Daniel Faurholt-Jepsen

Diabetes Is a Risk Factor for Pulmonary Tuberculosis: A Case-Control Study from Mwanza, Tanzania

Background Diabetes and TB are associated, and diabetes is increasingly common in low-income countries where tuberculosis (TB) is highly endemic. However, the role of diabetes for TB has not been assessed in populations where HIV is prevalent. Methods A case-control study was conducted in an urban population in Tanzania among culture-confirmed pulmonary TB patients and non-TB neighbourhood controls. Participants were tested for diabetes according to WHO guidelines and serum concentrations of acute phase reactants were measured. The association between diabetes and TB, and the role of HIV as an effect modifier, were examined using logistic regression. Since blood glucose levels increase during the acute phase response, we adjusted for elevated serum acute phase reactants. Results Among 803 cases and 350 controls the mean (SD) age was 34.8 (11.9) and 33.8 (12.0) years, and the prevalence of diabetes was 16.7% (95% CI: 14.2; 19.4) and 9.4% (6.6; 13.0), respectively. Diabetes was associated with TB (OR 2.2, 95% CI: 1.5; 3.4, p<0.001). However, the association depended on HIV status (interaction, p = 0.01) due to a stronger association among HIV uninfected (OR 4.2, 95% CI: 1.5; 11.6, p = 0.01) compared to HIV infected (OR 0.1, 95% CI: 0.01; 1.8, p = 0.13) after adjusting for age, sex, demographic factors and elevated serum acute phase reactants. Conclusion Diabetes is a risk factor for TB in HIV uninfected, whereas the association in HIV infected patients needs further study. The increasing diabetes prevalence may be a threat to TB control.

Potential of interferon-γ-inducible protein 10 in improving tuberculosis diagnosis in HIV-infected patients

To the Editors: In patients latently infected with Mycobacterium tuberculosis , immunosuppression significantly augments the risk of progression to active tuberculosis (TB) and TB is still one of the most frequent opportunistic infections worldwide. Prevention of TB in HIV-positive patients using the tuberculin skin testing (TST) followed by targeted preventive treatment is an effective strategy, but has thus far shown limited clinical success, in part due to the lack of a reliable test for latent TB infection (LTBI) 1. Interferon (IFN)-γ release assays (IGRAs) have shown great potential in the improvement of LTBI diagnosis, but the tests perform suboptimally in immunocompromised populations. We and others have previously shown that HIV-positive patients have high rates of indeterminate QuantiFERON®-TB Gold In-Tube test (QFT-IT) results and that this, at least in part, is due to low CD4 T-cell count 2–4. We and others have also shown that IFN-γ-inducible protein 10 (IP-10/CXCL-10) is an alternative biomarker may improve immunodiagnosis of M. tuberculosis infection. IP-10 is induced specifically and in large quantities upon in vitro stimulation of whole blood with M. tuberculosis -specific antigens. We have developed an IP-10 based test 5 and shown that the IP-10 test performs comparably to the QFT-IT in adult patients with intact immune function 6. We compared the sensitivity of an IP-10 based test with the QFT-IT for diagnosing M. tuberculosis infection in HIV-negative and HIV-positive patients with culture-confirmed active pulmonary tuberculosis (PTB). 300 patients newly diagnosed with PTB were recruited prospectively through the National Tuberculosis and Leprosy Programme (Mwanza, Tanzania). Blood was drawn for IGRA and HIV testing, and CD4 cell counts. Sputum was collected for microscopy and M. tuberculosis culture. Patients >15 yrs of age with a positive sputum culture result were enrolled. All HIV-positive patients were newly diagnosed in the study …

Diabetes is a strong predictor of mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients from Mwanza, Tanzania

Strong evidence suggests diabetes may be associated with tuberculosis (TB) and could influence TB treatment outcomes. We assessed the role of diabetes on sputum culture conversion and mortality among patients undergoing TB treatment.

