Tuberculosis Disease Spectrum Research Articles

Downregulation of monocyte miRNAs: implications for immune dysfunction and disease severity in drug-resistant tuberculosis.

Monocyte miRNAs govern both protective and pathological responses during tuberculosis (TB) through their differential expression and emerged as potent targets for biomarker discovery and host-directed therapeutics. Thus, this study examined the miRNA profile of sorted monocytes across the TB disease spectrum [drug-resistant TB (DR-TB), drug-sensitive TB (DS-TB), and latent TB] and in healthy individuals (HC) to understand the underlying pathophysiology and their regulatory mechanism. We sorted total monocytes including three subsets (HLA-DR+CD14+, HLA-DR+CD14+CD16+, and HLA-DR+CD16+cells) from peripheral blood mononuclear cells (PBMCs) of healthy and TB-infected individuals through flow cytometry and subjected them to NanoString-based miRNA profiling. The outcome was the differential expression of 107 miRNAs particularly the downregulation of miRNAs in the active TB groups (both drug-resistant and drug-sensitive). The miRNA profile revealed differential expression signatures: i) decline of miR-548m in DR-TB alone, ii) decline of miR-486-3p in active TB but significant elevation only in LTB iii) elevation of miR-132-3p only in active TB (DR-TB and DS-TB) and iv) elevation of miR-150-5p in DR-TB alone. The directionality of functions mediated by monocyte miRNAs from Gene Set Enrichment Analysis (GSEA) facilitated two phenomenal findings: i) a bidirectional response between active disease (activation profile in DR-TB and DS-TB compared to LTB and HC) and latent infection (suppression profile in LTB vs HC) and ii) hyper immune activation in the DR-TB group compared to DS-TB. Thus, monocyte miRNA signatures provide pathological clues for altered monocyte function, drug resistance, and disease severity. Further studies on monocyte miRNAs may shed light on the immune regulatory mechanism for tuberculosis.

The natural history of untreated pulmonary tuberculosis in adults: a systematic review and meta-analysis.

Stages of tuberculosis disease can be delineated by radiology, microbiology, and symptoms, but transitions between these stages remain unclear. In a systematic review and meta-analysis of studies of individuals with untreated tuberculosis who underwent follow-up (34 cohorts from 24 studies, with a combined sample of 139 063), we aimed to quantify progression and regression across the tuberculosis disease spectrum by extracting summary estimates to align with disease transitions in a conceptual framework of the natural history of tuberculosis. Progression from microbiologically negative to positive disease (based on smear or culture tests) in participants with baseline radiographic evidence of tuberculosis occurred at an annualised rate of 10% (95% CI 6·2-13·3) in those with chest x-rays suggestive of active tuberculosis, and at a rate of 1% (0·3-1·8) in those with chest x-ray changes suggestive of inactive tuberculosis. Reversion from microbiologically positive to undetectable disease in prospective cohorts occurred at an annualised rate of 12% (6·8-18·0). A better understanding of the natural history of pulmonary tuberculosis, including the risk of progression in relation to radiological findings, could improve estimates of the global disease burden and inform the development of clinical guidelines and policies for treatment and prevention.

Quantifying progression and regression across the spectrum of pulmonary tuberculosis: a data synthesis study

Prevalence surveys show a substantial burden of subclinical (asymptomatic but infectious) tuberculosis, from which individuals can progress, regress, or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of tuberculosis disease. We created a deterministic framework of untreated tuberculosis disease with progression and regression between three states of pulmonary tuberculosis disease: minimal (non-infectious), subclinical (asymptomatic but infectious), and clinical (symptomatic and infectious). We obtained data from a previous systematic review of prospective and retrospective studies that followed and recorded the disease state of individuals with tuberculosis in a cohort without treatment. These data were considered in a Bayesian framework, enabling quantitative estimation of tuberculosis disease pathways with rates of transition between states and 95% uncertainty intervals (UIs). We included 22 studies with data from 5942 individuals in our analysis. Our model showed that after 5 years, 40% (95% UI 31·3-48·0) of individuals with prevalent subclinical disease at baseline recover and 18% (13·3-24·0) die from tuberculosis, with 14% (9·9-19·2) still having infectious disease, and the remainder with minimal disease at risk of re-progression. Over 5 years, 50% (40·0-59·1) of individuals with subclinical disease at baseline never develop symptoms. For those with clinical disease at baseline, 46% (38·3-52·2) die and 20% (15·2-25·8) recover from tuberculosis, with the remainder being in or transitioning between the three disease states after 5 years. We estimated the 10-year mortality of people with untreated prevalent infectious tuberculosis to be 37% (30·5-45·4). For people with subclinical tuberculosis, classic clinical disease is neither an inevitable nor an irreversible outcome. As such, reliance on symptom-based screening means a large proportion of people with infectious disease might never be detected. TB Modelling and Analysis Consortium and European Research Council.

