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The Usefulness of Rapid Diagnostic Tests in the New Context of Low Malaria Transmission in Zanzibar
research-article
Author(s):
Delér Shakely
1
,
8
,
* ,
Kristina Elfving
1
,
4 ,
Berit Aydin-Schmidt
1 ,
Mwinyi I. Msellem
3 ,
Ulrika Morris
1 ,
Rahila Omar
3 ,
Xu Weiping
1 ,
Max Petzold
5 ,
Bryan Greenhouse
6 ,
Kimberly A. Baltzell
7 ,
Abdullah S. Ali
3 ,
Anders Björkman
1 ,
Andreas Mårtensson
1
,
2
Publication date (Electronic):
4 September 2013
Journal:
PLoS ONE
Publisher:
Public Library of Science
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Abstract
Background
We assessed if histidine-rich-protein-2 (HRP2) based rapid diagnostic test (RDT) remains an efficient tool for Plasmodium falciparum case detection among fever patients in Zanzibar and if primary health care workers continue to adhere to RDT results in the new epidemiological context of low malaria transmission. Further, we evaluated the performance of RDT within the newly adopted integrated management of childhood illness (IMCI) algorithm in Zanzibar.
Methods and Findings
We enrolled 3890 patients aged ≥2 months with uncomplicated febrile illness in this health facility based observational study conducted in 12 primary health care facilities in Zanzibar, between May-July 2010. One patient had an inconclusive RDT result. Overall 121/3889 (3.1%) patients were RDT positive. The highest RDT positivity rate, 32/528 (6.1%), was found in children aged 5–14 years. RDT sensitivity and specificity against PCR was 76.5% (95% CI 69.0–83.9%) and 99.9% (95% CI 99.7–100%), and against blood smear microscopy 78.6% (95% CI 70.8–85.1%) and 99.7% (95% CI 99.6–99.9%), respectively. All RDT positive, but only 3/3768 RDT negative patients received anti-malarial treatment. Adherence to RDT results was thus 3887/3889 (99.9%). RDT performed well in the IMCI algorithm with equally high adherence among children <5 years as compared with other age groups.
Conclusions
The sensitivity of HRP-2 based RDT in the hands of health care workers compared with both PCR and microscopy for P. falciparum case detection was relatively low, whereas adherence to test results with anti-malarial treatment was excellent. Moreover, the results provide evidence that RDT can be reliably integrated in IMCI as a tool for improved childhood fever management. However, the relatively low RDT sensitivity highlights the need for improved quality control of RDT use in primary health care facilities, but also for more sensitive point-of-care malaria diagnostic tools in the new epidemiological context of low malaria transmission in Zanzibar.
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Most cited references18
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Impact of Artemisinin-Based Combination Therapy and Insecticide-Treated Nets on Malaria Burden in Zanzibar
Achuyt Bhattarai, Abdullah S. Ali, S Patrick Kachur … (2007)
Introduction The increased malaria-related morbidity and mortality, especially in children under the age of 5 y (“under five”), due to emerging resistance of Plasmodium falciparum to conventional antimalarial drugs calls for immediate actions to “Roll Back Malaria” in sub-Saharan Africa. This need has been clearly recognized in the Millennium Development Goals “to halt and begin to reverse malaria incidence” [1] as well as in the Abuja Declaration objective to halve malaria mortality in Africa by 2010 through implementation of combined control strategies [2]. In the year 2000, the overall treatment failure of chloroquine was found to be 60% in a 14-d efficacy trial; consequently the Zanzibar Ministry of Health and Social Welfare decided in November 2001 to change both first- and second-line treatment guidelines for uncomplicated malaria from chloroquine and sulfadoxine-pyrimethamine to artemisinin-based combination therapies (ACT) [3]. The ACT policy was implemented in September 2003, when Zanzibar became one of the first regions in sub-Saharan Africa to recommend routine use of ACT. This action was followed by strengthened vector control, culminating in a nation-wide distribution campaign of long-lasting insecticidal nets (LLINs) from early 2006. Both ACT and vector control measures have independently proven to be efficacious malaria control strategies. Ecological studies have credited ACT with enhancing treatment efficacy, reducing malaria transmission, and possibly forestalling drug resistance in low-endemicity areas [4,5]. Moreover, specific African trials have indicated that the use of insecticide-treated nets (ITNs) or indoor residual spraying can reduce mortality of children under five in Africa [6–9]. This is, however, to our knowledge the first study to examine the public health impact of wide-scale deployment of ACTs alone and combined with ITNs through the general health structure/channels on malaria indices and general health parameters in