Weight, body composition and handgrip strength among pulmonary tuberculosis patients: a matched cross-sectional study in Mwanza, Tanzania.

This study aimed to estimate deficits in weight, arm fat area (AFA), arm muscle area (AMA) and handgrip strength among smear-positive pulmonary TB (PTB+) patients starting treatment. We conducted a cross-sectional study among PTB+ patients and age- and sex-matched neighborhood controls. HIV status, anthropometric measurements and handgrip strength were determined. Deficits in weight, AFA, AMA and handgrip strength associated with PTB+ and HIV were estimated using multiple regression analysis. We recruited 355 pairs of PTB+ patients and controls. PTB+ was associated with deficits of 10.0kg (95% CI 7.3; 12.7) in weight and 6.8kg (95% CI 5.2; 8.3) in handgrip strength among females and 9.1kg (95% CI 7.3; 10.9) in weight and 6.8kg (95% CI 5.2; 8.4) in handgrip strength among males. In both sexes, PTB+ was associated with deficits in AFA and AMA. Among females, HIV was associated with deficits in AMA and handgrip strength, but the deficit in handgrip strength was larger among PTB+ patients (3.2kg 95% CI 1.3; 5.2) than controls (-1.6kg 95% CI -4.8; 1.5) (interaction, P=0.009). These findings suggest that deficits in weight and handgrip strength among patients starting TB treatment are severe. Thus, nutritional support may be necessary to ensure reversal of the deficits, and may improve treatment outcomes.

Daily Multi-Micronutrient Supplementation during Tuberculosis Treatment Increases Weight and Grip Strength among HIV-Uninfected but Not HIV-Infected Patients in Mwanza, Tanzania

Undernutrition is common among tuberculosis (TB) patients. The objective of this study was to assess the effect of multi-micronutrient supplementation during TB treatment on weight, body composition, and handgrip strength. A total of 865 patients with smear-positive (PTB+) or -negative (PTB-) pulmonary TB were randomly allocated to receive a daily biscuit with or without multi-micronutrients for 60 d during the intensive phase of TB treatment. Weight, arm fat area, arm muscle area, and handgrip strength were assessed at baseline and after 2 and 5 mo. At 2 mo, the multi-micronutrient supplementation led to a higher handgrip gain (1.22 kg; 95% CI = 0.50, 1.94; P = 0.001) but had no effects on other outcomes. The effects of multi-micronutrient supplementation were modified by HIV infection (P-interaction = 0.002). Among HIV- patients, multi-micronutrient supplementation increased weight gain by 590 g (95% CI = -40, 1210; P = 0.07) and handgrip strength by 1.6 kg (95% CI = 0.78, 2.47; P < 0.001), whereas among HIV+ patients, it reduced weight gain by 1440 g (95% CI = 290, 2590; P = 0.002) and had no effect on handgrip strength (0.07 kg; 95% CI = -1.30, 1.46; P = 0.91). The reduced weight gain among HIV+ patients receiving multi-micronutrient supplementation seemed to be explained by a higher proportion of patients reporting fever. At 5 mo, the effects on weight were sustained, whereas there was no effect on handgrip strength. In conclusion, multi-micronutrient supplementation given as a biscuit is beneficial among HIV- PTB patients and may be recommended to TB programs. More research is needed to develop an effective supplement for HIV+ PTB patients.

