Improved Diagnostic Testing and Malaria Treatment Practices in Zambia FREE

Malaria is characterized by gross overdiagnosis and overtreatment; 32% to 96% of febrile patients have an antimalarial prescribed without evidence of peripheral Plasmodium falciparum infection, depending on the background level of malaria transmission.^1- 4 The recent introduction of efficacious but expensive artemisinin-based combination therapy for malaria throughout Africa has led to renewed interest in improving the accuracy of diagnosis.^1,5- 6

The most widely used approach to confirmatory diagnosis is malaria microscopy. However, this approach requires an organized health system infrastructure, with functioning microscopes used by trained technicians and with regular provision of reagents, supervision, and quality control. Because parasite detection is usually performed by someone other than the prescriber, there is a tendency to distrust or ignore the results of microscopy provided by the laboratory, as evidenced from work in Tanzania,³ Zambia,² and Kenya.⁴ To put testing and clinical decisions in the hands of the prescriber or provide diagnostic services in settings in which microscopy is not available or cannot be effectively supported, the use of rapid antigen-detection diagnostic tests (RDTs) has been encouraged as a potentially cost-effective approach to accompany the widespread implementation of expensive artemisinin-based combination therapy.^5,7- 8

Despite numerous studies on the sensitivity and specificity of RDT for malaria diagnosis,^7,9- 10 there have been no formal evaluations of their use under routine conditions. Here we present the results of an operational assessment of the use of microscopy and RDTs in the treatment of outpatients presenting to health facilities in 4 Zambian districts in 2006, approximately 1 year after RDTs were introduced as a diagnostic tool to support the introduction of a new artemisinin-based combination therapy, artemether-lumefantrine.

Zambia was one of the first African countries to replace its first-line antimalarial, chloroquine, with artemether-lumefantrine in response to rising rates of chloroquine treatment failures.¹¹ The nationwide implementation of the new drug policy began late in 2003, after the policy decision and securing of finances from the Global Fund for HIV/AIDS, Tuberculosis and Malaria to implement the drug change and procurement. The availability of artemether-lumefantrine, revised national treatment guidelines, wall charts, and in-service training for health workers significantly increased between 2004 and 2006.¹²

Early in 2003, it was also decided that, given the high cost of artemether-lumefantrine, there was a need to improve malaria diagnostics to rationalize the use of artemether-lumefantrine in peripheral clinics. A malaria diagnosis strategy was developed, with the aim of providing malaria microscopy in all health facilities and achieving a rate of at least 80% diagnostic testing of suspected malaria cases by 2008.¹³

With financial support from the Global Fund for HIV/AIDS, Tuberculosis and Malaria, 600 000 immunochromatographic test strips, designed to detect the histidine-rich protein II of P falciparum (Parachek Pf Rapid One Step; Orchid Biomedical Laboratories, Goa, India) were purchased in 2004 and 2005. This RDT has been shown in previous studies to have a sensitivity of 92.3% to 98.6% and specificity of 95.9% to 98.8% compared with microscopy.^14- 16 The RDTs were first distributed to district health facilities by the National Malaria Control Center in the first quarter of 2005, beginning with 10 target districts and then increasing to all 72 districts.

In collaboration with Novartis Pharma AG, in September 2004, National Malaria Control Center staff carried out a week-long malaria case management workshop, including training in the use and interpretation of RDTs. The 260 participants included clinical officers, nurses, and environmental health technicians from all 72 districts. Training materials in RDT use were developed from the training workshop and used to perform cascade training throughout the country at 9 provincial workshops and subsequent district-level workshops during the first and second quarters of 2005. Wall charts and pictorial guides were developed in English, Bemba, and Nyanja and demonstrated how to check the RDT expiration date, obtain a blood smear by finger prick, perform the test, and interpret a positive, negative, or invalid result. They did not provide any recommendations on how to respond to a positive or negative result.

We undertook a cross-sectional, cluster sample survey, with primary sampling units consisting of all functional government and mission health facilities that provide general outpatient care in 4 sentinel districts of Zambia: Chingola, an urban hypoendemic and mesoendemic district in Copperbelt Province; Kalomo, a semiarid mesoendemic district in Southern Province; Chipata, a mixed rural and urban mesoendemic and hyperendemic district in Eastern Province; and Samfya, a rural, swampy, hyperendemic district in Luapula Province. These 4 districts were purposely selected from the 11 Zambian National Malaria Control Center sentinel surveillance sites because they represent differing malaria ecologies.

At each health facility, data were collected during 1 working day, and a cluster was defined as all sick outpatients treated at the facility. Patients who presented with burns or trauma or for the follow-up of chronic conditions such as human immunodeficiency virus or tuberculosis were excluded. The survey was carried out between March and May 2006 during the high malaria transmission season. The protocol and consent form were reviewed and approved by the University of Zambia Research Ethics Committee and the Boston University Medical Center Institutional Review Board.

