Comorbidity between counnunicable and non-communicable diseases : the example of the dual burden of tuberculosis and diabetes in Dar es Salaam, Tanzania

Background Although recognized for centuries, the association between tuberculosis (TB) and diabetes mellitus (DM) was forgotten with the discovery of efficient treatments. In the last decade, the prevalence of DM has dramatically increased, particularly in low- and middle-income countries experiencing a high burden of TB, leading to a new interest in this association. DM increases TB risk while TB, as an infectious disease, leads to hyperglycemia. The relationship between TB and DM has been poorly studied in Sub-Saharan Africa, where the high incidence of TB is associated with HIV infection. Concentration of vitamin D is inversely associated with TB and DM, and it has been suggested that low vitamin D could mediate some of the association between TB and DM. DM affects the immune response to TB, but the precise mechanisms underlying this association are not clear. To address this issue of high public health relevance, we undertook a project on the association between TB, DM and HIV in Tanzania. The project had three major components: (1) Assessing the association of TB and its outcome with the presence and persistence of hyperglycemia in Tanzania, using three different DM screening tests. (2) Describing the association between vitamin D, TB and DM. (3) Studying the immunological features underlying TB and DM comorbidity in sub-Saharan Africa and testing the hypothesis of delayed adaptive immune response with increasing glycemia. The overall aim of the project was to improve knowledge on the dynamic interaction between TB and DM in an African setting with high HIV prevalence by integrating a longitudinal component into the case-control study. Methods A case-control study with longitudinal follow-up of cases was conducted in Dar es Salaam. Consecutive adults with new active TB were included and followed up for five months after the start of anti-TB treatment. Healthy controls, matched by age and sex to TB cases, were recruited among volunteering adults accompanying patients to the outpatient departments of the same hospitals. Exclusion criteria were a biological relationship to TB case, TB history, symptoms or signs of TB, other acute infection or major trauma within the last three months. All underwent 25-hydroxyvitamin D (25(OH)D) measurement and DM screening tests (fasting glucose (FCG), 2-hour capillary glucose after standard oral glucose tolerance test (2h-CG) and glycated hemoglobin (HbA1c)) at enrolment and TB patients were again tested after five months of TB treatment. Data on the outcome of TB (treatment failure, death, lost to follow-up) were collected. For the nested immunological study, four groups of HIV negative patients were included: i) active TB without DM, ii) active TB with DM, iii) latent TB patients without DM and iv) latent TB patients with DM. Latent TB patients were selected among the healthy volunteering adults, as well as among diabetic patients attending the DM clinic in the participating hospitals. Exclusion criteria for groups iii and iv were past TB history and symptoms or signs of active TB. Peripheral blood mononuclear cells were stimulated with Mycobacterium tuberculosis (Mtb)-specific peptide pools and live Mycobacterium bovis BCG and then analysed by polychromatic flow cytometry for Th1, Th2, Th9 and Th17 cytokine production. Cell culture supernatants were analysed by Luminex® for 34 cytokines and chemokines. Findings At enrolement, DM prevalence was significantly higher among TB patients (N=539; FCG>7mmol/L: 4.5%, 2-hCG>11mmol/L: 6.8% and HbA1c>6.5%: 9.3%) compared to controls (N=496; 1.2%, 3.1% and 2.2%). However, the association between hyperglycemia and TB disappeared after TB treatment (aOR(95% CI) at enrolment vs follow-up: FCG 9.6(3.7-24.7) vs 2.4(0.7-8.7); 2-hCG 6.6(4.0-11.1) vs 1.6(0.8-2.9); HbA1c 4.2(2.9-6.0) vs 1.4(0.9-2.0)). FCG hyperglycemia at enrolment was associated with TB treatment failure or death (aOR(95%CI) 3.3(1.2-9.3). The prevalence of 25(OH)D insufficiency (25(OH)D<75nmol/l) was not statistically different between TB patients and controls (25.8% versus 31.0%; p=0.22). But the association between 25(OH)D insufficiency and TB was modified by hyperglycemia (pinteraction=0.01). Patient with vitamin D insufficiency were only at higher risk for TB in the presence of underlying hyperglycemia. The OR (95%CI) for TB risk in patients with vitamin D insufficiency and hyperglycemia was 4.94(1.16-21.0) versus 0.68(0.39-1.17) for patients with vitamin D insufficiency and normoglycemia where normoglycemia and normal vitamin D were the reference category. Patients with active TB and DM had a lower frequency of INF-γ CD4+ T cells and a lower proportion of CD4+ T cells producing both TNF-α and IFN-γ after live M. bovis BCG but not after Mtb-specific peptide pool stimulation, compared to normoglycemic TB patients. A negative correlation between INF-γ or TNF-α CD4+ T cell frequency and increasing glycemia was observed in the context of live M. bovis BCG stimulation only. Conclusions Transient hyperglycemia is frequent during TB, and DM needs confirmation after TB treatment. However, DM screening at TB diagnosis gives the opportunity to detect patients at risk of adverse outcome. 25(OH)D insufficiency seams to increase the risk of TB only if associated with hyperglycemia. DM patients living in high TB burden settings might benefit from preventive vitamin D supplementation. The immunological findings suggest that DM might affect Mtb-specific CD4+ T cell immune responses at the level of reduced antigen processing and presentation, a defect that could be compensated by metformin. The results of the study are of public health and clinical utility. First, they lend support to the integration of care between TB and DM programs. Second, they imply that, at the time of TB diagnosis, patients should be screened for hyperglycemia using cost-effective fasting glucose tests. Treatment of hyperglycemia should be initiated to improve TB outcome. Third, before initiation of long-term DM treatment, DM diagnosis must be confirmed after the resolution of TB. Finally, in the absence of evidence for a strong contribution of DM to TB risk in this African setting with high HIV prevalence, DM patients should not be screened for TB with expensive test. DM physicians and patients should rather be trained for recognizing TB symptoms and signs as a cost-effective way to recognize TB early

