Late Tuberculosis Research Articles

Beneficial or detrimental activity of regulatory T cells, indoleamine 2,3-dioxygenase, and heme oxygenase-1 in the lungs is influenced by the level of virulence of Mycobacterium tuberculosis strain infection.

Tuberculosis (TB) caused by the complex Mycobacterium tuberculosis (Mtb) is the main cause of death by a single bacterial agent. Last year, TB was the second leading infectious killer after SARS-CoV-2. Nevertheless, many biological and immunological aspects of TB are not completely elucidated, such as the complex process of immunoregulation mediated by regulatory T cells (Treg cells) and the enzymes indoleamine 2,3-dioxygenase (IDO) and heme oxygenase 1 (HO-1). In this study, the contribution of these immunoregulatory factors was compared in mice infected with Mtb strains with different levels of virulence. First Balb/c mice were infected by intratracheal route, with a high dose of mild virulence reference strain H37Rv or with a highly virulent clinical isolate (strain 5186). In the lungs of infected mice, the kinetics of Treg cells during the infection were determined by cytofluorometry and the expression of IDO and HO-1 by RT-PCR and immunohistochemistry. Then, the contribution of immune-regulation mediated by Treg cells, IDO and HO-1, was evaluated by treating infected animals with specific cytotoxic monoclonal antibodies for Treg cells depletion anti-CD25 (PC61 clone) or by blocking IDO and HO-1 activity using specific inhibitors (1-methyl-D,L-tryptophan or zinc protoporphyrin-IX, respectively). Mice infected with the mild virulent strain showed a progressive increment of Treg cells, showing this highest number at the beginning of the late phase of the infection (28 days), the same trend was observed in the expression of both enzymes being macrophages the cells that showed the highest immunostaining. Animals infected with the highly virulent strain showed lower survival (34 days) and higher amounts of Treg cells, as well as higher expression of IDO and HO-1 one week before. In comparison with non-treated animals, mice infected with strain H37Rv with depletion of Treg cells or treated with the enzymes blockers during late infection showed a significant decrease of bacilli loads, higher expression of IFN-g and lower IL-4 but with a similar extension of inflammatory lung consolidation determined by automated morphometry. In contrast, the depletion of Treg cells in infected mice with the highly virulent strain 5186 produced diffuse alveolar damage that was similar to severe acute viral pneumonia, lesser survival and increase of bacillary loads, while blocking of both IDO and HO-1 produced high bacillary loads and extensive pneumonia with necrosis. Thus, it seems that Treg cells, IDO and HO-1 activities are detrimental during late pulmonary TB induced by mild virulence Mtb, probably because these factors decrease immune protection mediated by the Th1 response. In contrast, Treg cells, IDO and HO-1 are beneficial when the infection is produced by a highly virulent strain, by regulation of excessive inflammation that produced alveolar damage, pulmonary necrosis, acute respiratory insufficiency, and rapid death.

Ferritin as proinflamatory biomarker of iron metabolism in tuberculosis patients (review)

Traditional methods of tuberculosis (TB) diagnosis, including sputum microscopy and culture for Mycobacterium tuberculosis detection, are time-consuming or have unsatisfactory sensitivity. However, early diagnosis of TB with high accuracy and sensitivity is very important for disease outcomes and prevention. Therefore, there is an urgent need for new TB diagnostic methods based on TB-associated biomarkers, with rapid availability of results that do not require sputum analysis, are inexpensive, and have high sensitivity and specificity. Objective — to study the mechanisms of ferritin participation in the pathogenesis of tuberculosis basing on the literature data. Materials and methods. 242 literature sources were found in the PubMed system by the query «Ferritin AND Tuberculosis» and 40 of them were selected for further detailed study. Results and discussion. Studies have shown that serum iron and transferrin concentrations are lower and ferritin levels are higher in patients with TB compared to those without TB. These deviations in the concentration of ferritin and transferrin usually normalize after treatment. Lower transferrin levels are associated with both early and late TB progression, and higher ferritin and hepcidin levels are associated with a higher risk of early TB progression in TB contacts. In addition, the status of biomarkers of iron metabolism can be used as an indicator of treatment failure (low ferritin) and mortality (high ferritin). Finally, low levels of transferrin and serum iron, as well as high ferritin concentrations in HIV-infected patients predict an increased risk of TB disease and relapse. Conclusions. Iron metabolism between M. tuberculosis and the host organism is closely related and plays an important role in the pathogenesis of tuberculosis. Parameters of iron metabolism are promising markers of both the course and effectiveness of tuberculosis treatment. In particular, changes in the level of ferritin can be predictors of both the ineffectiveness of tuberculosis treatment and mortality from this disease, so the prognostic value of this marker requires further detailed study.