Diabetes is associated with lower tuberculosis antigen-specific interferon gamma release in Tanzanian tuberculosis patients and non-tuberculosis controls

Abstract Background: Diabetes is increasingly common in TB endemic regions and plays a role as a possible risk factor for increased progression from latent TB infection (LTBI) to active TB disease. Although the pathophysiological mechanisms are not fully understood, the immune system is weakened in diabetes patients and therefore the validity of interferon gamma release assays (IGRA) may be compromised. The aim of the present study was to assess the association between diabetes and Mycobacterium tuberculosis (Mtb) antigen-specific interferon gamma (IFN-γ) release in a TB endemic area among culture-confirmed TB patients and non-TB controls. Methods: Culture-confirmed pulmonary TB patients (n = 187) and healthy non-TB neighbourhood controls (n = 190) from Mwanza, Tanzania were tested for the presence of circulating T cells recognizing Mtb antigens using an IGRA. The diabetes status of all participants was assessed using a standard oral glucose tolerance test. The impact of diabetes on the performance of the IGRA was estimated using robust linear and logistic regression. Results: Compared to normal glucose tolerance, diabetes was associated with reduced levels of Mtb-specific IFN-γ. Increasing levels of fasting blood glucose (B − 0.3, 95% confidence interval − 0.6 to − 0.03, p = 0.033) was negatively associated with IFN-γ. Although TB patients had higher specific and lower unspecific mitogen IFN-γ responses compared to non-TB controls, the association between diabetes and IFN-γ did not depend on TB status. Conclusion: Diabetes is associated with lower levels of Mtb antigen-specific IFN-γ, and the validity of IFN- γ tests for LTBI may be questionable in individuals with diabetes.

Identification of biomarkers for Mycobacterium tuberculosis infection and disease in BCG-vaccinated young children in Southern India.

Pediatric tuberculosis (TB) often goes undiagnosed because of the lack of reliable diagnostic methods. With the aim of assessing biomarker(s) that can aid in the diagnosis of TB infection and disease, we investigated 746 Indian children with suspected TB. Whole-blood mRNA from 210 children was examined by dual-color Reverse-Transcriptase Multiple Ligation-dependent Probe-Amplification for the expression of 45 genes and a Bio-Plex assay for the expression of cytokines/chemokines in QuantiFERON supernatants. The study shows that transcription of SEC14L1, GUSB, BPI, CCR7 and TGFβ-1 (all P⩽0.05) was downregulated in TB disease compared with uninfected controls, while transcription of RAB33A was downregulated in TB disease compared with both latent TB (P<0.05) and controls (P<0.01). The transcription of CD4, TGFβ-1 (P<0.01) and the expression of IL-2 (P<0.01) and IL-13 (P<0.05) was upregulated in latent TB compared with that in controls. Using the Least Absolute Shrinkage and Selection Operator (lasso) model, RAB33A alone discriminated between TB disease and latent TB (area under the curve (AUC) 77.5%), whereas a combination of RAB33A, CXCL10, SEC14L1, FOXP3 and TNFRSF1A was effective in discriminating between TB disease and controls (AUC 91.7%). A combination of 11 biomarkers predicted latent TB with moderate discriminatory power (AUC 72.2%). In conclusion, RAB33A is a potential biomarker for TB disease, whereas CD4, TGFβ-1 and IL-2, IL-13 may identify latent TB in children.

Cardiorespiratory fitness and physical activity in Luo, Kamba, and Maasai of rural Kenya

Although habitual physical activity energy expenditure (PAEE) and cardio‐respiratory fitness (CRF) are now well‐established determinants of metabolic disease, there is scarcity of such data from Africa. The aim of this study was to describe objectively measured PAEE and CRF in different ethnic populations of rural Kenya.

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

ABSTRACT Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. A cohort of 100 TB patients (58 men; median age, 35 [interquartile range {IQR}, 29 to 40] years, and median body mass index [BMI], 18.8 [17.3 to 19.9] kg/m2) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (+14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC0–24) of 5.6 μg/ml and 28.6 μg · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher Cmax and AUC0–24 values of 6.4 μg/ml and 31.6 μg · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.)

The role of diabetes on the clinical manifestations of pulmonary tuberculosis.

Objective  Diabetes is associated with pulmonary tuberculosis (TB), possibly due to impaired immunity, and diabetes may exacerbate the clinical manifestations of TB. Our aim was to assess the role of diabetes in the clinical manifestations of TB.