an endemic area in sub-Saharan Africa. Methods Study Site The study was conducted in North A District, Zanzibar, situated just off the coast of mainland Tanzania. The district is rural and has a population of about 85,000. Subsistence farming and fishing are the main occupations. Plasmodium falciparum is the predominant malaria species and Anopheles gambiae complex is considered the main vector. Malaria transmission is stable with seasonal peaks related to rainfall in March–May and October–December. Malaria transmission in the district prior to the interventions has been reported to be high, but specific entomological data are not available to allow a precise characterization of malaria transmission intensity. However, during the screening process of a major antimalarial drug trial conducted in 2002–2003, a P. falciparum prevalence exceeding 30% was observed in febrile children under five [10], suggesting that North A District had been a high transmission area prior to ACT implementation in September 2003. North A District has one Primary Health Care Centre, which includes a hospital with inpatient and laboratory services, e.g., blood transfusion and malaria microscopy services. Basic medical treatment services without laboratory support are provided in 12 Primary Health Care Units located in different shehias (the smallest political administrative unit in Zanzibar). Drugs, including conventional and artemisinin monotherapies, are also available in private shops throughout the district. Malaria Control Interventions Figure 1 illustrates time of implementation of the two malaria control interventions. Figure 1 Malaria Interventions, Cross-Sectional Surveys, Monthly Rainfall, and Reported Clinical Malaria Diagnoses in Children under 5 Years of Age in North A District, Zanzibar (A) Start of the implementation of artemisinin-based combination therapy for treatment of uncomplicated malaria in September 2003. (B) Introduction of LLINs in February 2006. Promotion of ITNs started in January 2004; the use of conventional ITNs, however, remained low, until the introduction of LLINs. Outpatient data for 2006 are up to June. First intervention—ACT. A loose combination of artesunate and amodiaquine (AS+AQ; from various suppliers with preapproval from WHO) and a fixed combination of artemether–lumefantrine (Coartem; Novartis, Basel, Switzerland), were implemented as first- and second-line treatment, respectively, for uncomplicated malaria in all public health facilities from September 2003. In a pre-implementation assessment of the new treatment policy, partly conducted in North A District 2002–2003, both AS+AQ and artemether–lumefantrine were highly efficacious with PCR-adjusted cure rates by day 28 above 90% [10]. Quinine remained the drug of choice for severe malaria and sulfadoxine-pyrimethamine for intermittent preventive treatment during pregnancy. From September 2003, chloroquine was withdrawn from all health facilities and replaced by free provision of ACT to all malaria patients. Total treatment courses of AS+AQ dispensed in North A 2004 and 2005 were 34,724 and 12,819, respectively. The supply of ACT has been uninterrupted, with no reports of AS+AQ being out of stock from any public health facility in the district during 2003–2006 (unpublished data). ACTs were purchased with support from African Development Bank and Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM). Second intervention—vector control. A policy to distribute conventional ITNs to the most vulnerable groups—children under five and pregnant women—free of charge through antenatal clinics or local shehia leaders was officially launched in 2004. However, ITN coverage and use remained low in North A District 2004 and 2005 due to limited number of ITNs distributed, 4,026 and 1,550, respectively. A mass campaign was therefore initiated early 2006, with distribution of 23,000 LLINs to the two most vulnerable groups in North A. This campaign was supported by GFATM and the US Agency for International Development. Cross-Sectional Surveys Three cross-sectional surveys with the primary objective to determine P. falciparum prevalences were conducted in North A District between 2003 and 2006. A two-stage cluster sample technique was used. First shehias and then the households were randomly selected from the sampling frame obtained from the Office of Chief Government Statistician, Zanzibar. The sampling frame was updated before each survey. The first exploratory survey, conducted in May 2003, included 625 households and provided baseline data prior to ACT and widespread ITN implementation. Sample size calculations for the follow-up surveys conducted in May 2005 and 2006 were based on the proportion of children under five with malaria parasitemia in 2003, about 9%, and an assumed relative error of 20%. The calculated number of households to be included was 490 after adjusting for a design effect