Endomyocardial fibrosis: is it a systemic disease?

Background: Patients with endomyocardial fibrosis (EMF) characteristically present with gross ascites and absent or minimal pedal oedema. This has long puzzled clinicians, especially since this clinical picture remains the same regardless of whether there is left, right or biventricular ventricular heart failure. The development of ascites, therefore, may not be directly and solely related to changes in the heart, but to local changes in the peritoneum. In order to investigate this possibility we performed peritoneal biopsies on 28 EMF patients.Methods: Successful peritoneal biopsies were performed on 28 EMF patients and 11 age-matched healthy controls who had died in road accidents.Results: All 28 patients (100%) showed complete or partial peritoneal fibrosis. Twenty Six (93%) had additional signs of chronic peritonitis characterised mainly by lymphocytes (92%) eosinophils (27%) and plasma cells (23%). Neutrophils were not seen. Vascularisation was common (87%) with an increase in capillaries and granulation tissue. Other components were Russel bodies (50%), deposits of fibrin (50%) and haemosiderin pigment (32%). Only two samples showed fibrosis without signs of inflammation. None of the controls showed any of these changes.Conclusion: Peritoneal fibrosis was found in all and peritonitis in most of our EMF patients. This suggests that pathology of EMF is not confined to the heart but also involves the peritoneum. This local peritoneal inflammation may explain why marked ascites is often present with little or no peripheral oedema, and why conventional heart failure treatment is of limited value.Keywords: peritoneal-fibrosis, endomyocardial-fibrosis, ascites, histology, echocardiograph

Predictors of recurrent TB in sputum smear and culture positive adults: a prospective cohort study

Objective: To explore simple inexpensive non-culture based predictors of recurrent pulmonary tuberculosis (PTB). Setting and study population: HIV-infected and uninfected adults with the first episode of smear positive, culture-confirmed pulmonary tuberculosis in a high tuberculosis burden country.Design: A nested prospective cohort study of participants with pulmonary tuberculosis (PTB) presenting to a hospital out-patient clinic.Results: A total of 630 TB culture confirmed participants were followed up for eighteen months of which 57 (9%) developed recurrent recurrent TB. On univariate analysis,4.7% low grade(1+) pre-treatment sputum smear participants developed recurrent tuberculosis Vs 8.8% with high grade(3+) smears (OR=0.31,95%CI: 0.10-0.93, p=0.037).On multivariate analysis:participants with extensive fibro-cavitation had a high risk of recurrent TB Vs minimal end of treatment fibro-cavitation (18%Vs12%,OR=2.3,95%CI:1.09-4.68, p=0.03).Weight gain with HIV infection was assosciated with a high risk of recurrentTB Vs weight gain with no HIV infection(18%Vs 6%,OR=6.8,95%CI:165-27.83,p=0.008) where as weight gain with a low pre-treatment high bacillary burden was assosciated with a low risk of recurrent TB Vs weight gain with a high pre-treatmentbacillary burden(6.5%Vs7.9%,OR=0.2,95%CI:0.05-0.79,p=0.02).Conclusion: Extensive end of treatment pulmonary fibro-cavitation, high pre-treatment bacillary burden with no weight gain and HIV infection could be reliable predictors of recurrent tuberculosis.Keywords: Grade, fibrosis, cavities, weight

Update on the efficacy, effectiveness and safety of artemether–lumefantrine combination therapy for treatment of uncomplicated malaria

Artemether–lumefantrine is one of the artemisisnin-based combination therapies recommended for treatment of uncomplicated falciparum malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. It offers the advantage of rapid clearance of parasites by artemether and the slower elimination of residual parasites by lumefantrine. The combination can be used in all populations except pregnant mothers in the first trimester where safety is still uncertain. There are still concerns about safety and pharmacokinetics of the drug combination in children, especially infants, pregnant mothers and drug interactions with mainly non-nucleoside reverse transcriptase inhibitors and protease inhibitors used for HIV therapy

Artemether-Lumefantrine Combination Therapy for Treatment of Uncomplicated Malaria: The Potential for Complex Interactions with Antiretroviral Drugs in HIV-Infected Individuals

