Predictive value of clinical and laboratory features for the main febrile diseases in children living in Tanzania: A prospective observational study.

To construct evidence-based guidelines for management of febrile illness, it is essential to identify clinical predictors for the main causes of fever, either to diagnose the disease when no laboratory test is available or to better target testing when a test is available. The objective was to investigate clinical predictors of several diseases in a cohort of febrile children attending outpatient clinics in Tanzania, whose diagnoses have been established after extensive clinical and laboratory workup. From April to December 2008, 1005 consecutive children aged 2 months to 10 years with temperature ≥38°C attending two outpatient clinics in Dar es Salaam were included. Demographic characteristics, symptoms and signs, comorbidities, full blood count and liver enzyme level were investigated by bi- and multi-variate analyses (Chan, et al., 2008). To evaluate accuracy of combined predictors to construct algorithms, classification and regression tree (CART) analyses were also performed. 62 variables were studied. Between 4 and 15 significant predictors to rule in (aLR+>1) or rule out (aLR+<1) the disease were found in the multivariate analysis for the 7 more frequent outcomes. For malaria, the strongest predictor was temperature ≥40°C (aLR+8.4, 95%CI 4.7-15), for typhoid abdominal tenderness (5.9,2.5-11), for urinary tract infection (UTI) age ≥3 years (0.20,0-0.50), for radiological pneumonia abnormal chest auscultation (4.3,2.8-6.1), for acute HHV6 infection dehydration (0.18,0-0.75), for bacterial disease (any type) chest indrawing (19,8.2-60) and for viral disease (any type) jaundice (0.28,0.16-0.41). Other clinically relevant and easy to assess predictors were also found: malaria could be ruled in by recent travel, typhoid by jaundice, radiological pneumonia by very fast breathing and UTI by fever duration of ≥4 days. The CART model for malaria included temperature, travel, jaundice and hepatomegaly (sensitivity 80%, specificity 64%); typhoid: age ≥2 years, jaundice, abdominal tenderness and adenopathy (46%,93%); UTI: age <2 years, temperature ≥40°C, low weight and pale nails (20%,96%); radiological pneumonia: very fast breathing, chest indrawing and leukocytosis (38%,97%); acute HHV6 infection: less than 2 years old, (no) dehydration, (no) jaundice and (no) rash (86%,51%); bacterial disease: chest indrawing, chronic condition, temperature ≥39.7°c and fever duration >3 days (45%,83%); viral disease: runny nose, cough and age <2 years (68%,76%). A better understanding of the relative performance of these predictors might be of great help for clinicians to be able to better decide when to test, treat, refer or simply observe a sick child, in order to decrease morbidity and mortality, but also to avoid unnecessary antimicrobial prescription. These predictors have been used to construct a new algorithm for the management of childhood illnesses called ALMANACH

Beyond malaria--causes of fever in outpatient Tanzanian children.

BACKGROUND: As the incidence of malaria diminishes, a better understanding of nonmalarial fever is important for effective management of illness in children. In this study, we explored the spectrum of causes of fever in African children. METHODS: We recruited children younger than 10 years of age with a temperature of 38°C or higher at two outpatient clinics--one rural and one urban--in Tanzania. Medical histories were obtained and clinical examinations conducted by means of systematic procedures. Blood and nasopharyngeal specimens were collected to perform rapid diagnostic tests, serologic tests, culture, and molecular tests for potential pathogens causing acute fever. Final diagnoses were determined with the use of algorithms and a set of prespecified criteria. RESULTS: Analyses of data derived from clinical presentation and from 25,743 laboratory investigations yielded 1232 diagnoses. Of 1005 children (22.6% of whom had multiple diagnoses), 62.2% had an acute respiratory infection; 5.0% of these infections were radiologically confirmed pneumonia. A systemic bacterial, viral, or parasitic infection other than malaria or typhoid fever was found in 13.3% of children, nasopharyngeal viral infection (without respiratory symptoms or signs) in 11.9%, malaria in 10.5%, gastroenteritis in 10.3%, urinary tract infection in 5.9%, typhoid fever in 3.7%, skin or mucosal infection in 1.5%, and meningitis in 0.2%. The cause of fever was undetermined in 3.2% of the children. A total of 70.5% of the children had viral disease, 22.0% had bacterial disease, and 10.9% had parasitic disease. CONCLUSIONS: These results provide a description of the numerous causes of fever in African children in two representative settings. Evidence of a viral process was found more commonly than evidence of a bacterial or parasitic process. (Funded by the Swiss National Science Foundation and others.)

Clinical Outcome of Febrile Tanzanian Children with Severe Malnutrition Using Anthropometry in Comparison to Clinical Signs.

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

Safety and Efficacy of C-reactive Protein-guided Antibiotic Use to Treat Acute Respiratory Infections in Tanzanian Children: A Planned Subgroup Analysis of a Randomized Controlled Noninferiority Trial Evaluating a Novel Electronic Clinical Decision Algorithm (ePOCT).

The 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. This 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. A 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]). CRP 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. NCT02225769

A novel electronic algorithm using host biomarker point-of-care tests for the management of febrile illnesses in Tanzanian children (e-POCT): A randomized, controlled non-inferiority trial

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 NCT0222576

A novel electronic algorithm using host biomarker point-of-care tests for the management of febrile illnesses in Tanzanian children (e-POCT): A randomized, controlled non-inferiority trial.

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. 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 &lt; 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 &lt; 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. 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. ClinicalTrials.gov NCT02225769

Prevalence of respiratory viruses among febrile children with or without acute respiratory symptoms in Tanzania

Background Respiratory viruses are the most frequent cause of febrile illnesses in infants and young children but few investigations have assessed their impact and epidemiology in Africa . We investigated their rate in febrile outpatient children attending in Tanzania. Methods Children aged 2 months -10 years with fever &gt;38 _C were recruited prospectively between April and December 2008. Medical history and clinical examination were recorded in a standardized fashion and nasopharyngeal swabs analyzed for the presence of 12 viruses by real-time PCR (FLUAV, FLUBV, RSV, MPV, HPIV-1/3, four types of HCoV, HBoV, PIC and HAdV). Ct values were used to provide semi-quantitative viral loads.Results Of 1005 febrile children enrolled, 623 (62%) had respiratory symptoms (URTI in 66%, bronchiolitis in 7% and clinical pneumonia in 27%); 156 (16%) had febrile illness that remained of unspecified etiology and 226 (22%) had other infectious diseases and no ARI (62 malaria, 56 gastroenteritis, 36 urinary tract and 72 others). The proportions of patients with at least one respiratory virus were 70%, 61% and 47% (Pvalue &lt; 0.001) in these three groups. When excluding picornavirus and adenovirus these proportions were 48%, 24% and 26% (P-value &lt; 0.001). Apart from picornavirus and adenovirus, influenza A and B viruses were the most frequent followed by coronavirus and RSV. The proportion of children with presumably high viral titers (Ct &lt; 25) was higher in the group with respiratory symptoms (31%) than in the two other groups (21% and 16%). Influenza genotyping revealed strains that were similar to the ones circulating elsewhere in the world.Conclusion In African children with febrile illness, the prevalence of respiratory viruses, especially influenza A and B, is high particularly in the presence of respiratory symptoms, but also, although less so, in those with unspecified etiology or other infectious diseases. This highlights that these viruses are commonly circulating in Tanzanian children