10 to 0.78, P=0.005). All cases of tuberculosis confirmed by culture were in children in the placebo group. Conclusions Prophylaxis with isoniazid has an early survival benefit and reduces incidence of tuberculosis in children with HIV. Prophylaxis may offer an effective public health intervention to reduce mortality in such children in settings with a high prevalence of tuberculosis. Trial registration. Clinical Trials NCT00330304

BACKGROUND. Tuberculosis control programs place an almost exclusive emphasis on adults with sputum smear-positive tuberculosis, because they are most infectious. However, children contribute a significant proportion of the global tuberculosis caseload and experience considerable tuberculosis-related morbidity and mortality, but few children in endemic areas have access to antituberculosis treatment. The diagnostic difficulty experienced in endemic areas with limited resources has been identified as a major factor contributing to poor treatment access. In general, there is a sense of scepticism regarding the potential value of symptom-based diagnostic approaches, because current clinical diagnostic approaches are often poorly validated. The natural history of childhood tuberculosis demonstrates that symptoms may offer good diagnostic value if they are well defined and if appropriate risk stratification is applied. This study aimed to determine the value of well-defined symptoms to diagnose childhood pulmonary tuberculosis in a tuberculosis-endemic area. METHODS. A prospective, community-based study was conducted in Cape Town, South Africa. Specific well-defined symptoms were documented in all children 2 weeks' duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as “bacteriologically confirmed tuberculosis,” “radiologically certain tuberculosis,” “probable tuberculosis,” or “not tuberculosis.” Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of ≥10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion. RESULTS. In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of >2 weeks' duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (≥3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group ( DISCUSSION. The combined presence of 3 well-defined symptoms at presentation (persistent, nonremitting cough of >2 weeks' duration; objective weight loss [documented failure to thrive] during the preceding 3 months; and reported fatigue) provided good diagnostic accuracy in HIV-uninfected children ≥3 years of age, with clinical follow-up providing additional value. The approach performed less well in children CONCLUSIONS. Pulmonary tuberculosis can be diagnosed with a reasonable degree of accuracy in HIV-uninfected children using a simple symptom-based approach. This offers the exciting prospect of improving treatment access for children, particularly in resource-limited settings where current access to antituberculosis treatment is poor.

AIM: Continued surveillance of drug resistance amongst children presenting with culture-confirmed tuberculosis to a tertiary care hospital and to community clinics. METHODS: Drug susceptibility testing for isoniazid and rifampicin was prospectively done on all children presenting with culture-confirmed tuberculosis from three study populations: children diagnosed at Tygerberg Children's Hospital in the Western Cape Province, South Africa, between March 2003 and February 2005 (recent survey, hospital-based group), and August 1994 and April 1998 (previous hospital-based survey), and a community-based group from five clinics during the recent survey. RESULTS: Isoniazid resistance increased significantly from 6.9% (21/306 children) in the previous survey to 12.8% (40/313 children) in the recent survey (odds ratio (OR) 1.99, 95% confidence interval (CI) 1.11-3.59). Resistance to isoniazid and rifampicin (multidrug resistance) did not increase significantly between the surveys (7/306 in previous survey vs 17/313 in recent survey; OR 2.45, 95% CI 0.94-6.62). All resistance (isoniazid and/or rifampicin) was 18/127 (14.2%) in the community-based group compared to 23/192 (12.0%) in the hospital-based group (OR 0.82, 95% CI 0.41-1.68). CONCLUSION: The prevalence of drug-resistant tuberculosis in this setting is increasing, reflecting ongoing transmission of drug-resistant Mycobacterium tuberculosis.

Cervical lymphadenitis is the most common form of extrapulmonary tuberculosis in children although its relative contribution as a cause of persistent cervical adenopathy is not well-documented. The aim of this study was to determine the relative contribution of tuberculous lymphadenitis as a cause of persistent cervical adenopathy in a tuberculosis-endemic setting and to document its clinical presentation at the primary health care level. A prospective descriptive study was conducted from February 2003 through October 200 at 5 primary health care clinics in Cape Town South Africa. The study included all children younger than 13 years presenting with persistent cervical adenopathy to the local primary health care clinic. A total of 158 children were evaluated of whom 35 (22.2%) were diagnosed with tuberculous lymphadenitis. Bacteriologic confirmation was achieved in 27 of 35 (77.1%) children; all 35 responded to standard antituberculosis treatment. The majority of those without tuberculous lymphadenitis (105 of 123 85.4%) had a visible superficial lesion in the area drained by the affected nodes. In children with persistent lymphadenopathy = 2 x 2 cm tuberculosis lymphadenitis was diagnosed in 31 of 33 (93.9%); specificity was 98.4% sensitivity was 88.6% and the positive predictive value was 93.4%. Children commonly present with persistent cervical adenopathy to the primary health care clinic. The use of a simple clinical algorithm provided an accurate diagnosis of tuberculous lymphadenitis in the study setting. Fine needle aspirations provided a rapid and definitive diagnosis in the majority of children and will have added diagnostic value in settings where alternative diagnoses are more likely. (authors)

