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Children with malnutrition compared with those without are at higher risk of infection, with more severe outcomes. How clinicians assess nutritional risk factors in febrile children in primary care varies. We conducted a post hoc subgroup analysis of febrile children with severe malnutrition enrolled in a randomized, controlled trial in primary care centers in Tanzania. The clinical outcome of children with severe malnutrition defined by anthropometric measures and clinical signs was compared between two electronic clinical diagnostic algorithms: ePOCT, which uses weight-for-age and mid-upper arm circumference to identify and manage severe malnutrition, and ALMANACH, which uses the clinical signs of edema of both feet and visible severe wasting. Those identified as having severe malnutrition by the algorithms in each arm were prescribed antibiotics and referred to the hospital. From December 2014 to February 2016, 106 febrile children were enrolled and randomized in the parent study, and met the criteria to be included in the present analysis. ePOCT identified 56/57 children with severe malnutrition using anthropometric measures, whereas ALMANACH identified 2/49 children with severe malnutrition using clinical signs. The proportion of clinical failure, defined as the development of severe symptoms by day 7 or persisting symptoms at day 7 (per-protocol), was 1.8% (1/56) in the ePOCT arm versus 16.7% (8/48) in the Algorithm for the MANagement of Childhood illnesses arm (risk difference −14.9%, 95% CI −26.0%, −3.8%; risk ratio 0.11, 95% CI 0.01, 0.83). Using anthropometric measures to identify and manage febrile children with severe malnutrition may have resulted in better clinical outcomes than by using clinical signs alone.

Background Inappropriate antibiotics use in lower respiratory tract infections (LRTI) is a major contributor to resistance. We aimed to design an algorithm based on clinical signs and host biomarkers to identify bacterial community-acquired pneumonia (CAP) among patients with LRTI. Methods Participants with LRTI were selected in a prospective cohort of febrile (≥ 38 °C) adults presenting to outpatient clinics in Dar es Salaam. Participants underwent chest X-ray, multiplex PCR for respiratory pathogens, and measurements of 13 biomarkers. We evaluated the predictive accuracy of clinical signs and biomarkers using logistic regression and classification and regression tree analysis. Results Of 110 patients with LRTI, 17 had bacterial CAP. Procalcitonin (PCT), interleukin-6 (IL-6) and soluble triggering receptor expressed by myeloid cells-1 (sTREM-1) showed an excellent predictive accuracy to identify bacterial CAP (AUROC 0.88, 95%CI 0.78–0.98; 0.84, 0.72–0.99; 0.83, 0.74–0.92, respectively). Combining respiratory rate with PCT or IL-6 significantly improved the model compared to respiratory rate alone (p = 0.006, p = 0.033, respectively). An algorithm with respiratory rate (≥ 32/min) and PCT (≥ 0.25 μg/L) had 94% sensitivity and 82% specificity. Conclusions PCT, IL-6 and sTREM-1 had an excellent predictive accuracy in differentiating bacterial CAP from other LRTIs. An algorithm combining respiratory rate and PCT displayed even better performance in this sub-Sahara African setting.

Viral infections are the leading cause of childhood acute febrile illnesses motivating consultation in sub-Saharan Africa. The majority of causal viruses are never identified in low-resource clinical settings as such testing is either not part of routine screening or available diagnostic tools have limited ability to detect new/unexpected viral variants. An in-depth exploration of the blood virome is therefore necessary to clarify the potential viral origin of fever in children. Metagenomic next-generation sequencing is a powerful tool for such broad investigations, allowing the detection of RNA and DNA viral genomes. Here, we describe the blood virome of 816 febrile children (

Background 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. Methods 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. Results 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