Prolonged B-Lymphocyte-Mediated Immune and Inflammatory Responses to Tuberculosis Infection in the Lungs of TB-Resistant Mice.

During tuberculosis (TB) infection, B-lymphocytes migrate to the lungs and form B-cell follicles (BCFs) in the vicinity of TB granulomata. B-cell-lacking mice display enhanced susceptibility to TB infection, and early B-cell depletion in infected non-human primates alters T-lymphocyte cytokine responses and increases bacterial burdens in the lungs. However, the role of B cells during late TB stages remained unaddressed. Here, we demonstrate that B cells and BCFs persist up to weeks 25-45 post-challenge in the lungs of TB-resistant C57BL/6 (B6) mice. In hyper-susceptible I/St mice, B-cell content markedly drops between weeks 12-16 post-infection, paralleled by diffuse lung tissue inflammation and elevated gene expression levels for pro-inflammatory cytokines IL-1, IL-11, IL-17a, and TNF-α. To check whether B-cells/BCFs control TB infection at advanced stages, we specifically depleted B-cells from B6 mice by administrating anti-CD20 mAbs at week 16 post-infection. This resulted in more rapid cachexia, a shortened lifespan of the infected animals, an increase in (i) lung-infiltrating CD8+ T cells, (ii) IL-6 production by F4/80+ macrophages, (iii) expression levels of genes for neutrophil-attracting factors CXCL1 and IL-17, and tissue-damaging factors MMP8, MMP9, and S100A8. Taken together, our results suggest that lung B cells and BCFs are moderately protective against chronic TB infection.

The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis.

The cholinergic system is present in both bacteria and mammals and regulates inflammation during bacterial respiratory infections through neuronal and non-neuronal production of acetylcholine (ACh) and its receptors. However, the presence of this system during the immunopathogenesis of pulmonary tuberculosis (TB) in vivo and in its causative agent Mycobacterium tuberculosis (Mtb) has not been studied. Therefore, we used an experimental model of progressive pulmonary TB in BALB/c mice to quantify pulmonary ACh using high-performance liquid chromatography during the course of the disease. In addition, we performed immunohistochemistry in lung tissue to determine the cellular expression of cholinergic system components, and then administered nicotinic receptor (nAChR) antagonists to validate their effect on lung bacterial burden, inflammation, and pro-inflammatory cytokines. Finally, we subjected Mtb cultures to colorimetric analysis to reveal the production of ACh and the effect of ACh and nAChR antagonists on Mtb growth. Our results show high concentrations of ACh and expression of its synthesizing enzyme choline acetyltransferase (ChAT) during early infection in lung epithelial cells and macrophages. During late progressive TB, lung ACh upregulation was even higher and coincided with ChAT and α7 nAChR subunit expression in immune cells. Moreover, the administration of nAChR antagonists increased pro-inflammatory cytokines, reduced bacillary loads and synergized with antibiotic therapy in multidrug resistant TB. Finally, in vitro studies revealed that the bacteria is capable of producing nanomolar concentrations of ACh in liquid culture. In addition, the administration of ACh and nicotinic antagonists to Mtb cultures induced or inhibited bacterial proliferation, respectively. These results suggest that Mtb possesses a cholinergic system and upregulates the lung non-neuronal cholinergic system, particularly during late progressive TB. The upregulation of the cholinergic system during infection could aid both bacterial growth and immunomodulation within the lung to favor disease progression. Furthermore, the therapeutic efficacy of modulating this system suggests that it could be a target for treating the disease.