The Western Cape has a high incidence of tuberculosis (TB) and a rising prevalence of HIV infection. Children form 15-20% of this TB burden.To document the clinical features and outcome of TB among children admitted to a regional TB hospital.A retrospective, descriptive study was undertaken of children under 15 years of age admitted to Brooklyn Hospital for Chest Diseases from January 2000 to December 2001. Demographic and clinical details of children were recorded routinely in a register that formed the basis of this review.Two hundred and thirty-eight of the 250 children admitted had TB, of whom 120 (50.4%) were boys. The median age was 25 months. Reasons for admission were disease severity in 99 cases, social reasons in 36, and a combination in 103. Adult source cases were identified in 138 instances; 9 had drug-resistant TB, 31 drug-susceptible TB and in 98 cases susceptibility was unknown. TB was confirmed by culture in 119 children. Of 79 in whom susceptibility testing was done, 10 had isoniazid-resistant TB and 8 multidrug-resistant TB. HIV serology was positive in 43 of 138 children tested (31%). Previous antituberculosis treatment, severe malnutrition and weight under the 3rd percentile for age, a negative Mantoux test, and mortality were significantly more common in the HIV-infected children. Twenty-two of 41 previously negative Mantoux tests (5 mm induration) were positive on retesting.HIV infection is common in children with TB and malnutrition, and mortality in this group is high. Repeat Mantoux tests may show an increased number of positive results.

Recurrent tuberculosis (TB) is more common among human immunodeficiency virus (HIV)-infected than HIV uninfected adults. There are limited data regarding recurrence of TB in children. The objective was to determine the occurrence of recurrent TB in HIV infected children with culture-confirmed tuberculosis. HIV-infected children with culture-confirmed TB identified from 1992 to 2000 were followed until February 2004 for further confirmed TB episodes 6 months or more after completion of previous antituberculosis therapy. Clinical data and results of special investigations were recorded. Restriction fragment length polymorphism (RFLP) analysis of Mycobacterium tuberculosis isolates was done when possible. Of 87 children 9 had a second episode; 2 of these had a third episode of confirmed TB. Adherence to treatment was good in 8; 2 experienced hepatotoxicity and regimens were changed. Chest radiographs were normal in only 2 children after first treatment completion. Bacteriologic cure was documented in 7 episodes before recurrence. RFLP analysis showed 3 children infected with the same strain (relapse) and 1 child with a different strain between episodes 1 and 3 (reinfection). Two further cases had reinfection based on epidemiologic data and drug susceptibility test results. Full comparison of strains by RFLP was not possible because of the unavailability of isolates of the first episode in 5 cases. Recurrent TB in HIV-infected children is common in a high burden TB setting. Both relapse and reinfection occur. (authors)

The impact of HIV infection on clinical presentation and outcome of tuberculosis (TB) was studied in children hospitalised at the Brooklyn Hospital for Chest Diseases (BCH), Cape Town over the 2-year period January 1998 to December 1999. Clinical data were extracted from a prospectively compiled patient register. Of 261 children with TB, 114 (median age 24 mths) were not HIV-infected and 36 (median age 23 mths) were HIV-infected. The HIV status of 111 children (median age 37 mths) was not determined. Pulmonary TB with or without extrapulmonary TB occurred in 97 (85%) children who were not HIV-infected, 35 (97%) HIV-infected children and 87 (78%) of those not tested (p = 0.025). A tuberculin reactionor = 15 mm was elicited in ten (31%) of 32 HIV-infected children, 76 (72%) of 106 non-HIV-infected and 62 (71%) of those not tested (p0.001). Mycobacterium tuberculosis was cultured from 116 (49%) of 238 children and drug sensitivity was evaluated in 79. Nine isolates (11%) were resistant to isoniazid (INH) and 11 (14%) to INH and rifampicin (RMP). Two HIV-infected children treated previously in BCH for drug-sensitive TB were re-admitted with INH and RMP resistance. Two (2%) non-HIV-infected children, six (17%) HIV-infected children and one (1%) child with undetermined HIV status died (p0.001).