of 2. Trained interviewers visited all selected households. Interviews and blood sample collection were initiated upon written consent from head of each household and proxy consent from the mother or guardian of each child. Information was recorded using a structured questionnaire on recent febrile illness, mosquito net use, and care-seeking behavior from each individual present in the household at the time of the survey. We did not replace households in which residents were not present at time of survey, could not be located, or refused to participate. Thick blood films were collected from all consenting participants, stained with 5% Giemsa for 30 min, and examined by experienced microscopists for presence and density of P. falciparum parasites. If fewer than ten parasites were detected per 200 white blood cells, examinations were extended to 500 white blood cells. Blood slides were considered negative if no asexual parasites were found in 200 high-power fields. High-density parasitemia was defined as presence of ≥ 5,000 parasites/μl [11]. Quality control was conducted for all positive slides and 10% of the negative slides [12]. Health Facility Records Malaria-related indicators, i.e., outpatient attendances, hospital admissions and blood transfusions, from all 13 public health facilities in North A District were obtained from the Health Management and Information System (HMIS) records of the Zanzibar Ministry of Health and Social Welfare. The existing HMIS records were about 90% complete for the period 2000–2004. Data were validated and missing information retrieved by retrospective review of source documents from all 13 health facilities. This confirmed the HMIS records and resolved missing or inconsistent data, which increased the completeness to nearly 100%. A database of malaria-related indicators was created on the basis of this retrospective review. Data from 2005 were abstracted on quarterly basis. Vital Statistics Records of vital events, i.e., births and deaths, for the period 1998–2005 were obtained from the District Commissioner's Office (DCO) in North A. Annual crude mortalities of children under five were estimated from these data. Demographic estimates were obtained from Tanzania National Population and Housing Census 2002. Rainfall Complete records of monthly rainfall during 1999–2005 were obtained from official registers of the Tanzania Metrological Agency of the Ministry of Communications and Transport. On Unguja island, rainfall is centrally measured in one weather station, situated 26 km (radially) from North A District. The mean annual rainfalls recorded in 2003, 2004, 2005, and 2006 were 702, 1,934, 1,231, and 1,214 mm, respectively. The corresponding mean seasonal rainfall (March–May) between 2003 and 2006 was 285, 786, 890, and 613 mm, respectively. During the post-ACT intervention period (2004–2006) the mean annual and seasonal rainfall was 8%–12% lower than the pre-ACT intervention period (2000–2002). However, the only year with a marked reduction in the mean annual and seasonal rainfalls was the year 2003 with two- to three-fold lower rainfall, as compared to both the preceding and subsequent 3 y. Data Processing and Analysis Data were entered and validated using Microsoft Access and Excel. Statistical analyses for cross-sectional surveys, health facility records, vital statistics, and rainfall data were performed using Stata version 8. Analysis for the surveys was corrected for multi-stage sampling errors using the Rao-Scott second order correction [13]. A logistic regression model with robust standard errors (robust cluster) was used to adjust for the effect of age, sex, sleeping under a mosquito-net, and asset index on asexual P. falciparum prevalence and gametocyte carriage across the study years. Households were the primary sampling units in the surveys and were defined as clusters. Wald test was used to assess the fit of the model and interactions between covariates incorporated in the model. Odds ratios were adjusted for the complex sampling design and covariates listed above. Pearson correlation coefficients were calculated to assess the linear relationships between monthly rainfall and outpatient malaria diagnosis, and malaria-attributed deaths. Ethical Approval Protocols for the household surveys were reviewed and approved by the Medical Research Coordinating Committee of the Tanzanian Commission on Science and Technology, the Zanzibar Health Research Council and the institutional review board of US Centers for Disease Control and Prevention. Results Cross-Sectional Surveys The timings of the cross-sectional surveys in relation to start of each malaria control intervention and seasonal rainfalls are presented in Figure 1. The number of households enrolled and participant characteristics in the respective surveys are shown in Table 1. Over 95% of all participants agreed to both answer questionnaires and