Active tuberculosis in inflammatory bowel disease patients under treatment from an endemic area in Latin America.

BACKGROUNDThere has been an increase in cases of inflammatory bowel disease (IBD) in recent years. There is also greater access and availability of immunosuppressive and biological agents, which increase the risk of opportunistic infection despite improving the quality of life and promoting mucosal healing. Tuberculosis (TB) remains a public health problem, and it has a high incidence in several countries. Therefore, knowledge of the risk of developing TB in patients with IBD is important.AIMTo evaluate the risk of active TB in patients with IBD under treatment from an endemic area in Latin America.METHODSA standard questionnaire included demographic variables, clinical aspects of IBD disease, history of active TB during treatment, active TB characteristics and evolution, initial screening and results and time from the start of anti-tumor necrosis factor alpha (TNFα) to TB development.RESULTSAzathioprine, anti-TNFα and the combination of these two drugs were associated with a higher risk of active TB incidence. The TNFα blockers increased the relative risk of developing active TB compared to other treatments. All four multivariable models showed that the use of TNFα blockers alone or in combination with azathioprine was an important risk factor for the incidence of active TB. After adjustment for sex, age, type of IBD and latent TB, anti-TNFα with azathioprine increased the relative risk to 17.8 times more than conventional treatment. Late TB, which was diagnosed 3 mo after the start of anti-TNFα, was the most frequent.CONCLUSIONTreatment with anti-TNFα increased the risk of active TB in IBD patients from an endemic area in Latin America. This risk was increased when anti-TNFα was combined with azathioprine. The time from the beginning of the treatment to the active TB diagnosis suggests a new TB infection.

Tuberculosis contact investigation and short-course preventive therapy among young children in Africa

SETTING: The largest cities in Benin, Burkina Faso, Cameroon and Central African Republic.OBJECTIVE: To demonstrate the feasibility and document the effectiveness of household contact investigation and preventive therapy in resource-limited settings.DESIGN: Children under 5 years living at home with adults with bacteriologically confirmed pulmonary tuberculosis (TB) were screened using questionnaire, clinical examination, tuberculin skin test and chest X-ray. Children free of active TB were offered preventive treatment with a 3-month rifampicin-isoniazid (3RH) or 6-month isoniazid (6H) regimen in Benin. Children were followed-up monthly during treatment, then quarterly over 1 year. Costs of transportation, phone contacts and chest X-rays were covered.RESULTS: A total of 1965 children were enrolled, of whom 56 (2.8%) had prevalent TB at inclusion. Among the 1909 children free of TB, 1745 (91%) started preventive therapy, 1642 (94%) of whom completed treatment. Mild adverse reactions, mostly gastrointestinal, were reported in 2% of children. One case of incident TB, possibly due to a late TB infection, was reported after completing the 3RH regimen.CONCLUSION: Contact investigation and preventive therapy were successfully implemented in these resource-limited urban settings in programmatic conditions with few additional resources. The 3RH regimen is a valuable alternative to 6H for preventing TB.

GLOBAL DYNAMICS OF A MATHEMATICAL MODEL OF TUBERCULOSIS WITH AGE-DEPENDENT LATENCY AND ACTIVE INFECTION

In this paper, mathematical analysis is carried out for a mathematical model of Tuberculosis (TB) with age-dependent latency and active infection. The model divides latent TB infection into two stages: an early stage of high risk of developing active TB and a late stage of lower risk for developing active TB. Infected persons initially progress through the early latent TB stage and then can either progress to active TB infection or progress to late latent TB infection. The model is formulated by incorporating the duration that an individual has spent in the stages of the early latent TB, the late latent TB and the active TB infection as variables. By constructing suitable Lyapunov functionals and using LaSalle’s invariance principle, it is shown that the global dynamics of the disease is completely determined by the basic reproduction number: if the basic reproduction number is less than unity, the TB always dies out; if the basic reproduction number is greater than unity, a unique endemic steady state exists and is globally asymptotically stable in the interior of the feasible region and therefore the TB becomes endemic. Numerical simulations are carried out to illustrate the theoretical results.