Treatment of malaria in HIV-infected individuals receiving antiretroviral therapy (ART) poses significant challenges. Artemether-lumefantrine (AL) is one of the artemisisnin-based combination therapies recommended for treatment of malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. Both artemether and lumefantrine are metabolized by hepatic cytochrome P450 (CYP450) enzymes which metabolize the protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used for HIV treatment. Coadministration of NNRTIs and PIs with AL could potentially cause complex pharmacokinetic drug interactions. NNRTI by inducing CYP450 3A4 enzyme and PIs by inhibiting CYP450 3A4 enzymes could influence both artemether and lumefantrine concentrations and their active metabolites dihydroartemisinin and desbutyl-lumefantrine, predisposing patients to poor treatment response, toxicity, and risk for development of resistance. There are scanty data on these interactions and their consequences. Pharmacokinetic studies to evaluate these interactions in the target populations are urgently needed

Burden of tuberculosis disease among adolescents in a rural cohort in Eastern Uganda

BACKGROUND: The world health organization (WHO) declared tuberculosis (TB) a global emergency, mainly affecting people in sub-Saharan Africa. However there is little data about the burden of TB among adolescents. We estimated the prevalence and incidence of TB and assessed factors associated with TB among adolescents aged 12–18 years in a rural population in Uganda in order to prepare the site for phase III clinical trials with novel TB vaccines among adolescents. METHODS: In a prospective cohort study, we recruited 5000 adolescents and followed them actively, every 6 months, for 1–2 years. Participants suspected of having TB were those who had any of; TB signs and symptoms, history of TB contact or a positive tuberculin skin test (TST) of ≥10 mm. Laboratory investigations included sputum smear microscopy and culture. RESULTS: Of the 5000 participants, eight culture confirmed cases of TB were found at baseline: a prevalence of 160/100,000 (95% confidence interval (CI), 69–315). There were 13 incident TB cases detected in an average of 1.1 person years: an incidence of 235/100,000 person years (95% CI, 125–402). None of the confirmed TB cases were HIV infected. Predictors for prevalent TB disease were: a history of TB contact and a cough ≥ 2 weeks at baseline and being out of school, while the only predictor for incident TB was a positive TST during follow-up. CONCLUSION: The TB incidence among adolescents in this rural part of Uganda seemed too low for a phase III TB vaccine trial. However, the study site demonstrated capability to handle a large number of participants with minimal loss to follow-up and its suitability for future clinical trials. Improved contact tracing in TB program activities is likely to increase TB case detection among adolescents. Future studies should explore possible pockets of higher TB incidence in urban areas and among out of school youth

The effect of interrupted anti-retroviral treatment on the reconstitution of memory and naive T cells during tuberculosis treatment in HIV patients with active pulmonary tuberculosis

Background: The reconstitution of cellular immune components contributes to clinical outcome of HIV and Mycobacterium tuberculosis (MTB) infection. Interruption of anti-retroviral therapy (ART) could lead to perturbations in reconstitution of T cells in HIV/ tuberculosis (TB) patients. Objectives: To ascertain the effect of interrupted ART on reconstitution of CD4+ and CD8+ T sub-sets in TB patients.Methods: Participants with HIV (CD4>350 cells/μL) and TB were recruited under a larger phase 3 open label randomised controlled clinical trial. The CD45RO and CD62L markers were measured on CD4+ and CD8+ cells by flow cytometry. Samples were analysed at baseline, 3, 6, 12 months.Results: There was a significant increase of naive CD8+ cells (p = 0.003) and a decrease in effector CD8+ cells (p = 0.004) among participants in ART/TB treatment arm during the first 6 months. Withdrawing ART led to naive CD8+ cells reduction (p=0.02) to values close to baseline. An increase of naive CD8+ cells after 6 months of TB treatment in TB alone treatment arm (p=0.01) was observed. A trend towards increment of naive CD4+ sub sets in either treatment arms was observed.Conclusion: Interrupting ART alters CD8+ but not CD4+ sub-sets in patients with less advanced HIV infection and TB.Keywords: Interrupted anti-retroviral treatment, memory and naive T cells, HIV patients, active pulmonary tuberculosis