provide blood samples in the respective surveys. Table 1 Number of Households Surveyed and Characteristics of Survey Participants The parasite prevalences and odds ratios (ORs) of asexual P. falciparum parasitemia and gametocyte carriage at the time of cross-sectional surveys are shown in Table 2. Between 2003 and 2005 the parasite prevalence was reduced by about 50% in children under five. A further 10-fold decrease in P. falciparum prevalence was observed between 2005 and 2006, following mass distribution of LLINs specifically targeting this age group. Concomitant reductions of parasite prevalence were observed in children over the age of 5 y, although only by about 3-fold, between 2005 and 2006 (OR 0.41, 95% confidence interval [CI] 0.13–1.21), p = 0.08). Table 2 Parasite Prevalence and ORs of P. falciparum Asexual Parasitemia and Gametocytemia in Children 0–14 Years of Age in North A District, Zanzibar, in May 2003, 2005, and 2006 High-density parasitemia (≥5,000/μl) was found in 14 (2.7%) and 2 (0.6%) children under five in 2003 and 2005, respectively. No child carried high-density parasitemia in 2006. Reported fever within 14 d prior to the survey was similar in 2003 and 2006 among children under five (2003, 13% [95% CI 11–17]; 2006, 12% [95% CI 9–16]), whereas care-seeking at public health facilities by recently febrile children under five increased significantly (2003 was reference year; 2005, OR 3.91 [95% CI 0.85–17.9]; 2006, OR 5.5 [95% CI 2.3–13.3]; p-value for trend < 0.001). The proportions of children under five sleeping under effective ITNs were below 10% in both 2003 and 2005 (Table 1), whereas in 2006, 90% were reported sleeping under an LLIN on the night before survey. Health Facility Surveillance All reported clinical outpatient malaria diagnoses in North A District between January 1999 and June 2006 among children under five are shown by month in Figure 1 and by year in Table 3. Between 2002 and 2005 the total number of out-patient malaria diagnoses decreased by 77%. The annual incidences of malaria diagnoses standardized per 1,000 children under five in North A District were 843, 786, and 233 in 2003, 2004, and 2005, respectively. The total number of children under five attending public health facilities for any cause during 1999 and 2005 remained relatively constant, ranging from 31,069 to 39,374 annually. Up to 2003 malaria accounted for about 50% of all outpatient diagnoses in this age group, whereas in 2005 this proportion had decreased to 13%. Table 3 Outpatient Malaria Diagnoses, Hospital Admissions, Blood Transfusions, and Malaria-Attributed Deaths in North A District, Zanzibar, between 2000 and 2005 Malaria-related hospital admissions, non-malaria admissions, and blood transfusions in children under five between 2000 and 2005 are also shown in Table 3. From 2002 to 2005, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased by 77%, 67%, and 75%, respectively. Crude Mortality Data A total of 23,200 live births and 1,032 deaths in children under five (49% females) were registered between January 1998 and December 2005. The annual mortality figures for children under five, children (1–4 y), and infants (0–1 y) are shown in Table 4. Between 2002 and 2005, crude under five, infant, and child mortality decreased by 52%, 33%, and 71%, respectively. Table 4 Mortality of Children under 5 Years of Age in North A District, Zanzibar between 1998 and 2005 Relationships between Rainfall and Malaria Diagnosis and Deaths In the pre-ACT intervention period (2000–2002), significant positive correlations were found between monthly rainfall and both outpatient malaria diagnoses (Pearson correlation coefficient [r p] = 0.59, p < 0.001) and malaria-attributed deaths (r p = 0.75, p < 0.001), when data were adjusted to allow for a 1-mo lag between rainfall and malaria diagnoses and deaths. However, in the post-ACT intervention period (2003–2005), no significant correlations were found between monthly rainfall and outpatient malaria diagnosis (r p = −0.05; p = 0.75) or malaria-attributed deaths (rp = 0.23; p = 0.20). Discussion Malaria burden in Zanzibar, as in most parts of sub-Saharan Africa, has remained high and in many areas even increased during the last 10–20 y, a major reason being rapid spread of resistance to commonly used monotherapies against malaria. This problem has necessitated urgent implementation of new and effective control strategies to “Roll Back Malaria.” Two main cornerstones in this effort are the introduction of ACTs for treatment of uncomplicated malaria and the promotion of ITN use. The targets for the implementation of these new strategies have been defined by the UN Millennium Development Goals [1] and the Abuja Declaration [2], to be achieved by the years 2015 and 2010, respectively. Deployment of ACTs The ACTs were dispensed free of charge to all patients in the study area through public health facilities