Background The management of childhood infections remains inadequate in resource-limited countries, resulting in high mortality and irrational use of antimicrobials. Current disease management tools, such as the Integrated Management of Childhood Illness (IMCI) algorithm, rely solely on clinical signs and have not made use of available point-of-care tests (POCTs) that can help to identify children with severe infections and children in need of antibiotic treatment. e-POCT is a novel electronic algorithm based on current evidence; it guides clinicians through the entire consultation and recommends treatment based on a few clinical signs and POCT results, some performed in all patients (malaria rapid diagnostic test, hemoglobin, oximeter) and others in selected subgroups only (C-reactive protein, procalcitonin, glucometer). The objective of this trial was to determine whether the clinical outcome of febrile children managed by the e-POCT tool was non-inferior to that of febrile children managed by a validated electronic algorithm derived from IMCI (ALMANACH), while reducing the proportion with antibiotic prescription. Methods and findings We performed a randomized (at patient level, blocks of 4), controlled non-inferiority study among children aged 2–59 months presenting with acute febrile illness to 9 outpatient clinics in Dar es Salaam, Tanzania. In parallel, routine care was documented in 2 health centers. The primary outcome was the proportion of clinical failures (development of severe symptoms, clinical pneumonia on/after day 3, or persistent symptoms at day 7) by day 7 of follow-up. Non-inferiority would be declared if the proportion of clinical failures with e-POCT was no worse than the proportion of clinical failures with ALMANACH, within statistical variability, by a margin of 3%. The secondary outcomes included the proportion with antibiotics prescribed on day 0, primary referrals, and severe adverse events by day 30 (secondary hospitalizations and deaths). We enrolled 3,192 patients between December 2014 and February 2016 into the randomized study; 3,169 patients (e-POCT: 1,586; control [ALMANACH]: 1,583) completed the intervention and day 7 follow-up. Using e-POCT, in the per-protocol population, the absolute proportion of clinical failures was 2.3% (37/1,586), as compared with 4.1% (65/1,583) in the ALMANACH arm (risk difference of clinical failure −1.7, 95% CI −3.0, −0.5), meeting the prespecified criterion for non-inferiority. In a non-prespecified superiority analysis, we observed a 43% reduction in the relative risk of clinical failure when using e-POCT compared to ALMANACH (risk ratio [RR] 0.57, 95% CI 0.38, 0.85, p = 0.005). The proportion of severe adverse events was 0.6% in the e-POCT arm compared with 1.5% in the ALMANACH arm (RR 0.42, 95% CI 0.20, 0.87, p = 0.02). The proportion of antibiotic prescriptions was substantially lower, 11.5% compared to 29.7% (RR 0.39, 95% CI 0.33, 0.45, p < 0.001). Using e-POCT, the most common indication for antibiotic prescription was severe disease (57%, 103/182 prescriptions), while it was non-severe respiratory infections using the control algorithm (ALMANACH) (70%, 330/470 prescriptions). The proportion of clinical failures among the 544 children in the routine care cohort was 4.6% (25/544); 94.9% (516/544) of patients received antibiotics on day 0, and 1.1% (6/544) experienced severe adverse events. e-POCT achieved a 49% reduction in the relative risk of clinical failure compared to routine care (RR 0.51, 95% CI 0.31, 0.84, p = 0.007) and lowered antibiotic prescriptions to 11.5% from 94.9% (p < 0.001). Though this safety study was an important first step to evaluate e-POCT, its true utility should be evaluated through future implementation studies since adherence to the algorithm will be an important factor in making use of e-POCT’s advantages in terms of clinical outcome and antibiotic prescription. Conclusions e-POCT, an innovative electronic algorithm using host biomarker POCTs, including C-reactive protein and procalcitonin, has the potential to improve the clinical outcome of children with febrile illnesses while reducing antibiotic use through improved identification of children with severe infections, and better targeting of children in need of antibiotic prescription. Trial registration ClinicalTrials.gov NCT02225769, In a randomized controlled non-inferiority trial, Kristina Keitel and colleagues compare the use of an electronic algorithm using host biomarker point-of-care-tests to routine care for the management of febrile illnesses in Tanzanian children., Author summary Why was this study done? Case management of children with infections remains inadequate, and antibiotic overprescription is a major challenge. To improve case management of children with acute infections, we developed an innovative tool: e-POCT, a smartphone-based algorithm that uses tests performed at the patient care site (point-of-care tests: oximetry, hemoglobin, C-reactive protein, and procalcitonin). Given the innovative nature of this algorithm, we assessed the safety of e-POCT in treating children with acute infections. What did the researchers do and find? In a randomized trial in Dar es Salaam, Tanzania, we compared the clinical outcomes of 1,586 children under 5 years with acute infections treated using e-POCT with that of 1,583 children treated using the current reference smartphone algorithm (ALMANACH). We observed that e-POCT improved clinical outcomes while reducing antibiotic prescription from 30% to 11%. e-POCT better targeted those children truly in need of antibiotic treatment through enhanced identification of children with severe diseases. What do these findings mean? e-POCT, an innovative smartphone algorithm using point-of-care tests, has the potential to improve clinical outcomes for children with acute infections and to increase the rational use of antibiotics. Future studies should assess e-POCT’s performance in routine care settings.

