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

Nearly Complete Genome Sequence of a Novel Phlebovirus-Like Virus Detected in a Human Plasma Sample by High-Throughput Sequencing.

Here, we report a novel phlebovirus-like virus sequence detected in a plasma sample from a febrile adult patient collected in the United Republic of Tanzania in 2014. A nearly complete RNA sequence was generated by high-throughput sequencing on a HiSeq 2500 instrument and further confirmed after repeating the analysis, starting from the initial sample

Adequate plasma drug concentrations suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps.

Elastomeric pumps can be useful for the administration of antibiotics in the outpatient setting. To determine amoxicillin degradation in elastomeric pumps, as well as the effectiveness of amoxicillin treatment administered by elastomeric pumps. Antibiotic degradation was measured in elastomeric pumps filled with 6 g of amoxicillin in 240 mL of NaCl 0.9% by drawing samples at 12 h intervals when stored in the fridge for 48 h and when worn around the waist for 24 h. Subsequently nine patients were treated with continuous infusions of 8 or 12 g of amoxicillin per day. Plasma amoxicillin concentrations were measured on each visit to the outpatient parenteral antibiotic therapy unit. Clinical outcome was verified 3 months after the end of treatment. Amoxicillin degradation in elastomeric pumps reached 10% after 48 h in the fridge and an additional 30% when worn around the waist for 24 h. Mean plasma drug concentrations achieved with 12 g of amoxicillin per day were 18.5 mg/L (95% CI 13.5-23.5), which is largely above the MIC of amoxicillin-susceptible bacteria. Nine patients treated for various complicated infections were cured and had no unexpected adverse effects. Adequate plasma drug concentrations and favourable clinical outcomes suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps. This treatment modality does not fulfil formal requirements regarding pharmaceutical stability, but the resulting safety impact in patients is probably limited. Therapeutic drug monitoring and a close clinical follow-up are recommended if this route of administration is chosen

COVID-19 risk stratification algorithms based on sTREM-1 and IL-6 in emergency department.

The coronavirus disease 2019 (COVID-19) pandemic has led to surges of patients presenting to emergency departments (EDs) and potentially overwhelming health systems. We sought to assess the predictive accuracy of host biomarkers at clinical presentation to the ED for adverse outcome. Prospective observational study of PCR-confirmed COVID-19 patients in the ED of a Swiss hospital. Concentrations of inflammatory and endothelial dysfunction biomarkers were determined at clinical presentation. We evaluated the accuracy of clinical signs and these biomarkers in predicting 30-day intubation/mortality, and oxygen requirement by calculating the area under the receiver-operating characteristic curve and by classification and regression tree analysis. Of 76 included patients with COVID-19, 24 were outpatients or hospitalized without oxygen requirement, 35 hospitalized with oxygen requirement, and 17 intubated/died. We found that soluble triggering receptor expressed on myeloid cells had the best prognostic accuracy for 30-day intubation/mortality (area under the receiver-operating characteristic curve, 0.86; 95% CI, 0.77-0.95) and IL-6 measured at presentation to the ED had the best accuracy for 30-day oxygen requirement (area under the receiver-operating characteristic curve, 0.84; 95% CI, 0.74-0.94). An algorithm based on respiratory rate and sTREM-1 predicted 30-day intubation/mortality with 94% sensitivity and 0.1 negative likelihood ratio. An IL-6-based algorithm had 98% sensitivity and 0.04 negative likelihood ratio for 30-day oxygen requirement. sTREM-1 and IL-6 concentrations in COVID-19 in the ED have good predictive accuracy for intubation/mortality and oxygen requirement. sTREM-1- and IL-6-based algorithms are highly sensitive to identify patients with adverse outcome and could serve as early triage tools

Pulse Oximetry as an Aid to Rule Out Pneumonia among Patients with a Lower Respiratory Tract Infection in Primary Care.