from September 2003 onwards. The ACT implementation and deployment was very rapid, effective, and with high coverage. Monitoring of drug supplies confirmed that ACTs were available throughout the study period in all 13 public health care settings in North A District. This outcome also indicates that estimates were adequate of the needed and thus deployed numbers of ACT treatments in the district. This result was accomplished despite an apparent two-fold increase in care seeking among children under the age of 5 y at public health facilities as observed in the cross-sectional surveys. We believe that the observed shift in treatment-seeking behavior at public facilities may be related to availability of free, effective ACTs. A previous study in Zanzibar showed that people's attitudes towards health seeking at public health facilities (biomedical practices) are negatively influenced by the distribution of ineffective antimalarial drugs [14]. High ACT coverage was rapidly achieved in malaria patients despite availability of other drugs in the private sector. This achievement was probably influenced both by comprehensive information to the public and health care staff and by the strong commitment of the Zanzibar government to rapidly ensure free coverage of the ACTs. Also, in North A District, as well as in Zanzibar generally, the entire population has relatively easy access to public health facilities, which are located within 5 km from any community and are served by good transport links. However, the absence of co-formulation or even of co-blistering of the two compounds in the first-line treatment, artesunate and amodiaquine, may have resulted in some degree of monotherapy with either compound. Mortality Impact Our study provides the first, to our knowledge, observation of a reduction in mortality of children under five following introduction of ACTs solely in a stable malaria-endemic setting. The highly significant reduction of 52% in crude under-five mortality according to vital statistics between 2002 and 2005 also highlights the importance of malaria as a major cause of death among children in malaria-endemic areas. The 71% reduction among children aged 1–4 y indicates that the relative contribution of malaria to crude mortality is particularly important in this age group. Major reductions in crude under-five mortality has also been observed in previous randomized intervention studies with ITNs [6,7] and community-based malaria treatment [15,16], but the reduction rates (between 25% and 40%) have been less pronounced than those in our study in Zanzibar. We believe our findings are valid and represent a true picture of the effects of ACT deployment in North A District, Zanzibar. No other major political, socioeconomic, or health-care change with the potential to halve mortality in children under five occurred in Zanzibar after 2002. This includes Expanded Programme on Immunization coverage, which remained constantly above 80% in the district during 1999–2005. Furthermore, there was no significant change in rainfall that may have contributed to the observed reduction in malaria transmission. Indeed, the only year with reduced rainfall with potential influence on vector capacity occurred before the introduction of ACTs—in 2003. Increased use of ITNs may also represent a potential confounding factor in our study. However, the ITN use was below 10% during 2004 and 2005 as reported and observed during the cross-sectional surveys. A significant improvement in ITN coverage was only achieved in 2006 after the introduction of LLINs (see further below) and only affected the 2006 cross-sectional results. We chose 2002 as reference year in our analyses of health facility surveillance and under-five mortality, because 2002 represents the last complete year before ACT introduction in September 2003. Routinely collected mortality statistics may underestimate the true values. However, such data have been shown to provide valid mortality trends [17,18]. Morbidity Impact A significant reduction was found with regard to hospitalization of malaria patients and incidence of blood transfusions, which may be considered proxy indicators of severe malaria. The reduction of severe malaria showing a similar pattern thus supports the under-five mortality trends. This health impact probably represents effects of improved case management of uncomplicated malaria with ACT, thus preventing the development of severe manifestations of the disease. The decrease in malaria morbidity (and mortality) at health facilities between 2003 and 2005 confirms the therapeutic efficacy of ACT [10], but the reduction in outpatient malaria diagnoses may also reflect some transmission blocking effect of artemisinin derivatives through its gametocytocidal activity. Reduction in transmission potential has been suggested after the introduction of artemisinin derivatives (before vector