The study team underwent training and concordance testing the week before the survey. On the day of the survey, study teams arrived at each facility before the clinic opened. No one at the facility was informed in advance about when the assessment would occur. The person in charge of the facility was presented a letter of support from the Central Board of Health, specifying the purpose and nature of the survey.

In health facilities with laboratories, the RDT was performed by a laboratory technician. In facilities that had no laboratory, the health care worker performed the RDT and prescribed antimalarial treatment to the patient according to the test results. After completing the clinical evaluation, including diagnostic testing and receiving antimalarial treatment, if prescribed, the patients or caretakers of sick children were approached when they were ready to leave the facility at the end of the clinic visit and asked whether they would be willing to be interviewed. After obtaining written informed consent from potential participants, interviewers collected information about basic demographic characteristics of the patients; presenting complaints, including history of fever; the assessment by the health worker; and drug-dispensing practices undertaken during the facility visit. Information was also collected from patient-held records about diagnostic procedures requested, results reported, and medications administered or prescribed. At the end of the exit interview, participants were weighed and had their axillary temperatures taken. Health center records other than the patient-held records were not used to collect any of the patient-specific diagnostic or treatment data. However, each facility was assessed to provide information on the availability of antimalarial drugs, microscopy, and RDTs for malaria.

Data were double entered into Microsoft Access 2000 (Microsoft Inc, Redmond, Wash) by independent data entry clerks and completed data files compared for errors. Analysis was performed with STATA version 8.0 (StataCorp, College Station, Tex). The analysis reported in this article was restricted to health facilities with functional microscopy or RDTs and to patients whose weight and age were recorded. Fever was defined as a history of fever or presence of elevated temperature (≥37.5°C). Data are presented as frequencies and proportions, with corresponding 95% confidence intervals (CIs) adjusted for clustering by health facility.

An equipment survey in the 4 study districts revealed that only 17% of the 104 health facilities had functional microscopy. Sixty-three percent of facilities had RDTs available on the day of the survey. Overall, 73% of health facilities had at least 1 type of malaria diagnostics available. We evaluated 1717 patients of all ages who had fever and were evaluated by 105 health workers at the 76 health facilities that had the capacity to perform a parasitological malaria diagnosis. Two hundred seventy-six patients with fever were evaluated at health facilities with microscopy, 1207 in health facilities with RDTs, and 234 in facilities with both.

Malaria blood smears were performed in 27.8% (95% CI, 13.1%-42.5%) of patients treated at health facilities that had functional microscopy; RDTs were used for 22.8% (95% CI, 13.8%-31.8%) of patients treated in facilities that had RDTs available (Table 1). In facilities that had both diagnostic tests available, no subjects had both microscopy and RDT performed. There was no difference in the use of parasitological diagnostic tests when subjects were stratified by age. For patients who had a blood smear test performed, 45.4% (95% CI, 27.2%-63.6%) had a positive smear result reported, whereas for those who had RDTs performed, 44.2% (95% CI, 33.4%-55.0%) of the results were positive (44.6% overall positive).

An antimalarial was prescribed to all patients who had positive microscopy results (100%) and nearly all who had positive RDT results (96.6%; 95% CI, 93.2%-99.9%). In contrast, 58.4% (95% CI, 36.7%-80.2%) of the patients with negative blood smear results were provided antimalarials, whereas 35.5% (95% CI, 16.0%-55.0%) of those with negative RDT results were treated.

Most patients with fever (1248/1717; 72.6%) did not have any diagnostic procedure performed. Antimalarials were prescribed to 66% of these patients; about half of this group received artemether-lumefantrine (Table 2). Artemether-lumefantrine was prescribed more frequently to patients with positive blood smear results or RDTs relative to those who had negative diagnostic test results. We further analyzed patients presenting with fever to health facilities that had artemether-lumefantrine in stock and diagnostics available on the day of the survey. At these facilities, artemether-lumefantrine was prescribed to a larger proportion of febrile patients with a positive diagnostic test (blood smear 75.0% [95% CI, 51.7%-98.3%]; RDT 70.4% [95% CI, 39.3%-100.0%]) compared with those with a negative diagnostic test result (blood smear 30.4% [95% CI, 8.0%-52. 9%]; RDT 26.7% [95% CI, 5.7%-47.7%]). The use of artemether-lumefantrine for patients who did not have any parasitological diagnostic evaluation was 42.1% (95% CI, 32.8%-51.4%) overall. The proportion of patients who had negative blood smear results and were not provided treatment (28.3%; 95% CI, 1.7%-55.4%) was similar to that of those who had no diagnostic procedure performed (35.1%; 95% CI, 27.0%-43.1%). In contrast, patients with negative RDT results were about twice as likely to not receive any antimalarial as those with negative blood smear results (61.0%; 95% CI, 29.0%-93.0% vs 28.9%; 95% CI, 1.7%-55.4%).