Host blood-based biosignatures for subclinical TB and incipient TB: A prospective study of adult TB household contacts in Southern India.

A large proportion of the global tuberculosis (TB) burden is asymptomatic and not detectable by symptom-based screening, driving the TB epidemic through continued M. tuberculosis transmission. Currently, no validated tools exist to diagnose incipient and subclinical TB. Nested within a large prospective study in household contacts of pulmonary TB cases in Southern India, we assessed 35 incipient TB and 12 subclinical TB cases, along with corresponding household active TB cases (n=11), and household controls (n=39) using high throughput methods for transcriptional and protein profiling. We split the data into training and test sets and applied a support vector machine classifier followed by a Lasso regression model to identify signatures. The Lasso regression model identified an 11-gene signature (ABLIM2, C20orf197, CTC-543D15.3, CTD-2503O16.3, HLADRB3, METRNL, RAB11B-AS1, RP4-614C10.2, RNA5SP345, RSU1P1, and UACA) that distinguished subclinical TB from incipient TB with a very good discriminatory power by AUCs in both training and test sets. Further, we identified an 8-protein signature comprising b-FGF, IFNγ, IL1RA, IL7, IL12p70, IL13, PDGF-BB, and VEGF that differentiated subclinical TB from incipient TB with good and moderate discriminatory power by AUCs in the training and test sets, respectively. The identified 11-gene signature discriminated well between the distinct stages of the TB disease spectrum, with very good discriminatory power, suggesting it could be useful for predicting TB progression in household contacts. However, the high discriminatory power could partly be due to over-fitting, and validation in other studies is warranted to confirm the potential of the immune biosignatures for identifying subclinical TB.

Feasibility of novel approaches to detect viable Mycobacterium tuberculosis within the spectrum of the tuberculosis disease.

Tuberculosis (TB) is a global disease caused by Mycobacterium tuberculosis (Mtb) and is manifested as a continuum spectrum of infectious states. Both, the most common and clinically asymptomatic latent tuberculosis infection (LTBI), and the symptomatic disease, active tuberculosis (TB), are at opposite ends of the spectrum. Such binary classification is insufficient to describe the existing clinical heterogeneity, which includes incipient and subclinical TB. The absence of clinically TB-related symptoms and the extremely low bacterial burden are features shared by LTBI, incipient and subclinical TB states. In addition, diagnosis relies on cytokine release after antigenic T cell stimulation, yet several studies have shown that a high proportion of individuals with immunoreactivity never developed disease, suggesting that they were no longer infected. LTBI is estimated to affect to approximately one fourth of the human population and, according to WHO data, reactivation of LTBI is the main responsible of TB cases in developed countries. Assuming the drawbacks associated to the current diagnostic tests at this part of the disease spectrum, properly assessing individuals at real risk of developing TB is a major need. Further, it would help to efficiently design preventive treatment. This quest would be achievable if information about bacterial viability during human silent Mtb infection could be determined. Here, we have evaluated the feasibility of new approaches to detect viable bacilli across the full spectrum of TB disease. We focused on methods that specifically can measure host-independent parameters relying on the viability of Mtb either by its direct or indirect detection.

Differential Frequencies of Intermediate Monocyte Subsets Among Individuals Infected With Drug-Sensitive or Drug-Resistant Mycobacterium tuberculosis.