control) for routine treatment in a low and seasonal malaria transmission setting in Thailand [4]. Data obtained from routine health facility records have inherent potential pitfalls and need to be interpreted cautiously. However, the fact that they all show the same downward trend after improved coverage of malaria prevention and treatment interventions, and with no change in the climatic conditions that are favorable for malaria transmission, supports the plausible conclusion that enhanced malaria control interventions contributed to the observed public health benefits. Deployment of ITNs The deployment of LLINs in early 2006 provided a high coverage, i.e., over 90% reported use in children under five in the cross-sectional survey in May 2006. Importantly, this high mosquito-net use was observed after strong government commitment and after free LLIN distribution to children under five and pregnant women. The most significant decrease in prevalence of asymptomatic parasitemia was achieved in 2006, when LLINs were widely used by the children under five, whereas the major impact on the under-five mortality was achieved earlier with ACT use only. Strengthened vector control and the use of ACT also resulted in marked and sustained malaria control in South Africa [5]. The similar public health benefits observed in North A supports the concomitant use of vector control and ACT for malaria control. However, it should be emphasized that our study captures short-term trends in malaria control in North A, which may be too short to generalize long-term trends in the burden of malaria. Sustained coverage and use of LLINs by vulnerable groups is yet to be demonstrated, especially under declining malaria endemicity and if the free LLIN distribution scheme were to be changed. Conclusions The declining under-five mortality, malaria morbidity, and malaria prevalence observed in our study is the first comprehensive evidence supporting the major public health benefits of ACT and ITNs in a stable endemic malaria transmission setting in sub-Saharan Africa. The findings suggest that ACTs with high coverage of ITN use may potentially even eliminate malaria as a public health problem in highly endemic areas of sub-Saharan Africa. High community uptake of the two interventions is probably required but indeed achievable if, as in our study, they are easily available free of charge. The UN Millennium Development Goals to alleviate malaria as a major public health problem and substantially reduce the under-five mortality in sub-Saharan Africa are thus achievable even in settings with historically intense malaria transmission. The sustainability of these efforts as well as surveillance to prevent resurgence of malaria represent key research and programmatic follow-up issues of malaria control in Africa.
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Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial.
Hugh Reyburn, Hilda Mbakilwa, Rose Mwangi … (2007)
To compare rapid diagnostic tests (RDTs) for malaria with routine microscopy in guiding treatment decisions for febrile patients. Randomised trial. Outpatient departments in northeast Tanzania at varying levels of malaria transmission. 2416 patients for whom a malaria test was requested. Staff received training on rapid diagnostic tests; patients sent for malaria tests were randomised to rapid diagnostic test or routine microscopy Proportion of patients with a negative test prescribed an antimalarial drug. Of 7589 outpatient consultations, 2425 (32%) had a malaria test requested. Of 1204 patients randomised to microscopy, 1030 (86%) tested negative for malaria; 523 (51%) of these were treated with an antimalarial drug. Of 1193 patients randomised to rapid diagnostic test, 1005 (84%) tested negative; 540 (54%) of these were treated for malaria (odds ratio 1.13, 95% confidence interval 0.95 to 1.34; P=0.18). Children aged under 5 with negative rapid diagnostic tests were more likely to be prescribed an antimalarial drug than were those with negative slides (P=0.003). Patients with a negative test by any method were more likely to be prescribed an antibiotic (odds ratio 6.42, 4.72 to 8.75; P<0.001). More than 90% of prescriptions for antimalarial drugs in low-moderate transmission settings were for patients for whom a test requested by a clinician was negative for malaria. Although many cases of malaria are missed outside the formal sector, within it malaria is massively over-diagnosed. This threatens the sustainability of deployment of artemisinin combination treatment, and treatable bacterial diseases are likely to be missed. Use of rapid diagnostic tests, with basic training for clinical staff, did not in itself lead to any reduction in over-treatment for malaria. Interventions to improve clinicians' management of febrile illness are essential but will not be easy. Clinical trials NCT00146796 [ClinicalTrials.gov].
