Research Article: 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

Date Published: October 23, 2017

Publisher: Public Library of Science

Author(s): Kristina Keitel, Frank Kagoro, Josephine Samaka, John Masimba, Zamzam Said, Hosiana Temba, Tarsis Mlaganile, Willy Sangu, Clotilde Rambaud-Althaus, Alain Gervaix, Blaise Genton, Valérie D’Acremont, James K. Tumwine

Abstract: BackgroundThe 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 findingsWe 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.Conclusionse-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 NCT02225769

Partial Text: Febrile illnesses comprise the vast majority of pediatric outpatient consultations in resource-poor settings [1]. Only a small percentage of these children require antibiotic treatment or referral for hospital-based supportive care, such as oxygen therapy [2]. However, correct identification of this minority of children is pivotal; substandard management of children with infections has led to 2 major public health challenges: first, persistent high mortality from common childhood infections [3] and, second, the tremendous overprescription of antibiotics at the peripheral healthcare level [4], which contributes to spreading antimicrobial resistance [5].

In this multicenter, randomized, controlled non-inferiority trial including 3,739 children with febrile illnesses in Dar es Salam, Tanzania, we showed that e-POCT, a novel patient management algorithm using host biomarker POCTs, was non-inferior to a reference electronic IMCI-based algorithm (ALMANACH) in terms of clinical outcome. e-POCT actually achieved a reduction of 43% in the proportion of clinical failures by day 7 and a reduction of 58% in the proportion of severe adverse events compared to ALMANACH, while substantially lowering the proportion of antibiotic prescriptions from 30% to 11%. e-POCT categorized more patients as having severe disease on day 0. Using e-POCT, the pattern of antibiotic prescription was shifted away from non-severe respiratory infections towards patients with severe disease when compared to the IMCI-based control algorithm. We also observed routine care among children in Dar es Salaam. Compared to children treated per routine care, e-POCT resulted in a 49% reduction in relative risk of clinical failure. In the routine care cohort, 95% of children were prescribed an antibiotic at day 0. The high proportion of antibiotic prescriptions is in line with previous studies in Dar es Salaam [2].

e-POCT, an innovative electronic algorithm using host biomarker POCTs, has the potential to improve clinical outcome for children with febrile illnesses in low-resource settings while reducing antibiotic use through improved identification of children with severe infections and increased targeting of children in need of antibiotic prescriptions. Using CRP and PCT cutoffs, integrated into an overall disease management algorithm, for the management of children with respiratory infections and FWS was safe in terms of clinical outcome. Notwithstanding the need for replication of these findings in other geographical settings and further implementation studies, our results provide first evidence that such an innovative patient management approach is beneficial. Electronic algorithms in general are important tools to increase compliance with IMCI—the integration of POCTs would make even better use of such technologies. A key advantage of using host biomarker tests, as compared with a series of disease etiology tests, is that such an approach is likely more robust to seasonal and geographical variations in disease etiology. POCTs should include tests both for identification of patients with severe disease (e.g., severe anemia) and for detection of bacterial infections (such as CRP and PCT). To make the best use of these POCTs, they should be integrated into a patient management tool that helps clinicians not only select patient subgroups for which testing is useful, but also interpret results within an overall patient assessment. This will also allow the continuation of an integrated approach to the treatment of childhood infections as advocated by IMCI.



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