The rampant increase in drug-resistant tuberculosis (TB) remains a major challenge not only for treatment management but also for diagnosis, as well as drug design and development. Drug-resistant mycobacteria affect the quality of life owing to the delayed diagnosis and require prolonged treatment with multiple and toxic drugs. The phenotypic modulations defining the immune status of an individual during tuberculosis are well established. The present study aims to explore the phenotypic changes of monocytes & dendritic cells (DC) as well as their subsets across the TB disease spectrum, from latency to drug-sensitive TB (DS-TB) and drug-resistant TB (DR-TB) using traditional immunophenotypic analysis and by uniform manifold approximation and projection (UMAP) analysis. Our results demonstrate changes in frequencies of monocytes (classical, CD14++CD16-, intermediate, CD14++CD16+ and non-classical, CD14+/-CD16++) and dendritic cells (DC) (HLA-DR+CD11c+ myeloid DCs, cross-presenting HLA-DR+CD14-CD141+ myeloid DCs and HLA-DR+CD14-CD16-CD11c-CD123+ plasmacytoid DCs) together with elevated Monocyte to Lymphocyte ratios (MLR)/Neutrophil to Lymphocyte ratios (NLR) and alteration of cytokine levels between DS-TB and DR-TB groups. UMAP analysis revealed significant differential expression of CD14+, CD16+, CD86+ and CD64+ on monocytes and CD123+ on DCs by the DR-TB group. Thus, our study reveals differential monocyte and DC subset frequencies among the various TB disease groups towards modulating the immune responses and will be helpful to understand the pathogenicity driven by Mycobacterium tuberculosis.

Alteration of Endocrine Hormones and Antibody Responses in Different Spectrum of Tuberculosis Disease.

Effective control of Mycobacterium tuberculosis (Mtb) infection is mediated by multifaceted factors that involve both the endocrine and immune system. Profiling hormones and antibodies in different stages of TB provides insight in the pathogenesis of the disease. In this study, we profiled endocrine hormones (dehydroepiandrosterone (DHEA), cortisol, testosterone, estradiol, growth hormone and leptins) and Mtb strain H37RV lipoarabinomannan (LAM)-specific antibody levels in plasma samples, collected from pulmonary TB (PTB) patients, TB lymphadenitis (TBLN) patients and latently infected (QFT-positive) or uninfected (QFT-negative) apparently healthy individuals using ELISA. Plasma levels of leptin and DHEA were significantly low in PTB and TBLN patients compared to healthy controls (P<0.0001 and P=0.02, respectively), whereas these levels significantly increased following anti-TB treatment (P=0.002 and P=0.0001, respectively) among TB patients. The levels of estradiol and testosterone significantly improved following anti-TB treatment (P=0.03 and P=0.0003, respectively), whereas cortisol and growth hormones declined significantly (P <0.05). Similarly, LAM-specific IgG, IgM and IgA were significantly higher in PTB patients compared to other groups, whereas levels of IgG1 subtype were significantly higher among LTBI groups compared to both TB patients and QFT-negative individuals (P<0.0001). Overall, we observed significantly variable levels of endocrine hormones as well as immunoglobulins across the spectrum of TB illness and such profiling has a significant contribution in selection of effective biomarkers that have roles in TB treatment monitoring or diagnostics. Although this study did not show a functional association between hormones and antibodies, alterations in the levels of these biomarkers suggest the key roles these markers play in TB pathogenesis.

The definition of tuberculosis infection based on the spectrum of tuberculosis disease.

Latent tuberculosis infection was the term traditionally used to indicate tuberculosis (TB) infection. This term was used to define “a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens through tests such as the tuberculin skin test (TST) or an interferon-γ release assay (IGRA) without clinically active TB”. Recent evidence indicates that the spectrum from TB infection to TB disease is much more complex, including a “continuum” of situations didactically reported as uninfected individual, TB infection, incipient TB, subclinical TB without signs/symptoms, subclinical TB with unrecognised signs/symptoms, and TB disease with signs/symptoms. Recent evidence suggests that subclinical TB is responsible for important M. tuberculosis transmission. This review describes the different stages described above and their relationships. It also summarises the new developments in prevention, diagnosis and treatment of TB infection as well as their public health and policy implications.Educational aimsTo describe the evolution of the definition of “tuberculosis infection” and didactically describe the continuum of stages existing between TB infection and disease.To discuss the recommended approaches to prevent, diagnose and treat TB infection.

The monocyte-to-lymphocyte ratio: Sex-specific differences in the tuberculosis disease spectrum, diagnostic indices and defining normal ranges.

