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Sunday, 24th of March 2013

• INFLUENCE OF RAPID MALARIA DIAGNOSTIC TESTS ON TREATMENT AND HEALTH OUTCOME IN FEVER PATIENTS, ZANZIBAR—A CROSSOVER VALIDATION STUDY

Abstract and editors’ summary below; full text, with figures, is accessible online at

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000070

 

Mwinyi I. Msellem,

Affiliations: Malaria Control Programme, Ministry of Health and Social Welfare, Zanzibar, Tanzania, Infectious Diseases Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Andreas Mårtensson,

Affiliations: Infectious Diseases Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, Division of International Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm

Guida Rotllant,

Affiliation: Médecins Sans Frontières, Dar es Salaam, Tanzania

Achuyt Bhattarai,

Affiliation: Infectious Diseases Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Johan Strömberg,

Affiliation: Infectious Diseases Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Elizeus Kahigwa,

Affiliation: World Health Organization (WHO) Country Office, Dar es Salaam, Tanzania

Montse Garcia,

Affiliation: Médecins Sans Frontières, Dar es Salaam, Tanzania

Max Petzold,

Affiliation: Nordic School of Public Health, Gothenburg, Sweden

Peter Olumese,

Affiliation: Global Malaria Programme, WHO, Geneva, Switzerland

Abdullah Ali,

Affiliation: Malaria Control Programme, Ministry of Health and Social Welfare, Zanzibar, Tanzania

Anders Björkman mail

* E-mail: anders.bjorkman@karolinska.se

Affiliation: Infectious Diseases Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Abstract

Background

The use of rapid diagnostic tests (RDTs) for Plasmodium falciparum malaria is being suggested to improve diagnostic efficiency in peripheral health care settings in Africa. Such improved diagnostics are critical to minimize overuse and thereby delay development of resistance to artemisinin-based combination therapies (ACTs). Our objective was to study the influence of RDT-aided malaria diagnosis on drug prescriptions, health outcomes, and costs in primary health care settings.

Methods and Findings

We conducted a cross-over validation clinical trial in four primary health care units in Zanzibar. Patients of all ages with reported fever in the previous 48 hours were eligible and allocated alternate weeks to RDT-aided malaria diagnosis or symptom-based clinical diagnosis (CD) alone. Follow-up was 14 days. ACT was to be prescribed to patients diagnosed with malaria in both groups. Statistical analyses with multilevel modelling were performed. A total of 1,887 patients were enrolled February through August 2005. RDT was associated with lower prescription rates of antimalarial treatment than CD alone, 361/1005 (36%) compared with 752/882 (85%) (odds ratio [OR] 0.04, 95% confidence interval [CI] 0.03–0.05, p<0.001). Prescriptions of antibiotics were higher after RDT than CD alone, i.e., 372/1005 (37%) and 235/882 (27%) (OR 1.8, 95%CI 1.5–2.2, p<0.001), respectively. Reattendance due to perceived unsuccessful clinical cure was lower after RDT 25/1005 (2.5%), than CD alone 43/882 (4.9%) (OR 0.5, 95% CI 0.3–0.9, p = 0.005). Total average cost per patient was similar: USD 2.47 and 2.37 after RDT and CD alone, respectively.

Conclusions

RDTs resulted in improved adequate treatment and health outcomes without increased cost per patient. RDTs may represent a tool for improved management of patients with fever in peripheral health care settings.

Trial Registration

Clinicaltrials.gov NCT00549003

Please see later in the article for Editors' Summary

Citation: Msellem MI, Mårtensson A, Rotllant G, Bhattarai A, Strömberg J, et al. (2009) Influence of Rapid Malaria Diagnostic Tests on Treatment and Health Outcome in Fever Patients, Zanzibar—A Crossover Validation Study. PLoS Med 6(4): e1000070. doi:10.1371/journal.pmed.1000070

Academic Editor: Christopher J. M. Whitty, London School of Hygiene & Tropical Medicine, United Kingdom