Background: Viral infections are the leading cause of childhood acute febrile illnesses motivating consultation in sub-Saharan Africa. The majority of causal viruses are never identified in low-resource clinical settings as such testing is either not part of routine screening or available diagnostic tools have limited ability to detect new/unexpected viral variants. An in-depth exploration of the blood virome is therefore necessary to clarify the potential viral origin of fever in children. Untargeted metagenomic next-generation sequencing is a powerful tool for such broad investigations, allowing the detection of RNA and DNA viral genomes. Results: Here, we describe the blood virome of 816 febrile children (Conclusions: This study highlighted several DNA and RNA viral sequences on a population of young children with fever of unknown origin and/or severe outcomes living in Tanzania, and provides a large list of novel viruses that should be considered as a potential cause of human infections.

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.

Background A novel ultrasensitive malaria rapid diagnostic test (us-RDT) has been developed for improved active Plasmodium falciparum infection detection. The usefulness of this us-RDT in clinical diagnosis and fever management has not been evaluated. Methods Diagnostic performance of us-RDT was compared retrospectively to that of conventional RDT (co-RDT) in 3000 children and 515 adults presenting with fever to Tanzanian outpatient clinics. The parasite density was measured by an ultrasensitive qPCR (us-qPCR), and the HRP2 concentration was measured by an enzyme-linked immunosorbent assay. Results us-RDT identified few additional P. falciparum–positive patients as compared to co-RDT (276 vs 265 parasite-positive patients detected), with only a marginally greater sensitivity (75% vs 73%), using us-qPCR as the gold standard (357 parasite-positive patients detected). The specificity of both RDTs was >99%. Five of 11 additional patients testing positive by us-RDT had negative results by us-qPCR. The HRP2 concentration was above the limit of detection for co-RDT (>3653 pg of HRP2 per mL of blood) in almost all infections (99% [236 of 239]) with a parasite density >100 parasites per µL of blood. At parasite densities 793 pg/mL) and co-RDT in 29 (25%) and 24 (20%) of 118 patients, respectively. Conclusion There is neither an advantage nor a risk of using us-RDT, rather than co-RDT, for clinical malaria diagnosis. In febrile patients, only a small proportion of infections are characterized by a parasite density or an HRP2 concentration in the range where use of us-RDT would confer a meaningful advantage over co-RDT., Ultrasensitive rapid diagnostic tests (RDTs) for malaria, designed for Plasmodium falciparum elimination campaigns, may be used off label in clinical practice. The diagnostic performances of ultrasensitive and conventional RDTs were similar in febrile Tanzanian outpatients, which is explained by the underlying HRP2 concentration and parasite density distributions.