Will we reach the Sustainable Development Goals target for tuberculosis in the European Union/European Economic Area by 2030?

We assessed progress towards the Sustainable Development Goals target for tuberculosis in the European Union/European Economic Area using the latest tuberculosis (TB) surveillance and Eurostat data. Both the TB notification rate and the number of TB deaths were decreasing before 2015 and the TB notification rate further declined between 2015 and 2017. With the current average decline in notification rate and number of TB deaths however, the EU/EEA will not reach the targets by 2030.

Immunotherapeutic effects of recombinant adenovirus encoding interleukin 12 in experimental pulmonary tuberculosis.

High dose of Mycobacterium tuberculosis (Mtb) strain H37Rv administered by intratracheal injection in BALB/c mice induce progressive tuberculosis (TB). In this model, during the first month there is a temporal control of bacillary growth, in coexistence with macrophage activation, granuloma formation and Th-1 response. Then, bacterial proliferation recommences, accompanied by progressive pneumonia and decreasing expression of protective cytokines (IFN-γ and TNF-α). In this model, we studied the IL-12 gene expression kinetics and cellular source. There is a rapid and progressive IL-12 expression peaking at day 14, when granulomas start their formation and numerous macrophages show strong IL-12 immunostaining, while during progressive TB there is a significant decrease of IL-12 expression and occasional macrophages showed IL-12 immunolabeling. In the second part of this study, we determined the immunotherapeutic effect of recombinant adenoviruses that codify IL-12 (AdIL-12). Intratracheal administration of only one dose of AdIL-12 one day before Mtb infection produced significant decrease of bacterial loads, lesser pneumonia and higher expression of TNF-α, IFN-γ and iNOS. When only one dose of AdIL-12 was given in healthy mice cohoused with infected mice with highly virulent and transmissible Mtb, total prevention of infection was conferred. Moreover, when AdIL-12 was administered by intranasal route in animals suffering late active TB after 2months of infection, a very low pulmonary bacilli burdens was detected. These experimental data confirm that IL-12 is a significant cytokine in the immune protection against Mtb, and gene therapy based in adenoviruses coding this cytokine increased protective immunity and prevent Mtb transmission.

Modelling heterogeneity in host susceptibility to tuberculosis and its effect on public health interventions.

A tuberculosis (TB) model that accounts for heterogeneity in host susceptibility to tuberculosis is proposed, with the aim of investigating the implications this may have for the effectiveness of public health interventions. The model examines the possibility that recovered individuals treated from active TB and individuals treated with preventive therapy acquire different levels of immunity. This contrasts with recent studies that assume the two cohorts acquire the same level of immunity, and therefore both groups are reinfected at the same rate. The analysis presented here examines the impact of this assumption when designing intervention strategies. Comparison of reinfection rates between cohorts treated with preventive therapy and recovered individuals who were previously treated for active TB provides important epidemiological insights. It is found that the reinfection rate of the cohort treated with preventive therapy is the one that plays the key role in qualitative changes in TB dynamics. By contrast, the reinfection rate of recovered individuals (previously treated from active TB) plays a minor role. Moreover, the study shows that preventive treatment of individuals during early latency is always beneficial regardless of the level of susceptibility to reinfection. Further, if patients have greater immunity following treatment for late latent infection, then treatment is again beneficial. However, if susceptibility increases following treatment for late latent infection, the effect of treatment depends on the epidemiological setting. That is: (i) in (very) low burden settings, the effect on reactivation predominates and the burden declines with treatment; (ii) in moderate to high burden settings the effect of reinfection predominates and burden increases with treatment. The effect is most dominant between the two reinfection thresholds, RT2 and RT1, respectively associated with individuals being treated with preventive therapy and individuals with untreated late latent TB infection.