Point prevalence study of antibiotic appropriateness and possibility of early discharge from hospital among patients treated with antibiotics in a Swiss University Hospital.

BACKGROUND The growing threat of multidrug resistant organisms have led to increasingly promote prudent and rational use of antimicrobials as well as early hospital discharge plan. Antibiotic stewardship programs (ASP) have been developed as multifaceted approaches to improve use of current antibiotics and are now widely applied through different strategies. Proactive interventions are still limited in Switzerland and data on antimicrobial appropriateness and early discharge strategies are lacking. We aimed to describe the opportunities of antibiotics prescriptions optimization at Lausanne University Hospital, Switzerland and evaluate the suitability for early discharge among patients receiving antibiotics. The need for outpatient medical structures was also assessed. METHODS We conducted a point prevalence survey of antibiotic prescriptions in adult medical and surgical units with exclusion of intermediate and intensive care units. All hospitalized patients receiving a systemic antibiotic on the day of evaluation were included. An infectious diseases specialist evaluated antimicrobial appropriateness and assessed suitability for discharge according to medical and nursing observations. The need of flexible additional outpatient facility for a close medical follow-up was evaluated concomitantly. RESULTS A total of 564 patients' files were reviewed. 182 (32%) patients received one or more systemic antibiotic: 62 (34%) as a prophylaxis and 120 (66%) as a treatment with or without concomitant prophylaxis. 37/62 (60%) patients receiving prophylaxis had no indication to continue the antibacterial. Regarding the patients treated with antibiotics, 69/120 (58%) presented at least one opportunity for treatment optimization, mainly interruption of treatment. A previous ID consultation was recorded for 55/120 (46%) patients, of whom 21 (38%) could have benefited from antimicrobial therapy optimization on the day of the point assessment. 9.2% patients were eligible for discharge of whom 64% could leave the hospital with a close outpatient follow-up for infectious issues. CONCLUSIONS This point prevalence study offers precious indicators for tailoring future antibiotic stewardship interventions that can be combined with early discharge. Any centre considering implementing ASP should conduct this type of analysis with a pragmatic approach to gain insight into local practices and needed resources

Association Between Tuberculosis, Diabetes and 25 Hydroxyvitamin D in Tanzania: A Longitudinal Case Control Study.