BackgroundThe monocyte-to-lymphocyte ratio (MLR) has been advocated as a biomarker in tuberculosis. Our objective was to evaluate its clinical value and associations.MethodsBlood counts, inflammatory markers and clinical parameters were measured in patients with and those screened for tuberculosis. Complete blood counts (CBCs) from a multi-ethnic population aged 16 to 65 years were evaluated; a sub-group with normal hematological indices was used to define the range of MLRs.ResultsMultivariate analysis in proven tuberculosis (n = 264) indicated MLR associated with low serum albumin, high white cell counts and a positive culture; values were higher in sputum smear-positive pulmonary tuberculosis (S+PTB). Analysis in S+PTB (n = 296) showed higher MLRs in males and those with high neutrophil counts, low serum albumin and high C-reactive protein. The diagnostic value of MLRs was assessed by comparing notified patients with TB (n = 264) with denotified cases (n = 50), active case-finding in non-contacts (TB n = 111 and LTBI n = 373) and contacts of S+PTB (n = 149) with S+PTB found at screening (n = 75). Sensitivities and specificities ranged from 58.0–62.5% and 50.0–70.0% respectively for optimal cut-off values, defined by ROC curves. In CBCs obtained over one month, ratios correlated with neutrophil counts (ρ = 0.48, P<0.00001, n = 14,573; MLR = 0.45 at 8–8.9 x 109/L) and were higher in males than females (P<0.0001). The MLR range (mean ± 2SD) in those with normal hematological indices (n = 3921: females 0.122–0.474; males 0.136–0.505) paralleled LTBI MLRs. Ratios did not predict death (n = 29) nor response to treatment (n = 178 S+PTB with follow-up CBCs). Ratios were higher in males than female in the 16–45 years age group, where immune differences due to sex hormones are likely greatest.ConclusionsSevere tuberculosis and male sex associated with high MLRs; the same variables likely affect the performance of other biomarkers. The ratio performed poorly as a clinical aid.

The Spectrum of Tuberculosis Disease in an Urban Ugandan Community and Its Health Facilities.

New, sensitive diagnostic tests facilitate identification and investigation of milder forms of tuberculosis (TB) disease. We used community-based TB testing with the Xpert MTB/RIF Ultra assay ("Ultra") to characterize individuals with previously undiagnosed TB and compare them to those from the same community who were diagnosed with TB through routine care. We offered community-based sputum Ultra testing to adult residents of a well-defined area (population 34 000 adults) in Kampala, Uganda, via door-to-door screening and venue-based testing, then used detailed interview and laboratory testing to characterize TB-positive individuals. We compared these individuals to residents diagnosed with pulmonary TB at local health facilities and a representative sample of residents without TB (controls). Of 12 032 residents with interpretable Ultra results, 113 (940 [95% confidence interval {CI}, 780-1130] per 100 000) tested positive, including 71 (63%) positive at the lowest (trace) level. A spectrum of TB disease was observed in terms of chronic cough (93% among health facility-diagnosed cases, 77% among residents with positive community-based Ultra results at levels above trace, 33% among trace-positive community participants, and 18% among TB-negative controls), TB symptom prevalence (99%, 87%, 60%, and 38%, respectively), and C-reactive protein (75th percentile: 101 mg/L, 28 mg/L, 6 mg/L, and 4 mg/L, respectively). Community-diagnosed cases were less likely than health facility-diagnosed cases to have human immunodeficiency virus coinfection or previous TB. The specificity of Ultra was 99.4% (95% CI, 99.2%-99.5%) relative to a single spot sputum culture. People with undiagnosed prevalent TB in the community have different characteristics than those diagnosed with pulmonary TB in health facilities. Newer diagnostic tests may identify a group of people with early or very mild disease.

Metformin and Rifampicin combination augments active to latent tuberculosis conversion: A computational study

Tuberculosis, a global threat, is a highly infectious disease intensified by the emergence of drug-resistant strains. In tuberculosis disease spectrum, a typical situation is a dormant or latent phase where a person exposed to Mycobacterium tuberculosis has the reservoir of the disease that may or may not result in an active state. Existence of the dormant state is retarding the eradication of tuberculosis. Transcription of several genes helps M. tuberculosis to survive in nonreplicative mode. DosR transcription factor is the hallmark for this genesis. Diabetes mellitus is a predisposition factor leading to the development of tuberculosis and latent tuberculosis. High plasma insulin concentrations in the prediabetic state can increase the tuberculosis bacterium. On the other hand, antidiabetic drug metformin is known to reduce active tuberculosis disease when provided in combination with antitubercular therapy. However, the effect of the same on latent tuberculosis is still unknown. In the present work using tools of computational biology, we have tried to find the consequence of adding metformin in combination with rifampicin, a well-known antitubercular drug, on molecular mechanisms of latent tuberculosis. We have investigated whether metformin and rifampicin interact with DosR machinery or not. Our results indicate that if metformin-bound DosR-DNA complex binds with rifampicin, it will result in the conversion of active tuberculosis to latent tuberculosis.