Heterologous Boost Following Mycobacterium bovis BCG Reduces the Late Persistent, Rather Than the Early Stage of Intranasal Tuberculosis Challenge Infection

Adults are the leading population affected by tuberculosis (TB) epidemic and death. Developing an effective vaccine against adult TB is urgently needed. Mycobacterium bovis Bacillus Calmette-Guerin (BCG) prime-heterologous boost strategy has been explored extensively to protect adults against primary TB infection, but the majority of experimental regimens have not improved the protection primed by the BCG vaccine. The reason attributed to the failure remains unknown. In this study, CTT3H-based vaccines, namely DMT adjuvanted CTT3H subunit or DNA vaccine (pCTT3H-DMT), and recombinant adenovirus rAdCTT3H were constructed. Protective efficacy and immunogenicity of BCG prime-CTT3H based boosters were compared in C57BL/c mice models of primary or late persistent TB infection. Similar protective efficacy against early intranasal infection was provided by different CTT3H-based vaccines alone in vaccinated mice, and their protection was inferior to that of the BCG vaccine. In addition, CTT3H-based heterologous boosters did not enhance the protection conferred by the BCG vaccine against primary infection. However, all of these three boosters provided stronger protection against late persistent TB infection than BCG alone, regardless of vaccine types. Although BCG prime-boosters elicited Th1-biased responses to the antigen CTT3H, the number of CTT3H-sepcific IFN-γ-expressing TEM (CD62LloCD44hi) and IL-2-expressing TCM (CD62LhiCD44hi) cells in the spleen was not improved before exposure to Mycobacterium tuberculosis infection. In contrast, IFN-γ+ TEM and IL-2+ TCM cells in spleens, especially in lungs were significantly increased in BCG prime-boosters after exposure vaccination. Our results indicate that BCG prime-boost strategy might be a promising measure for the prevention against late persistent TB infection by induction of IFN-γ+ TEM and IL-2+ TCM cells in the lung, which can be used as alternative biomarkers for guiding the clinical practice and future development of TB vaccine for adults.

Dual role of hypoxia-inducible factor 1 α in experimental pulmonary tuberculosis: its implication as a new therapeutic target.

Investigate the role of hypoxia-inducible factor-1α (HIF-1α) in pulmonary tuberculosis (TB). A model of progressive pulmonary TB in BALB/c mice, immunohistochemistry and digital pathology were used. High HIF-1α expression was observed during early TB in activated macrophages. During late TB, even higher HIF-1α expression was observed in foamy macrophages, which are resistant to apoptosis. Blocking HIF-1α during early infection with 2-methoxyestradiol worsened the disease, while during late TB, it induced macrophage apoptosis and decreased bacillary loads. HIF-1α has a dual role in experimental TB. This finding could have therapeutic implications because combined treatment with 2-methoxyestradiol and antibiotics appeared to eliminate mycobacteria more efficiently than conventional chemotherapy during advanced disease.

Spinal infections: diagnosis, clinical assessment and treatment

Spinal infection is a collection of a diverse group of pathologies. Untreated the consequences are generally severe. In spondylodiscitis early diagnosis can be challenging because of the initially non-specific symptoms. Once a diagnosis has been made clinicians must chose the correct antibiotics and ensure their administration for a sufficient length of time. Late pain and disability in adults is a common and disappointing outcome though children generally do much better. Infection is a common complication of spinal surgery, often presenting late. Modifiable risk factors should be addressed preoperatively and instrumentation and bone graft should be used only when necessary. In deformity surgery an attempt should be made to retain the instrumentation in those cases which present within 2 years of index procedure. Tuberculosis (TB) is endemic in the developing world and becoming increasingly common in the Western countries. Treatment is aimed at eliminating the disease, preventing deformity and avoiding neurological compromise all of which will be aided by an early diagnosis. The surgical management of late presenting TB can challenge even the most experienced surgeons. In spinal infections identification of the organism is vitally important. Prolonged antibiotic courses should be given and surgery should be utilised judiciously to improve outcomes.

Tuberculosis Treatment Outcomes of Patients Co-Infected With Tuberculosis And HIV At Jaramogi Oginga Odinga Teaching And Referral Hospital (JOOTRH), Kenya.

