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
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, 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
Abstract
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.
Conflict of interest statement
The authors have declared that no competing interests exist.
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References
- Burton DC, Flannery B, Onyango B, Larson C, Alaii J, Zhang X, et al. Healthcare-seeking behaviour for common infectious disease-related illnesses in rural Kenya: a community-based house-to-house survey. J Heal Popul Nutr. 2011;29:61–70. doi:
- Shao AF, Rambaud-Althaus C, Samaka J, Faustine AF, Perri-Moore S, Swai N, et al. New algorithm for managing childhood illness using mobile technology (ALMANACH): a controlled non-inferiority study on clinical outcome and antibiotic use in Tanzania. PLoS ONE. 2015;10:e0132316 doi:
- Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, et al. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2014;385:430–40. doi:
- Risk R, Naismith H, Burnett A, Moore SE, Cham M, Unger S. Rational prescribing in paediatrics in a resource-limited setting. Arch Dis Child. 2013;98:503–9. doi:
- Okeke IN, Laxminarayan R, Bhutta ZA, Duse AG, Jenkins P, O’Brien TF, et al. Antimicrobial resistance in developing countries. Part I: recent trends and current status. Lancet Infect Dis. 2005;5:481–93. doi:
- Horwood C, Butler LM, Vermaak K, Rollins N, Haskins L, Nkosi P, et al. Disease profile of children under 5 years attending primary health care clinics in a high HIV prevalence setting in South Africa. Trop Med Int Health. 2011;16:42–52. doi:
- World Health Organization. IMCI chart booklet. Geneva: World Health Organization; 2014. [cited 2017 Sep 22]. Available: .
- Gera T, Shah D, Garner P, Richardson M, Sachdev HS. Integrated management of childhood illness (IMCI) strategy for children under five. Cochrane Database Syst Rev. 2016;6:CD010123 doi:
- Horwood C, Vermaak K, Rollins N, Haskins L, Nkosi P, Qazi S. An evaluation of the quality of IMCI assessments among IMCI trained health workers in South Africa. PLoS ONE. 2009;4:e5937 doi:
- Baiden F, Owusu-Agyei S, Bawah J, Bruce J, Tivura M, Delmini R, et al. An evaluation of the clinical assessments of under-five febrile children presenting to primary health facilities in rural Ghana. PLoS ONE. 2011;6:e28944 doi:
- Arifeen SE, Bryce J, Gouws E, Baqui AH, Black RE, Hoque DME, et al. Quality of care for under-fives in first-level health facilities in one district of Bangladesh. Bull World Health Organ. 2005;83:260–7. /S0042-96862005000400009 doi:
- Mitchell M, Hedt-Gauthier BL, Msellemu D, Nkaka M, Lesh N. Using electronic technology to improve clinical care—results from a before-after cluster trial to evaluate assessment and classification of sick children according to Integrated Management of Childhood Illness (IMCI) protocol in Tanzania. BMC Med Inform Decis Mak. 2013;13:95 doi:
- D’Acremont V, Kahama-Maro J, Swai N, Mtasiwa D, Genton B, Lengeler C. Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study. Malar J. 2011;10:107 doi:
- Rambaud-Althaus C, Shao AF, Kahama-Maro J, Genton B, D’Acremont V. Managing the sick child in the era of declining malaria transmission: development of ALMANACH, an electronic algorithm for appropriate use of antimicrobials. PLoS ONE. 2015;10:e0127674 doi:
- D’Acremont V, Kilowoko M, Kyungu E, Philipina S, Sangu W, Kahama-Maro J, et al. Beyond malaria—causes of fever in outpatient Tanzanian children. N Engl J Med. 2014;370:809–17. doi:
- Thompson M, Van den Bruel A, Verbakel J, Lakhanpaul M, Haj-Hassan T, Stevens R, et al. Systematic review and validation of prediction rules for identifying children with serious infections in emergency departments and urgent-access primary care. Health Technol Assess. 2012;16:1–100. doi:
- Van den Bruel A, Thompson MJ, Haj-Hassan T, Stevens R, Moll H, Lakhanpaul M, et al. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. BMJ. 2011;342:d3082 doi:
- Do NTT, Ta NTD, Tran NTH, Than HM, Vu BTN, Hoang LB, et al. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob Heal. 2016;4:e633–41. doi:
- Thompson M, Harnden A, Perera R, Mayon-White R, Smith L, McLeod D, et al. Deriving temperature and age appropriate heart rate centiles for children with acute infections. Arch Dis Child. 2009;94:361–5. doi:
- Nijman RG, Thompson M, van Veen M, Perera R, Moll HA, Oostenbrink R. Derivation and validation of age and temperature specific reference values and centile charts to predict lower respiratory tract infection in children with fever: prospective observational study. BMJ. 2012;345:e4224 doi:
- Cummings P. Methods for estimating adjusted risk ratios. Stata J. 2009;9:175–96.
- World Health Organization. WHO child growth standards. Geneva: World Health Organization; 2006.