BackgroundThe inability to identify individuals with acute fever at risk of death is a barrier to effective triage and management of severe infections, especially in low-resource settings. Since endothelial and immune activation contribute to the pathogenesis of various distinct life-threatening infections, we hypothesized that measuring mediators of these pathways at clinical presentation would identify febrile adults at risk of death.MethodsPlasma concentrations of markers of endothelial (angiopoetin-1/2, soluble fms-like tyrosine kinase-1, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1) and immune (soluble triggering receptor expressed on myeloid cells [sTREM-1], interleukin-6, interleukin-8, chitinase-3-like protein-1, soluble tumor necrosis factor receptor-1, procalcitonin [PCT], C-reactive protein [CRP]) activation pathways were determined in consecutive adults with acute fever (≥38°C) at presentation to outpatient clinics in Dar es Salaam, Tanzania. We evaluated the accuracy of these mediators in predicting all-cause mortality and examined whether markers could improve the prognostic accuracy of clinical scoring systems, including the quick sequential organ failure assessment (qSOFA) and Glasgow coma scale (GCS).ResultsOf 507 febrile adults, 32 died (6.3%) within 28 days of presentation. We found that sTREM-1 was the best prognostic marker for 28-day mortality (area under the receiver operating characteristic [AUROC] 0.87, 95% confidence interval [CI] 0.81–0.92) and was significantly better than CRP (P < .0001) and PCT (P = .0001). The prognostic accuracy of qSOFA and the GCS were significantly enhanced when sTREM-1 was added (0.80 [95% CI 0.76–0.83] to 0.91 [95% CI 0.88–0.94; P < .05] and 0.72 [95% CI 0.63–0.80] to 0.94 [95% CI 0.91–0.97; P < .05], respectively).ConclusionsMeasuring sTREM-1 at clinical presentation can identify febrile individuals at risk of all-cause febrile mortality. Adding severity markers such as sTREM-1 to simple clinical scores could improve the recognition and triage of patients with life-threatening infections in resource-limited settings.

Fever is the leading cause of paediatric outpatient consultations in Sub-Saharan Africa. Although most are suspected to be of viral origin, a putative causative pathogen is not identified in over a quarter of these febrile episodes. Using a de novo assembly sequencing approach, we report the detection (15.4%) of dicistroviruses (DicV) RNA in sera collected from 692 febrile Tanzanian children. In contrast, DicV RNA was only detected in 1/77 (1.3%) plasma samples from febrile Tanzanian adults, suggesting that children could represent the primary susceptible population. Estimated viral load by specific quantitative real-time RT–PCR assay ranged from < 1.32E3 to 1.44E7 viral RNA copies/mL serum. Three DicV full-length genomes were obtained, and a phylogenetic analyse on the capsid region showed the presence of two clusters representing tentative novel genus. Although DicV-positive cases were detected throughout the year, a significantly higher positivity rate was observed during the rainy season. This study reveals that novel DicV RNA is frequently detected in the blood of Tanzanian children, paving the way for further investigations to determine if DicV possibly represent a new agent in humans.

Objectives Exploring fever aetiologies improves patient management. Most febrile adults are outpatients, but all previous studies were conducted in inpatients. This study describes the spectrum of diseases in adults attending outpatient clinics in urban Tanzania. Methods We recruited consecutive adults with temperature ≥38°C in a prospective cohort study. We collected medical history and performed a clinical examination. We performed 27 364 microbiological diagnostic tests (rapid tests, serologies, cultures and molecular analyses) for a large range of pathogens on blood and nasopharyngeal samples. We based our diagnosis on predefined clinical and microbiological criteria. Results Of 519 individuals, 469 (89%) had a clinically or microbiologically documented infection and 128 (25%) were human immunodeficiency virus (HIV) -infected. We identified 643 diagnoses: 264 (41%) acute respiratory infections (36 (5.6%) pneumonia, 39 (6.1%) tuberculosis), 71 (11%) infections with another focus (31 (4.8%) gastrointestinal, 26 (4.0%) urogenital, 8 (1.2%) central nervous system) and 252 (39%) infections without focus (134 (21%) dengue, 30 (4.7%) malaria, 28 (4.4%) typhoid). Of the 519 individuals, 318 (61%), 179 (34%), 30 (6%) and 15 (3%), respectively, had a viral, bacterial, parasitic and fungal acute infection. HIV-infected individuals had more bacterial infections than HIV-negative (80/122 (66%) versus 100/391 (26%); p 200 cells/mm3, p 0.02). Conclusions Viral diseases caused most febrile episodes in adults attending outpatient clinics except in HIV-infected patients. HIV status and a low CD4 level strongly determined the need for antibiotics. Systematic HIV screening is essential to appropriately manage febrile patients.