Background:Human Immunodeficiency Virus (HIV) infection and Tuberculosis (TB) increase the rate of disease progression of each other, thereby reducing the survival time of the patients. TB disease is considered a preventable, detectable and curable disease that requires wider public- private partnerships. Causes of mortality include late TB and/or HIV diagnosis, late HAART initiation, overlapping drug toxicities or comorbidities, drug-drug interactions between rifamycin and antiretroviral drugs, and immune reconstitution syndrome of TB after ART initiation etc. The Kenya National TB cohort analysis showed poorer treatment outcomes to be higher among patients with unknown or undocumented HIV status followed by HIV positive TB patients. Nyanza province contributes TB(20%) and HIV (30%) burden of the national burden, with coinfection rate of 70% of TB patients against 53% national rate. Early diagnosis, treatment initiation and monitoring leads to improved survival. Methods: This was a retrospective study aimed at evaluating socio-demographic characteristics of 350 TB/HIV co-infected patients (adults and children) enrolled in JOOTRH and documented treatment outcomes, risk factors associated with mortality and lost to follow up between January 2012 and July 3013 who were followed up 8 months after completion of treatment. Conclusion:Early ART initiation in the intensive phase of TB treatment, use of Cotrimoxazole, being WHO stage I & II and CD4> 350cells/mm 3 were associated with reduced deaths or loss to follow up while being male gender, initiating or delaying treatment after 2 months of TB treatment, WHO stage III and IV and CD4 < 350cells/mm 3 were significantly associated with high mortality.

The contribution of the sympathetic nervous system to the immunopathology of experimental pulmonary tuberculosis

The role of norepinephrine (NE) in the immunopathology of experimental tuberculosis (TB) was studied by measuring pulmonary NE and determining its cellular sources and targets. Functional studies were performed administrating adrenergic and anti-adrenergic drugs at different TB phases. Results showed high production of NE during early infection by adrenergic nerve terminals and lymphocytes located in the lungs and mediastinal lymph nodes, these cells highly expressed β2 adreno-receptors (β2AR) which by an autocrine mechanism promote Th-1 cell differentiation favoring protection. During advanced infection, the production of NE and β2AR sharply decreased, suggesting that adrenergic activity is less important during late TB.

High Rates of Tuberculosis in Patients Accessing HAART in Rural South Africa

The challenge of early tuberculosis (TB) infection among rural patients accessing highly active antiretroviral therapy (HAART) in a resource-limited setting with high HIV and TB burden has not been fully quantified. This is a retrospective study nested within a prospective study of 969 patients consecutively initiated onto HAART at the CAPRISA AIDS Treatment programme in rural KwaZulu-Natal between January 2007 and December 2010. Patients were screened for clinical symptoms consistent with TB using a standardized checklist, and routine clinical investigations that included sputum microscopy and chest x-ray diagnosis. Of 969 HIV-infected patients initiated on HAART, 173 [17.9%; 95% confidence interval (CI): 15.5 to 20.4] had active TB at HAART initiation. TB incidence rates were 3-fold higher in the first 3 months (early incident TB) after HAART initiation [11.5/100 person-years (py); 95% CI: 7.1 to 17.5] compared with 4-24 months (late incident TB) post-HAART initiation (3.2/100 py; 95% CI: 2.2 to 4.5; incidence rate ratio: 3.6; 95% CI: 2.0 to 6.4; P < 0.001). Immune status of patients at HAART initiation did not impact TB incidence rates in patients with CD4 counts of <50 (5.3/100) and >200 (4.9/100 py; P = 0.81) cells per cubic millimeter. CD4 count gains achieved 12 months post-HAART initiation were significantly different in patients with early incident TB versus late incident TB; P = 0.03. Rural HIV treatment programmes in TB-endemic settings experience high rates of TB irrespective of immunologic status of patients at HAART initiation, or duration on HAART.