Burden, spectrum and outcomes of children with tuberculosis diagnosed at a district-level hospital in South Africa.

The Khayelitsha subdistrict has the highest burden of reported tuberculosis (TB) cases in Cape Town, Western Cape Province, South Africa. To characterise the TB burden, spectrum and treatment outcomes among children managed at a district-level hospital, the Khayelitsha District Hospital. Retrospective medical record review of all children (age <13 years) diagnosed with TB in January-July 2014. A lay health care worker completed daily surveillance and supported linkage to TB care. Symptoms and investigations at presentation, TB disease spectrum, referral pathways and outcomes were reported. Most children were aged 2 years (84/99, 85%), 18/96 (19%) were infected with the human immunodeficiency virus, 31/91 (34%) were malnourished and 80/99 (81%) had pulmonary TB only. The majority of the children (63/80, 79%) presented with cough of acute onset (<2 weeks). Only 5/36 (14%) eligible child contacts had documentation of receiving isoniazid preventive therapy. Twelve (13%) children had bacteriologically confirmed pulmonary TB. Overall, 93/97 (96%) children successfully continued TB care after hospital discharge. Favourable TB treatment outcomes were recorded in only 77 (78%) children. Children with TB managed at this district-level hospital were young, and frequently had acute symptoms and substantial comorbidities. Missed opportunities for TB prevention were identified. Linkage to care support resulted in excellent continuation of TB care; however, treatment outcomes could be further improved.

Approaching a diagnostic point-of-care test for pediatric tuberculosis through evaluation of immune biomarkers across the clinical disease spectrum.

The World Health Organization (WHO) calls for an accurate, rapid, and simple point-of-care (POC) test for the diagnosis of pediatric tuberculosis (TB) in order to make progress “Towards Zero Deaths”. Whereas the sensitivity of a POC test based on detection of Mycobacterium tuberculosis (MTB) is likely to have poor sensitivity (70–80% of children have culture-negative disease), host biomarkers reflecting the on-going pathological processes across the spectrum of MTB infection and disease may hold greater promise for this purpose. We analyzed transcriptional immune biomarkers direct ex-vivo and translational biomarkers in MTB-antigen stimulated whole blood in 88 Indian children with intra-thoracic TB aged 6 months to 15 years, and 39 asymptomatic siblings. We identified 12 biomarkers consistently associated with either clinical groups “upstream” towards culture-positive TB on the TB disease spectrum (CD14, FCGR1A, FPR1, MMP9, RAB24, SEC14L1, and TIMP2) or “downstream” towards a decreased likelihood of TB disease (BLR1, CD3E, CD8A, IL7R, and TGFBR2), suggesting a correlation with MTB-related pathology and high relevance to a future POC test for pediatric TB. A biomarker signature consisting of BPI, CD3E, CD14, FPR1, IL4, TGFBR2, TIMP2 and TNFRSF1B separated children with TB from asymptomatic siblings (AUC of 88%).

Severe manifestations of extrapulmonary tuberculosis in HIV-infected children initiating antiretroviral therapy before 2 years of age

BackgroundEarly initiation of antiretroviral therapy (ART) in HIV-infected infants reduces mortality and opportunistic infections including tuberculosis (TB). However, young HIV-infected children remain at high risk of TB disease following mycobacterial...

The presence of LAG-3 in nonhuman primates undergoing an active Mycobacterium tuberculosis infection (HEM4P.252)

Abstract Th1 T cells are essential in the immune response against Mycobacterium tuberculosis (Mtb) infections. Lymphocyte activation gene-3 (LAG-3) regulates this response through the diminishment of effector T cells and the impairment of monocyte differentiation. We hypothesize that LAG-3 up-regulation within Mtb infected nonhuman primates (NHPs) will suppress the Th1 portion of the host immune response resulting in conditions that favor the pathogen and create active tuberculosis (TB) within the host. Here we are studying LAG-3 expression in rhesus macaques infected with aerosolized Mtb. We have chosen the macaque model due to their similarities to humans in the spectrum of TB disease, as well as the architecture of Mtb induced lung granulomas. Previous studies have implied that LAG-3 may have a role in the activation of Mtb infections. There is increasing evidence that up-regulation of LAG-3 occurs in the lungs of animals experiencing TB activation. Further investigation of the lung tissue of these infected animals with fluorescent immunohistochemistry visualized with confocal microscopy has illustrated LAG-3 to be largely present within the outer periphery of the lung. Cells expressing LAG-3 have shown to include T cells and NK cells, with large numbers of these cells appearing in close vicinity to certain populations of antigen presenting cells. These results show that in animals undergoing TB activation, LAG-3 has potential to play an immunomodulatory role in this process.