- Hazir T, Nisar YB, Abbasi S, Ashraf YP, Khurshid J, Tariq P, et al. Comparison of oral amoxicillin with placebo for the treatment of world health organization-defined nonsevere pneumonia in children aged 2–59 months: a multicenter, double-blind, randomized, placebo-controlled trial in pakistan. Clin Infect Dis. 2011;52:293–300. doi:
- Fox MP, Thea DM, Sadruddin S, Bari A, Bonawitz R, Hazir T, et al. Low rates of treatment failure in children aged 2–59 months treated for severe pneumonia: a multisite pooled analysis. Clin Infect Dis. 2013;56:978–87. doi:
- Thompson M, Vodicka TA, Blair PS, Buckley DI, Heneghan C, Hay AD. Duration of symptoms of respiratory tract infections in children: systematic review. BMJ. 2013;347:f7027 doi:
- Begovac J, Soldo I, Presecki V. Cytomegalovirus mononucleosis in children compared with the infection in adults and with Epstein-Barr virus mononucleosis. J Infect. 1988;17:121–5. doi:
- Aabenhus R, Jensen JU, Jorgensen KJ, Hrobjartsson A, Bjerrum L. Biomarkers as point-of-care tests to guide prescription of antibiotics in patients with acute respiratory infections in primary care. Cochrane Database Syst Rev. 2014;11:CD010130 doi:
- Burkhardt O, Ewig S, Haagen U, Giersdorf S, Hartmann O, Wegscheider K, et al. Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection. Eur Respir J. 2010;36:601–7. doi:
- Schuetz P, Briel M, Mueller B. Clinical outcomes associated with procalcitonin algorithms to guide antibiotic therapy in respiratory tract infections. JAMA. 2013;309:717–8. doi:
- Cals JWL, Butler CC, Hopstaken RM, Hood K, Dinant G-J. Effect of point of care testing for C reactive protein and training in communication skills on antibiotic use in lower respiratory tract infections: cluster randomised trial. BMJ. 2009;338:b1374 doi:
- Lubell Y, Blacksell SD, Dunachie S, Tanganuchitcharnchai A, Althaus T, Watthanaworawit W, et al. Performance of C-reactive protein and procalcitonin to distinguish viral from bacterial and malarial causes of fever in Southeast Asia. BMC Infect Dis. 2015;15:511 doi:
- Erdman LK, D’Acremont V, Hayford K, Rajwans N, Kilowoko M, Kyungu E, et al. Biomarkers of host response predict primary end-point radiological pneumonia in Tanzanian children with clinical pneumonia: a prospective cohort study. PLoS ONE. 2015;10:e0137592 doi:
- Verbakel JY, Lemiengre MB, De Burghgraeve T, De Sutter A, Aertgeerts B, Shinkins B, et al. Should all acutely ill children in primary care be tested with point-of-care CRP: a cluster randomised trial. BMC Med. 2016;14:131 doi:
- Enoch AJ, English M, Shepperd S. Does pulse oximeter use impact health outcomes? A systematic review. Arch Dis Child. 2016;101(8):694–700. doi:
- Chalco JP, Huicho L, Alamo C, Carreazo NY, Bada CA. Accuracy of clinical pallor in the diagnosis of anaemia in children: a meta-analysis. BMC Pediatr. 2005;5:46 doi:
- Calis JCJ, Phiri KS, Faragher EB, Brabin BJ, Bates I, Cuevas LE, et al. Severe anemia in Malawian children. N Engl J Med. 2008;358:888–99. doi:
- Brabin BJ, Premji Z, Verhoeff F. An analysis of anemia and child mortality. J Nutr. 2001;131:636S–45S.
- Gowraiah V, Awasthi S, Kapoor R, Sahana D, Venkatesh P, Gangadhar B, et al. Can we distinguish pneumonia from wheezy diseases in tachypnoeic children under low-resource conditions? A prospective observational study in four Indian hospitals. Arch Dis Child. 2014;99:899–906. doi:
- Jain DL, Sarathi V, Jawalekar S. Predictors of treatment failure in hospitalized children [3–59 months] with severe and very severe pneumonia. Indian Pediatr. 2013;50:787–9. doi:
- Reed C, Madhi SA, Klugman KP, Kuwanda L, Ortiz JR, Finelli L, et al. Development of the Respiratory Index of Severity in Children (RISC) score among young children with respiratory infections in South Africa. PLoS ONE. 2012;7:e27793 doi:
- English M, Esamai F, Wasunna A, Were F, Ogutu B, Wamae A, et al. Assessment of inpatient paediatric care in first referral level hospitals in 13 districts in Kenya. Lancet 2004;363:1948–53. doi:
- Naik P, Voller A. Serum C-reactive protein levels and falciparum malaria. Trans R Soc Trop Med Hyg. 1984;78:812–3. doi:
- Church J, Maitland K. Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review. BMC Med. 2014;12:31 doi:
- Lim Y-W, Steinhoff M, Girosi F, Holtzman D, Campbell H, Boer R, et al. Reducing the global burden of acute lower respiratory infections in children: the contribution of new diagnostics. Nature. 2006;444(Suppl 1):9–18. doi:
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