In low-resource settings, where qualified health workers (HWs) are scarce and childhood mortality high, rational antimicrobial prescription for childhood illnesses is a challenge. To assess whether smartphones running guidelines, as compared with paper support, improve consultation process and rational use of medicines for children, a pilot cluster-randomized controlled study was conducted in Tanzania. Nine primary health-care facilities (HFs) were randomized into three arms: 1) paper algorithm, 2) electronic algorithm on a smartphone, and 3) control. All HWs attending children aged 2-59 months for acute illness in intervention HFs were trained on a new clinical algorithm for management of childhood illness (ALMANACH) either on 1) paper or 2) electronic support; 4 months after training, consultations were observed. An expert consultation was the reference for classification and treatment. Main outcomes were proportion of children checked for danger signs, and antibiotics prescription rate. A total of 504 consultations (166, 171, and 167 in control, paper, and phone arms, respectively) were observed. The use of smartphones versus paper was associated with a significant increase in children checked for danger signs (41% versus 74%, P = 0.04). Antibiotic prescriptions rate dropped from 70% in the control to 26%, and 25% in paper and electronic arms. The HWs-expert agreement on pneumonia classification remained low (expert's pneumonia identified by HWs in 26%, 30%, and 39% of patients, respectively).Mobile technology in low-income countries is implementable and has a potential to improve HWs' performance. Additional point-of-care diagnostic tests are needed to ensure appropriate management. Improving the rational use of antimicrobial is a challenge that ALMANACH can help to take up.

BackgroundThe safety and efficacy of using C-reactive protein (CRP) to decide on antibiotic prescription among febrile children at risk of pneumonia has not been tested.MethodsThis was a randomized (1:1) controlled noninferiority trial in 9 primary care centers in Tanzania (substudy of the ePOCT trial evaluating a novel electronic decision algorithm). Children aged 2–59 months with fever and cough and without life-threatening conditions received an antibiotic based on a CRP-informed strategy (combination of CRP ≥80 mg/L plus age/temperature-corrected tachypnea and/or chest indrawing) or current World Health Organization standard (respiratory rate ≥50 breaths/minute). The primary outcome was clinical failure by day (D) 7; the secondary outcomes were antibiotic prescription at D0, secondary hospitalization, or death by D30.ResultsA total of 1726 children were included (intervention: 868, control: 858; 0.7% lost to follow-up). The proportion of clinical failure by D7 was 2.9% (25/865) in the intervention arm vs 4.8% (41/854) in the control arm (risk difference, –1.9% [95% confidence interval {CI}, –3.7% to –.1%]; risk ratio [RR], 0.60 [95% CI, .37–.98]). Twenty of 865 (2.3%) children in the intervention arm vs 345 of 854 (40.4%) in the control arm received antibiotics at D0 (RR, 0.06 [95% CI, .04–.09]). There were fewer secondary hospitalizations and deaths in the CRP arm: 0.5% (4/865) vs 1.5% (13/854) (RR, 0.30 [95% CI, .10–.93]).ConclusionsCRP testing using a cutoff of ≥80 mg/L, integrated into an electronic decision algorithm, was able to improve clinical outcome in children with respiratory infections while substantially reducing antibiotic prescription.Clinical Trials RegistrationNCT02225769.

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., 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. IMPORTANCE 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.

Background 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. Methods 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. Results 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

Volume 3, no. 4, e00311-18, 2018, [https://doi.org/10.1128/mSphere.00311-18][1]. Page 4 of the PDF, Fig. 1 legend: in the third line of the legend, “coding regions” should be replaced with “genes.” [1]: /lookup/doi/10.1128/mSphere.00311-18

INTRODUCTION: The decline of malaria and scale-up of rapid diagnostic tests calls for a revision of IMCI. A new algorithm (ALMANACH) running on mobile technology was developed based on the latest evidence. The objective was to ensure that ALMANACH was safe, while keeping a low rate of antibiotic prescription. METHODS: Consecutive children aged 2-59 months with acute illness were managed using ALMANACH (2 intervention facilities), or standard practice (2 control facilities) in Tanzania. Primary outcomes were proportion of children cured at day 7 and who received antibiotics on day 0. RESULTS: 130/842 (15∙4%) in ALMANACH and 241/623 (38∙7%) in control arm were diagnosed with an infection in need for antibiotic, while 3∙8% and 9∙6% had malaria. 815/838 (97∙3%;96∙1-98.4%) were cured at D7 using ALMANACH versus 573/623 (92∙0%;89∙8-94∙1%) using standard practice (p