Within a year of Zambia's decision to expand the provision of new diagnostic tools, in concert with improving malaria case management through use of new, expensive, artemisinin-based combination treatment, 63% of health facilities had RDTs available for use, and more than 73% of facilities had either RDTs or microscopy available for malaria diagnosis. However, only 27% of febrile patients presenting to these facilities had a parasitological diagnostic test performed. When diagnostic tests were performed and reported as negative for P falciparum, more than 35% of patients were still prescribed an antimalarial.

The prevalence of malaria in the study districts ranges from 15.6% in Chipata and 18.2% in Chingola, 2 districts with mesoendemic and hyperendemic malaria, to 40.4% in Samfya, a hyperendemic district.¹⁷ Although these data derive from a survey carried out in the dry season in 2004, a more recent nationwide survey carried out in the late rainy season showed similar findings, with malaria parasite prevalence rates ranging from 8.6% in Southern Province (where Kalomo District is located) to 37.5% in Luapula Province (Samfya District).¹⁸ Given the high specificity of the RDTs used in district health centers in the current study, the prevalence of malaria in children is not high enough to warrant routine treatment of all patients with a negative malaria diagnostic test result.

Among patients who had no parasitological diagnostic tests performed, 42% were prescribed artemether-lumefantrine. Although slightly fewer patients with negative microscopy or RDT results were provided with artemether-lumefantrine in health facilities where this drug was available, artemether-lumefantrine was nevertheless used in more than a quarter of all patients with a negative diagnostic test result, including a substantial proportion of febrile older children and adults.

RDTs have been proposed as a cost-effective approach to reducing overtreatment of malaria^5,7- 8; under current practice in Zambia, however, their use will not achieve this goal. Assuming an estimated cost of US $0.5 per RDT against the recently reduced price per adult treatment course of artemether-lumefantrine of US $1 per course, for every 1000 febrile patients with a negative RDT, the cost savings would be only $0.33 per patient, or $330 per 1000 patients, assuming 27% of patients with negative test results still received artemether-lumefantrine treatment, as suggested by our findings. Given the additional costs associated with training of health care workers in RDT use and interpretation, it does not appear that use of these diagnostics is cost-effective.

Although the national malaria guidelines in Zambia recommend the use of microscopy whenever possible, they state that the “presence of signs and symptoms of disease with negative blood smear does not preclude the diagnosis of malaria.”¹⁹ Similarly ambiguous recommendations are provided in malaria training manuals.^20- 21 None of the training materials or national guidelines in Zambia provides specific instructions on how to respond to negative RDT results. Although patients with negative RDT results were less likely to receive antimalarial treatment than those with negative blood smear results, this difference was not statistically significant, possibly because the small numbers of patients in these groups resulted in our not having sufficient power to detect a difference.

A recent randomized trial that compared the use of malaria microscopy to RDT in Tanzania found that slightly more than half of patients with negative blood smear results or negative RDT results were prescribed an antimalarial.¹⁶ In many countries in Africa, there continues to be a clinical dogma that regards blood smear–negative results as “suspected” malaria.^1,4 Our study and that by Reyburn et al¹⁶ suggest that this clinical dogma is being extended to RDT results. Because the malaria parasite prevalence in the study districts is likely to be less than 50% during much of the calendar year, the routine treatment of negative RDT or blood smear results is not warranted. In the absence of a paradigm shift away from treatment of patients with negative blood smear results toward the appropriate interpretation of RDTs, with specific guidelines on the evaluation of fever if the rapid test is negative, this new diagnostic intervention is unlikely to improve clinical management or result in the anticipated cost-savings from the misuse of expensive artemisinin-based combination therapy in Africa.

Given the widespread increase of artemisinin-based combination therapy in sub-Saharan Africa for management of uncomplicated malaria, there is a need to limit inappropriate use of these expensive new combinations. The increasing body of evidence that a substantial proportion of febrile patients do not have malaria, especially in low to moderate transmission zones,¹⁶ emphasizes the need to educate health center staff on the rational use of artemisinin-based combination therapy, which will require strengthening the availability of malaria diagnostics and enhancing quality control measures so that health care providers will have confidence in the test results. The RDT training program in Zambia needs to be restructured such that trainees are provided with clear instructions about how to respond to a negative test result. Without taking these steps, we may rapidly be confronted with widespread resistance of P falciparum to artemisinin-based combination therapy, and the lifespan of these highly effective new therapies will be reduced.