Vitamin D level is inversely associated with tuberculosis (TB) and diabetes (DM). Vitamin D could be a mediator in the association between TB and DM. We examined the associations between vitamin D, TB and DM. Consecutive adults with TB and sex- and age-matched volunteers were included in a case-control study in Dar es Salaam, Tanzania. Glycemia and total vitamin D (25(OH)D) were measured at enrolment and after TB treatment in cases. The association between low 25(OH)D (<75 nmol/l) and TB was evaluated by logistic regression adjusted for age, sex, body mass index, socioeconomic status, sunshine hours, HIV and an interaction between low 25(OH)D and hyperglycemia. The prevalence of low 25(OH)D was similar in TB patients and controls (25.8 % versus 31.0 %; p = 0.22). In the subgroup of patients with persistent hyperglycemia (i.e. likely true diabetic patients), the proportion of patients with low 25(OH)D tended to be greater in TB patients (50 % versus 29.7 %; p = 0.20). The effect modification by persistent hyperglycemia persisted in the multivariate analysis (pinteraction = 0.01). Low 25(OH)D may increase TB risk in patients with underlying DM. Trials should examine if this association is causal and whether adjunct vitamin D therapy is beneficial in this population

Prognostic value of quickSOFA as a predictor of 28-day mortality among febrile adult patients presenting to emergency departments in Dar es Salaam, Tanzania

Quick Sequential Organ Failure Assessment (qSOFA) is a three-item clinical instrument for bedside identification of sepsis patients at risk of poor outcome. qSOFA could be a valuable triage tool in emergency departments of low-income countries, yet its performance in resource-limited settings remains unknown. The prognostic accuracy of qSOFA for 28-day all-cause mortality in febrile adults treated at the EDs in a low-income country was evaluated.; Retrospective analysis of a prospective cohort study of consecutive patients (≥18 years) with fever (tympanic temperature ≥38°C and fever ≤7 days) who presented between July 2013 and May 2014 at four emergency departments in Dar es Salaam, Tanzania. Medical history, clinical examination, laboratory and microbiological data were collected to document the cause of fever. Variables for the previous and new sepsis criteria were collected at inclusion and qSOFA, SOFA and SIRS were measured at inclusion. Patients were followed up by phone at day 28. The performance (sensitivity, specificity and area under the receiver operating curve [AUROC]) of qSOFA (score ≥2), SOFA (increase of ≥2 points) and SIRS (≥2 criteria) as predictors of 28-day all-cause mortality was evaluated.; Among the 519 patients (median age: 30 years) included in the analysis, 47% were female and 25% were HIV positive. Overall, 85% had a microbiologically and/or clinically documented infection and 15% a fever of unknown origin. The most common site and causes of infections were the respiratory tract (43%), dengue (26%), malaria (6%) and typhoid fever (5%). Twenty-eight-day all-cause mortality was 6%: 3% for patients with a qSOFA &lt;2 and 24% for those with a score ≥2 (absolute difference, 21%; 95% CI 12%-31%). The prognostic accuracy of qSOFA (AUROC 0.80, 95% CI 0.73-0.87) for 28-day mortality was similar to SOFA (AUROC 0.79, 0.71-0.87; p = 0.1) and better than SIRS (AUROC 0.61, 0.52-0.71; p&lt;0.001).; Among patients with fever at emergency departments in Tanzania, qSOFA had a prognostic accuracy for 28-day mortality comparable to SOFA and superior to SIRS. These results support the use of qSOFA as a triage tool to identify patients with sepsis and at risk of poor outcome in resource-limited countries.; Clinicaltrials.gov Identifier: NCT01947075

Procalcitonin and lung ultrasonography point-of-care testing to decide on antibiotic prescription in patients with lower respiratory tract infection in primary care: protocol of a pragmatic cluster randomized trial