Incidence and risk factors for tuberculosis in HIV-infected patients while on antiretroviral treatment in Cambodia

Given the lack of detailed studies on tuberculosis (TB) in patients on antiretroviral treatment (ART) in South-East Asia, we aimed to determine the incidence and risk factors for early (after ≤6 months of ART) and late (after >6 months of ART) incident TB in Cambodia. We conducted a retrospective analysis of all patients started on ART at a non-governmental hospital in Phnom Penh (March 2003-December 2010). TB diagnosis was performed according to WHO algorithms. Risk factor analysis was performed using multivariate Cox regression modeling. Overall, 2984 patients started ART. The median baseline CD4 count was 89 cells µl(-1) (IQR 25-209), median age 34 years (IQR 29-40). Fifty-three percent of the patients were female. Median follow-up time on ART was 2.4 years. In addition to 932 (31.2%) patients already on TB treatment at ART initiation, 313 (10.5%) developed TB, with an overall incidence rate of 3.9/100 patient-years. Of those developing TB, 179 (6.0%) patients were diagnosed with early TB and 134 (4.5%) with late TB, corresponding with a rate of 13.5 and 2.0 per 100 patient-years respectively. Risk factors for early TB included low body mass index, low baseline CD4 count and low hemoglobin levels. Low on-treatment CD4 counts and hemoglobin levels, being underweight while on ART and prevalent TB were identified as risk factors for late TB. The incidence of early TB was high, and predominantly associated with advanced HIV progression markers. Earlier ART initiation and enhanced TB screening prior to and after ART initiation is warranted. Late TB amounts to almost half of the total TB burden, meriting specific preventive and diagnostic approaches.

Tuberculosis in Patients Receiving Antiretroviral Treatment: Incidence, Risk Factors, and Prevention Strategies

To determine tuberculosis (TB) incidence rates and risk factors among individuals receiving antiretroviral treatment (ART). Observational cohort in Johannesburg, South Africa. Incident TB was classified as early (less than 6 months of ART) or late (greater than 6 months of ART) incident TB. CD4 cell counts, viral load, body mass index, and hemoglobin were measured 6-monthly. Hazard ratios for factors associated with early and late incident TB were assessed using Cox proportional hazards regression. During 13,416 person-years of follow-up, 501 TB cases occurred among 7536 individuals, corresponding to a 10% risk in the first 4 years of ART and an overall incidence rate of 4.2 cases/100 person-years. The highest incidence rate (21.7 per 100 person-years) was observed in the first 3 months of ART among people with CD4 count below 50 cells/mm3. Low baseline CD4 count, anemia, and low body mass index were the strongest risk factors for early incident TB. Low updated CD4 count, low updated body mass index, anemia, and high viral load on ART were strong risk factors for late incident TB. Severity of HIV disease and unfavorable response to ART are associated with early and late incident TB, respectively. Early ART initiation and intensified TB screening at ART initiation are crucial to reduce incident TB.

Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy?

To assess whether highly active anti-retroviral therapy (HAART) contributes to the presentation of active tuberculosis (TB). Retrospective single-centre cohort study. A total of 111 HIV-infected individuals with active TB were identified at an urban teaching hospital between February 1997 and April 2004. Those receiving HAART at the time of TB diagnosis were assessed. Nineteen of 111 (17%) were receiving HAART when TB developed. Within this group there appeared to be two distinct populations. Thirteen of 19, 12 from ethnic or social groups with high background rates of TB, developed disease a median of 41 days (range, 7-109) after starting HAART ('early TB' group). In six of 19 ('late TB' group), TB occurred a median of 358 days after HAART initiation (range, 258-598). The 'early TB' group had lower CD4 cell counts when starting HAART in comparison with the 'late TB' group (median; 87 versus 218 x 10 cells/l; P = 0.04); however no difference was observed in the rate of change of CD4 cell count (P = 0.5) or HIV load. Paradoxical reaction rate in the 'early TB' group was significantly greater than in the 'late-TB' group (62 versus 0%, P = 0.02) and greater than in a similar control population who started HAART while taking anti-TB therapy (62 versus 30%, P = 0.05). These data suggest anti-HIV treatment may amplify the presentation of active TB. This has implications for antiretroviral programmes in countries with high TB rates and warrants prospective investigation of a larger cohort.

Global strategy needed to fight latest tuberculosis epidemic

Global strategy needed to fight latest tuberculosis epidemic