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Influence of Rapid Malaria Diagnostic Tests on Treatment and Health Outcome in Fever Patients, Zanzibar—A Crossover Validation Study
Introduction Morbidity and mortality due to Plasmodium falciparum malaria have been increasing in sub-Saharan Africa since the early 1990s, concomitantly with spread of resistance to commonly used monotherapies, i.e., chloroquine and sulfadoxine-pyrimethamine [1], [2]. This increased resistance has necessitated that many African countries change their treatment policy to artemisinin-based combination therapy (ACT) as a first-line treatment for uncomplicated malaria. The restricted use of ACT to confirmed malaria patients is critical. Overuse of the more expensive ACTs will not only put an extra heavy financial burden on malaria control programmes in Africa, but also enhance drug resistance and prevent other causes of fever from being appropriately treated, for example, pneumonias, which require antibiotics. Symptom-based or clinical malaria diagnosis has proven to be quite unspecific [3]–[7]. Malaria diagnosis based on parasitological confirmation is therefore increasingly advocated. Integrated Management of Childhood Illness (IMCI) algorithms based on clinical symptoms could potentially be made more efficient and cost-effective if simple parasitological diagnostic methodologies were incorporated. The use of microscopy has been tried in various health care settings, but is associated with problems of logistics, sustainability, and quality control [8], [9]. The development of rapid diagnostic tests (RDTs) for P. falciparum malaria offers a potential alternative in remote and poorly resourced health facilities that are beyond the reach of high-quality microscopy services [10]–[14]. The combination of RDT and ACT provides an important strategic opportunity to reduce malaria-associated mortality in Africa, and RDT use will potentially improve treatment of other causes of fever, for example, life-threatening bacterial diseases [15], [16]. However, the evidence base is still inadequate for malaria control programmes to recommend the use of RDTs on a large scale. There are several studies on sensitivities and specificities of various malaria diagnostic methods [11]–[14], [16]–[19]. In two recently published studies on the implication of RDT use at the health facility level on drug prescription, both describe major problems with test efficiency when used in clinical practice [15], [20]. However, this may be attributed to different messages regarding the risk of withholding malaria treatment to patients with negative test results [21]. Also, these studies did not describe staff training on technique and validation of RDTs, a prerequisite for the malaria diagnostic tests to become cost effective [22]. Furthermore, and importantly, there are no randomized control trials on the health impact and cost-effectiveness of confirmatory malaria diagnosis based on RDTs [18]. Zanzibar was among the first regions in sub-Saharan Africa to introduce ACT, free of charge through public health care, as both as first- and second- line treatment for uncomplicated malaria, which are provided free of charge through public health care. In view of the fact that many patients with fever are prescribed ACT without being malaria infected, the present study was undertaken to assess, on a wide scale, the added value of RDT to clinical diagnosis (CD) alone for management of patients of all ages presenting with fever at primary health care facilities. The hypothesis was that RDT-aided diagnosis of fever patients would improve rational use of ACTs and possibly other necessary treatments, such as antibiotics to non-malaria patients, with