Received: August 21, 2007; Accepted: March 20, 2009; Published: April 28, 2009

Copyright: © 2009 Msellem et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was funded by MSF Spain, WHO-AFRO, Italian Co-operation and Zanzibar Malaria Control Programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ACT, artemisinin-based combination therapy; BS, blood smear; CD, clinical diagnosis; CI, confidence interval; GM, geometrical mean; ICMI, Integrated Management of Childhood Illness; OR, odds ratio; PHCU, Primary Health Care Unit; R, reader; RDT, rapid diagnostic test; WBC, white blood cell

Editors' Summary

Background

Every year, nearly one million people (mainly children living in sub-Saharan Africa) die because of malaria, a subtropical and tropical parasitic disease. Although several parasites cause malaria, Plasmodium falciparum is responsible for most of these deaths. Indeed, infection with P. falciparum can be fatal within hours if left untreated. For the past 50 years, the main treatments for P. falciparum malaria have been chloroquine and sulfadoxine/pyrimethamine. Unfortunately, parasitic resistance to both of these “monotherapies” is now widespread and the illness and death caused by P. falciparum in sub-Saharan Africa and elsewhere has been increasing. To combat this increase, the World Health Organization now recommends artemisinin combination therapy (ACT) for P. falciparum malaria in all regions with drug-resistant malaria. In ACT, artemisinin derivatives (new, fast-acting antimalarial drugs) are used in combination with another antimalarial to reduce the chances of P. falciparum becoming resistant to either drug.

Why Was This Study Done?

The chances of P. falciparum becoming resistant to ACT should also be reduced by giving ACT only to people who definitely have malaria. Unfortunately, many people who do not have malaria are given ACT because symptom-based (clinical) diagnosis cannot always distinguish between patients whose fever is caused by malaria and those who have a different infection and who would, therefore, gain more benefit from other treatments. Microscopic detection of parasites in blood smears would greatly improve the accuracy of malaria diagnosis, but this test is rarely available in rural clinics in developing countries. Might the recently developed “rapid diagnostic tests” (RDTs) for P. falciparum provide an alternative way to improve malaria diagnosis and thus reduce the overuse of ACT? In this “cross-over trial,” the researchers investigate the effect of the routine use of an RDT for the diagnosis of malaria on ACT prescribing, health outcomes, and costs in four primary health-care clinics in Zanzibar (part of the United Republic of Tanzania), one of the first regions in sub-Saharan Africa to introduce ACT.

What Did the Researchers Do and Find?

Each clinic used RDT-aided symptom-based clinical diagnosis of malaria (the RDT arm of the trial) and symptom-based clinical diagnosis (the CD arm) in alternate weeks to decide whether patients attending with fever had malaria. ACT was prescribed to everyone diagnosed with malaria; during RDT weeks only patients with positive RDT results were prescribed ACT. During the trial, 36% of the 1,005 patients in the RDT arm were prescribed ACT compared to 85% of the 882 patients in the CD arm. 37% and 27% of the RDT and CD arm patients, respectively, were prescribed antibiotics and fewer RDT-arm patients than CD-arm patients returned to the clinic because they still felt ill. The overall cost per patient was similar in both arms. The researchers also report that 23% of the antimalarial treatments given to patients in the RDT arm and 80% of those given to patients in the CD arm were given to people with no microscopically detectable parasites in their blood. Importantly, none of the 26 patients in the RDT group who had positive smears but who were not treated with antimalarial drugs because of a negative RDT result developed severe malaria.

What Do These Findings Mean?

These findings suggest that the replacement of clinical diagnosis alone with RDT-aided diagnosis may reduce the number of people prescribed ACT who do not have malaria and may increase the number of patients given antibiotics for nonmalarial illnesses without increasing costs. However, while the health-care workers involved in this study only prescribed ACT to those patients in the RDT arm who had a positive RDT result (as stipulated in the trial protocol), evidence from other studies suggests that health-care workers often give antimalarials to patients with negative RDT results. Consequently, these findings may not be generalizable to other clinics. Nevertheless, it is reassuring that none of the patients who had malaria that was detected by blood smear but that was missed by RDT subsequently developed severe malaria. This finding, if replicated, might persuade health-care workers to trust RDT results rather than prescribing ACT to everyone with a fever “just in case.”

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1​000070.

This study is further discussed in a PLoS Medicine Perspective by Zeno Bisoffi and colleagues