A minority of patients presenting with lower respiratory tract infection (LRTI) to their general practitioner (GP) have community-acquired pneumonia (CAP) and require antibiotic therapy. Identifying them is challenging, because of overlapping symptomatology and low diagnostic performance of chest X-ray. Procalcitonin (PCT) can be safely used to decide on antibiotic prescription in patients with LRTI. Lung ultrasound (LUS) is effective in detecting lung consolidation in pneumonia and might compensate for the lack of specificity of PCT. We hypothesize that combining PCT and LUS, available as point-of care tests (POCT), might reduce antibiotic prescription in LRTIs without impacting patient safety in the primary care setting. This is a three-arm pragmatic cluster randomized controlled clinical trial. GPs are randomized either to PCT and LUS-guided antibiotic therapy or to PCT only-guided therapy or to usual care. Consecutive adult patients with an acute cough due to a respiratory infection will be screened and included if they present a clinical pneumonia as defined by European guidelines. Exclusion criteria are previous antibiotics for the current episode, working diagnosis of sinusitis, severe underlying lung disease, severe immunosuppression, hospital admission, pregnancy, inability to provide informed consent and unavailability of the GP. Patients will fill in a 28 day-symptom diary and will be contacted by phone on days 7 and 28. The primary outcome is the proportion of patients prescribed any antibiotic up to day 28. Secondary outcomes include clinical failure by day 7 (death, admission to hospital, absence of amelioration or worsening of relevant symptoms) and by day 28, duration of restricted daily activities, episode duration as defined by symptom score, number of medical visits, number of days with side effects due to antibiotics and a composite outcome combining death, admission to hospital and complications due to LRTI by day 28. An evaluation of the cost-effectiveness and of processes in the clinic using a mixed qualitative and quantitative approach will also be conducted. Our intervention targets only patients with clinically suspected CAP who have a higher pretest probability of definite pneumonia. The intervention will not substitute clinical assessment but completes it by introducing new easy-to-perform tests. The study was registered on the 19th of June 2017 on the clinicaltrials.gov registry using reference number; NCT03191071

Brief Report: Switching From TDF to TAF in HIV/HBV-Coinfected Individuals With Renal Dysfunction-A Prospective Cohort Study.

Whereas tenofovir disoproxil fumarate (TDF) can lead to renal adverse events, tenofovir alafenamide (TAF) has a more favorable renal safety profile. However, the impact of replacing TDF with TAF on renal function and liver parameters among HIV/hepatitis B virus (HBV)-coinfected individuals with renal dysfunction remains unclear. We included all participants from the Swiss HIV Cohort Study with an HIV/HBV coinfection who switched from TDF to TAF and had an estimated glomerular filtration rate (eGFR) &lt;90 mL/min/1.73 m and a suppressed HIV viral load (&lt;200 cp/mL). We assessed changes in eGFR, urine protein-to-creatinine ratio, and alanine aminotransferase (ALT) after 1 year using mixed-effect models with interrupted time series. Among 106 participants (15.1% women, median age 53 years), eGFR was 60-89 mL/min/1.73 m in 84 (79.2%) and &lt;60 mL/min/1.73 m in 22 (20.8%) individuals at the time of switch. One year after the switch from TDF to TAF, individuals with an eGFR between 60 and 89 mL/min/1.73 m experienced increases in eGFR of 3.2 mL/min/1.73 m (95% confidence interval [CI] 1.2 to 5.2), whereas those with an eGFR &lt;60 mL/min/1.73 m experienced improvements of 6.2 mL/min/1.73 m (95% CI 2.4 to 10.0). Urine protein-to-creatinine ratio decreased overall (-6.3 mg/mmol, 95% CI -10.0 to -2.7), and ALT levels declined in patients with elevated baseline levels (-11.8 IU/L, 95% CI -17.3 to -6.4) 1 year after replacing TDF with TAF. Switching from TDF to TAF among HIV/HBV-coinfected individuals with renal impairment led to improvements in eGFR, a decline in proteinuria, and to ALT normalization in those with elevated ALT levels

Dengue fever in Dar es Salaam, Tanzania: clinical features and outcome in populations of black and non-black racial category