Antiretroviral Treatment-Associated Tuberculosis in a Prospective Cohort of HIV-Infected Patients Starting ART

Commencement of antiretroviral treatment (ART) in severely immunosuppressed HIV-infected persons is associated with unmasking of subclinical disease. The subset of patients that are diagnosed with tuberculosis (TB) disease while on ART have been classified as ART-associated TB. Few studies have reported the incidence of ART-associated TB and unmasking TB-IRIS according to the International Network for the Study of HIV-Associated IRIS (INSHI) consensus definition. To determine the incidence and predictors of ART-associated TB, we screened 219 patients commencing ART at the Infectious Diseases Clinic in Kampala, Uganda for TB by symptoms, sputum microscopy, and chest X-rays and followed them for one year. Fourteen (6.4%) patients were diagnosed with TB during followup. Eight (3.8%) patients had ART-associated TB (incidence rate of 4.3 per 100 person years); of these, three patients fulfilled INSHI criteria for unmasking TB-associated IRIS (incidence rate of 1.6 per 100 person years). A body mass index of less than 18.5 kg/m2 BMI (HR 5.85 95% CI 1.24–27.46, P = .025) and a C-reactive protein greater than 5 mg/L (HR 8.23 95% CI 1.36–38.33, P = .020) were risk factors for ART-associated TB at multivariate analysis. In conclusion, with systematic TB screening (including culture and chest X-ray), the incidence of ART-associated TB is relatively low in settings with high HIV and TB prevalence

Potential for false positive HIV test results with the serial rapid HIV testing algorithm

Background: Rapid HIV tests provide same-day results and are widely used in HIV testing programs in areas with limited personnel and laboratory infrastructure. The Uganda Ministry of Health currently recommends the serial rapid testing algorithm with Determine, STAT-PAK, and Uni-Gold for diagnosis of HIV infection. Using this algorithm, individuals who test positive on Determine, negative to STAT-PAK and positive to Uni-Gold are reported as HIV positive. We conducted further testing on this subgroup of samples using qualitative DNA PCR to assess the potential for false positive tests in this situation. Results: Of the 3388 individuals who were tested, 984 were HIV positive on two consecutive tests, and 29 were considered positive by a tiebreaker (positive on Determine, negative on STAT-PAK, and positive on Uni-Gold). However, when the 29 samples were further tested using qualitative DNA PCR, 14 (48.2%) were HIV negative. Conclusion: Although this study was not primarily designed to assess the validity of rapid HIV tests and thus only a subset of the samples were retested, the findings show a potential for false positive HIV results in the subset of individuals who test positive when a tiebreaker test is used in serial testing. These findings highlight a need for confirmatory testing for this category of individuals

Effect of anti-retroviral therapy on oxidative stress in hospitalized HIV-infected adults with and without TB.

BackgroundHIV infection and opportunistic infections cause oxidative stress (OS), which is associated with tissue damage. Anti-retroviral therapy (ART) is used to treat HIV and decrease the risk of opportunistic infections, but it is unclear whether ART reduces OS. Association of ART with OS was investigated.MethodsWe stratified a convenience sample of frozen serum or plasma from HIV-infected, ART-naïve (n=21); HIV-infected, ART-treated (n=14); HIV and PTB co-infected, ART-naïve (n=21); HIV and PTB co-infected, ART-treated (n=25) patients. Controls (n=21) were HIV-negative adults without TB symptoms. Concentration of OS markers namely: transaminases (ALT and AST), gamma glutamyl transpeptidase (GGT), albumin, total protein, malondialdehyde (MDA), vitamin C, and total anti-oxidant status (TAS) were determined.ResultsAST (p<0.001), GGT (p<0.001), total protein (p=0.001) and MDA (p<0.001) were higher in HIV patients compared to controls. Vitamin C (P<0.0001) and albumin (p<0.01) were lower in HIV-patients relative to controls. ART was only associated with higher albumin (p=0.001), higher GGT (p=0.02) and lower vitamin C (p=0.009). HIV and PTB co-infection was only significantly associated with higher GGT (p=0.01) and AST (p=0.03).ConclusionWe identified severe OS among HIV-patients. ART was associated with both increased and reduced markers of OS hence suggesting that ART may not attenuate OS