Guidelines recommend chest X-rays (CXRs) to diagnose pneumonia and guide antibiotic treatment. This study aimed to identify clinical predictors of pneumonia that are visible on a chest X-ray (CXR+) which could support ruling out pneumonia and avoiding unnecessary CXRs, including oxygen saturation. A secondary analysis was performed in a clinical trial that included patients with suspected pneumonia in Swiss primary care. CXRs were reviewed by two radiologists. We evaluated the association between clinical signs (heart rate &gt; 100/min, respiratory rate ≥ 24/min, temperature ≥ 37.8 °C, abnormal auscultation, and oxygen saturation &lt; 95%) and CXR+ using multivariate analysis. We also calculated the diagnostic performance of the associated clinical signs combined in a clinical decision rule (CDR), as well as a CDR derived from a large meta-analysis (at least one of the following: heart rate &gt; 100/min, respiratory rate ≥ 24/min, temperature ≥ 37.8 °C, or abnormal auscultation). Out of 469 patients from the initial trial, 107 had a CXR and were included in this study. Of these, 26 (24%) had a CXR+. We found that temperature and oxygen saturation were associated with CXR+. A CDR based on the presence of either temperature ≥ 37.8 °C and/or an oxygen saturation level &lt; 95% had a sensitivity of 69% and a negative likelihood ratio (LR-) of 0.45. The CDR from the meta-analysis had a sensitivity of 92% and an LR- of 0.37. The addition of saturation &lt; 95% to this CDR increased the sensitivity (96%) and decreased the LR- (0.21). In conclusion, this study suggests that pulse oximetry could be added to a simple CDR to decrease the probability of pneumonia to an acceptable level and avoid unnecessary CXRs

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

Retrospective study on the usefulness of pulse oximetry for the identification of young children with severe illnesses and severe pneumonia in a rural outpatient clinic of Papua New Guinea.

This secondary analysis of data of a randomized controlled trial (RCT) retrospectively investigated the performance of pulse oximetry in identifying children with severe illnesses, with and without respiratory signs/symptoms, in a cohort of children followed for morbid episodes in an intervention trial assessing the efficacy of Intermittent Preventive Treatment for malaria in infants (IPTi) in Papua New Guinea (PNG) from June 2006 to May 2010. The IPTi study was conducted in a paediatric population visiting two health centres on the north coast of PNG in the Mugil area of the Sumkar District. A total of 669 children visited the clinic and a total of 1921 illness episodes were recorded. Inclusion criteria were: age between 3 and 27 months, full clinical record (signs/symptoms) and pulse oximetry used systematically to assess sick children at all visits. Children were excluded if they visited the clinic in the previous 14 days. The outcome measures were severe illness, severe pneumonia, pneumonia, defined by the Integrated Management of Childhood Illness (IMCI) definitions, and hospitalization. Out of 1921 illness episodes, 1663 fulfilled the inclusion criteria. A total of 139 severe illnesses were identified, of which 93 were severe pneumonia. The ROC curves of pulse oximetry (continuous variable) showed an AUC of 0.63, 0.68 and 0.65 for prediction of severe illness, severe pneumonia and hospitalization, respectively. Pulse oximetry allowed better discrimination between severe and non-severe illness, severe and non-severe pneumonia, admitted and non-admitted patients, in children ≤12-months of age relative to older patients. For the threshold of peripheral arterial oxygen saturation ≤ 94% measured by pulse oximetry (SpO2), unadjusted odds ratios for severe illness, severe pneumonia and hospitalization were 6.1 (95% Confidence Interval (CI) 3.9-9.8), 8.5 (4.9-14.6) and 5.9 (3.4-10.3), respectively. Pulse oximetry was helpful in identifying children with severe illness in outpatient facilities in PNG. A SpO2 of 94% seems the most discriminative threshold. Considering its affordability and ease of use, pulse oximetry could be a valuable additional tool assisting the decision to admit for treatment

Patient satisfaction in an outpatient parenteral antimicrobial therapy (OPAT) unit practising predominantly self-administration of antibiotics with elastomeric pumps.

Self-administration of antibiotics using elastomeric pumps has become the most frequently used treatment modality at the outpatient parenteral antimicrobial therapy (OPAT) unit of the University Hospital of Lausanne. However, it remains unknown how comfortable patients feel using this mode of treatment. A questionnaire was offered to all patients treated at the OPAT unit between June 2014 and December 2015. The questionnaire was distributed to 188 patients and 112 questionnaires were returned. Seventy-one patients were treated by self-administration, 21 attended the OPAT unit on a daily basis, and 20 received their antibiotics from home-care nurses. Overall, 83-97% of the patients gave the highest possible scores to the four items evaluating their global satisfaction. Subjects treated by self-administration gave a significantly better rating to 6 of the 17 semi-quantitative questions than the patients treated at the OPAT unit or by home-care nurses. There was no item which was more poorly rated by patients treated by self-administered OPAT than by the other treatment groups. In conclusion satisfaction was high in all patients treated by OPAT. The particularly high satisfaction of patients treated by self-administration of antibiotics with elastomeric pumps suggests that a significant number of patients are happy to take over some responsibility for their treatment. Patients' capacity to appropriate their care themselves should not be underestimated by health care professionals