A Proposed Comprehensive Classification of Tuberculosis Disease Severity in Children

Tuberculosis (TB) in children has conventionally been classified as pulmonary TB (PTB) and extrapulmonary TB (EPTB) disease, including disseminated TB (TB meningitis and miliary disease). There is no existing approach that comprehensively characterizes the spectrum and severity of pediatric TB. This limits accurate classification of patients and comparison across cohorts. To develop a classification of pediatric TB that reflects the spectrum and severity of clinical disease better than currently available approaches. We propose a framework for the standard classification of TB disease severity in children. From a literature search, the following sources of information were used: clinical data, bacteriologic, histopathologic, and imaging data (including information from chest radiography, computerized tomography, and bronchoscopy). Each individual disease entity was systematically considered. Based on the extent and the presence of complications, each entity was then classified as "severe" or "nonsevere." As an initial application, we compared the proposed classification with the convention (PTB, EPTB) in a cohort of HIV-infected and -uninfected infants with culture-confirmed TB. Agreement between the 2 systems was poor. The proposed comprehensive disease classification system may more accurately reflect the clinical TB disease spectrum in children, is relevant to clinical management, and may be valuable to inform research on diagnostic tools and TB treatment strategies in children. Prospective studies are required to evaluate this approach in representative pediatric populations, correlating TB disease severity with diagnostic yield, treatment response, and application in existing and novel treatment strategies.

Pulmonary immune-compartment-specific interferon gamma responses in HIV-infected individuals with active tuberculosis (TB) in an area of high TB prevalence.

There is a paucity of data on the pulmonary immune-compartment interferon gamma (IFNγ) response to M. tuberculosis, particularly in settings of high tuberculosis (TB) prevalence and in HIV-coinfected individuals. This data is necessary to understand the diagnostic potential of commercially available interferon gamma release assays (IGRAs) in both the pulmonary immune-compartment and peripheral blood. We used intracellular cytokine staining by flow cytometry to assess the IFNγ response to purified protein derivative (PPD) and early secretory antigen 6 (ESAT6) in induced sputa (ISp) and blood samples from HIV-infected, smear-negative, TB suspects. We found that individuals with active TB disease produced significantly less IFNγ in response to PPD in their induced sputa samples than individuals with non-active TB (control group). This difference was not reflected in the peripheral blood, even within the CD27− CD4+ memory T lymphocyte population. These findings suggest that progression to active TB disease may be associated with the loss of IFNγ secretion at the site of primary infection. Our findings highlight the importance of studying pulmonary immune-compartment M. tuberculosis specific responses to elucidate IFNγ secretion across the spectrum of TB disease.

Bacteriologically confirmed tuberculosis in HIV-infected infants: disease spectrum and survival

The human immunodeficiency virus (HIV) has resulted in epidemiological shifts with an emergence of tuberculosis (TB) amongst HIV-infected women and infants. There are limited data on the TB disease spectrum and outcome amongst HIV-infected infants. We describe the clinical characteristics, treatment and survival of HIV-infected infants with culture-confirmed TB. This retrospective hospital-based study from Cape Town, South Africa, used routine laboratory-based surveillance among infants diagnosed with culture-confirmed TB from 1 January 2004 to 31 December 2006. Folder and chest radiographic review were completed and vitality status established. TB was classified as pulmonary, extra-pulmonary or disseminated disease. Of 52 infants, 37 (71.1%) had pulmonary, 2 (3.9%) extra-pulmonary only, 7 (13.5%) pulmonary and extra-pulmonary and 6 (11.5%) disseminated TB. Forty-six (88.5%) were started anti-tuberculosis therapy; 37 (71.2%) received antiretroviral therapy (ART) and 17 (32.7%) died, 10 (19.2%) of whom never started ART. HIV stage 4 disease was associated with death. TB treatment outcome was poorly documented. TB is associated with advanced HIV disease and high mortality in HIV-infected infants. Missed opportunities for initiation of ART were frequent. Although the effects of young age, TB disease spectrum and HIV co-infection are difficult to distinguish, our findings support the initiation of early ART in HIV-infected infants with TB.