Although the incidence of dengue across Africa is high, severe dengue is reported infrequently. We describe the clinical features and the outcome of dengue according to raceduring an outbreak in Dar es Salaam, Tanzania that occurred in both native and expatriate populations. Adults with confirmed dengue (NS1 and/or IgM on rapid diagnostic test and/or PCR positive) were included between December 2013 and July 2014 in outpatient clinics. Seven-day outcome was assessed by a visit or a call. Association between black race and clinical presentation, including warning signs, was assessed by logistic regression adjusted for age, malaria coinfection, secondary dengue and duration of symptoms at inclusion. The independent association between demographic and comorbidities characteristics of the patients and severe dengue was evaluated by multivariate logistic regression that included potential confounders. After exclusion of 3 patients of mixed race, 431 patients with dengue (serotype 2, genotype Cosmopolitan) were included: 241 of black and 190 of non-black race. Black patients were younger (median age 30 versus 41 years; p &lt; 0.001) and attended care after a slightly longer duration of symptoms (median of 2.9 versus 2.7 days; p = 0.01). Malaria coinfection was not significantly different between black (5%) and non-black (1.6%) patients (p = 0.06). The same proportion of patients in both group had secondary dengue (13 and 14%; p = 0.78). Among warning signs, only mucosal bleed was associated with race, black race being protective (adjusted OR 0.44; 95% CI 0.21-0.92). Overall, 20 patients (4.7%) presented with severe dengue. Non-black race (adjusted OR 3.9; 95% CI 1.3-12) and previously known diabetes (adjusted OR 43; 95% CI 5.2-361) were independently associated with severe dengue. Although all patients were infected with the same dengue virus genotype, black race was independently protective against a severe course of dengue, suggesting the presence of protective genetic or environmental host factors among people of African ancestry. The milder clinical presentation of dengue in black patients might partly explain why dengue outbreaks are under-reported in Africa and often mistaken for malaria. These results highlight the need to introduce point-of-care tests, beside the one for malaria, to detect outbreaks and orientate diagnosis. Clinicaltrials.gov Identifier: NCT01947075, retrospectively registered on the 13 of September 2014

Epidemiology and outcomes of bone and joint infections in solid organ transplant recipients

Bone and joint infection (BJI) epidemiology and outcomes in solid organ transplant recipients (SOTr) remain largely unknown. We aim to describe BJI in a multi-center cohort of SOTr (Swiss Transplant Cohort Study). All consecutive SOTr with BJI (01.05.2008-31.12.2019) were included. A nested case-control study to identify risk factors for BJI was performed. Among 4482 patients, 61 SOTr with 82 BJI were included, at an incidence of 1.4% (95% CI 1.1-1.7), higher in heart and kidney-pancreas SOTr (Gray's test p < .01). Although BJI were predominately late events (median of 18.5 months post-SOT), most infections occurred during the first year post-transplant in thoracic SOTr. Diabetic foot osteomyelitis was the most frequent infection (38/82, 46.3%), followed by non-vertebral osteomyelitis (26/82, 31.7%). Pathogens included Gram-positive cocci (70/131, 53.4%), Gram-negative bacilli (34/131, 26.0%), and fungi (9/131, 6.9%). BJI predictors included male gender (OR 2.94, 95% CI 1.26-6.89) and diabetes (OR 2.97, 95% CI 1.34-6.56). Treatment failure was observed in 25.9% (21/81) patients and 1-year mortality post-BJI diagnosis was 14.8% (9/61). BJI remain a rare event in SOTr, associated with subtle clinical presentations, high morbidity and relapses, requiring additional studies in the future

Erratum for Williams et al., "Investigation of the Plasma Virome from Cases of Unexplained Febrile Illness in Tanzania from 2013 to 2014: a Comparative Analysis between Unbiased and VirCapSeq-VERT High-Throughput Sequencing Approaches"

High-throughput sequencing can provide insights into epidemiology and medicine through comprehensive surveys of viral genetic sequences in environmental and clinical samples. Here, we characterize the plasma virome of Tanzanian patients with unexplained febrile illness by using two high-throughput sequencing methods: unbiased sequencing and VirCapSeq-VERT (a positive selection system). Sequences from dengue virus 2, West Nile virus, human immunodeficiency virus type 1, human pegivirus, and Epstein-Barr virus were identified in plasma. Both sequencing strategies recovered nearly complete genomes in samples containing multiple viruses. Whereas VirCapSeq-VERT had better sensitivity, unbiased sequencing provided better coverage of genome termini. Together, these data demonstrate the utility of high-throughput sequencing strategies in outbreak investigations. &lt;b&gt;IMPORTANCE&lt;/b&gt; Characterization of the viruses found in the blood of febrile patients provides information pertinent to public health and diagnostic medicine. PCR and culture have historically played an important role in clinical microbiology; however, these methods require a targeted approach and may lack the capacity to identify novel or mixed viral infections. High-throughput sequencing can overcome these constraints. As the cost of running multiple samples continues to decrease, the implementation of high-throughput sequencing for diagnostic purposes is becoming more feasible. Here we present a comparative analysis of findings from an investigation of unexplained febrile illness using two strategies: unbiased high-throughput sequencing and VirCapSeq-VERT, a positive selection high-throughput sequencing system