an overall improved health impact. Material and Methods Study Area and Study Health Centres The trial was conducted in four Primary Health Care Units (PHCUs) in Zanzibar, namely, Muyuni and Uzini on Unguja Island, and Kinyasini and Mzambarauni on Pemba Island. The selection of the four study sites aimed to provide a representative picture of Zanzibar with regard to malaria epidemiology as well as previous use of RDT in Zanzibar. By the time of the trial, malaria transmission in Zanzibar was generally considered endemic [23], with recorded malaria parasite rates between 10% and 50% in different age groups (unpublished data, Zanzibar Ministry of Health). A previous clinical trial conducted in two comparable PHCUs had shown an overall malaria parasite prevalence of about 30% among febrile children aged 15 y Total CD+RDT 228/544 (42%) 93/210 (44%) 40/251 (16%) 361/1,005 (36%) CD alone 423/503 (84%) 169/196 (86%) 160/183 (87%) 752/882 (85%) Microscopy 374/1,047 (36%) 128/406 (32%) 50/434 (12%) 552/1,887 (29%) A majority of antimalarial prescriptions were for children below 5 y, 228/361 (63%) in CD+RDT group and 423/752 (56%) in CD alone group. Prescription in relation to microscopy results are presented in Table 2. 10.1371/journal.pmed.1000070.t002 Table 2 Proportions of patients receiving antimalarial drugs and antibiotics in relation to day 0 microscopy results. Drugs Received by Patients Diagnostic Testing Blood Slide Result 15 years Total Antimalarials CD+RDT BS positive 186/200 (93%) 71/72 (99%) 22/33 (67%) 279/305 (91%) BS negative 42/344 (12%) 22/138 (16%) 18/218 (8%) 82/700 (12%) CD alone BS positive 174/174 (100%) 54/56 (96%) 17/17 (100%) 245/247 (99%) BS negative 249/329 (76%) 115/140 (82%) 143/166 (86%) 507/635 (80%) Antibiotics CD+RDT BS positive 51/200 (26%) 4/72 (6%) 3/33 (9%) 58/305 (19%) BS negative 190/344 (55%) 52/138 (38%) 72/218 (33%) 314/700 (45%) CD alone BS positive 38/174 (22%) 4/56 (7%) 1/17 (6%) 43/247 (17%) BS negative 140/329 (43%) 28/140 (20%) 24/166 (14%) 192/635 (30%) A total of 607/1,887 (32%) patients were prescribed antibiotics, including mainly cotrimoxazole, but also ampicillin, amoxicillin, and erythromycin. Prescription of antibiotics was significantly higher in the CD+RDT than CD-alone group, 372/1,005 (37%) and 235/882 (27%) (OR 1.8, 95%CI 1.5–2.2, p 99% for detecting a parasite density of ≥1,000 parasites/µl, 76% and 59% for parasite densities 100–999 and 99% Specificity 88% 20% Positive predictive value 77% 33% Negative predictive value 96% 98% Antimalarial and antibiotic prescriptions in relation to age and BS results are presented in Table 2. Among a total of 552 BS-positive patients, 28 (14 children below age 5 y) were not prescribed antimalarial treatment, 26 after CD+RDT (RDT negative), and two after CD alone. Their parasite densities at enrolment were, however, relatively low (GM 174 parasites/µl blood, range 32–2029). Among patients with BS negative results a total of 82/700 (12%) were prescribed antimalarial drugs in the CD+RDT group (RDT positive) compared with 507/635 (80%) in the CD-alone group (Table 2). A total of 82/361 (23%) antimalarial treatments in the CD+RDT group and 507/635 (80%) in the CD-alone group may thus have been unnecessary according to microscopy results (Tables 1 and 2). In contrast, BS-negative patients received significantly more antibiotics in the CD+RDT group, 314/700 (45%) patients compared with 192/635 (30%) in the CD alone group (OR 2.1, 95%CI 1.6–2.6, p 15 y All ages CD+RDT group General costs 1.90 1.90 1.90 1.90 Drugs 0.39 0.63 0.69 0.51 Reattendance 0.08 0.06 0.03 0.06 Total mean costs 2.37 2.59 2.62 2.47 CD alone group General costs 1.40 1.40 1.40 1.40 Drugs 0.58 0.89 1.55 0.85 Reattendance 0.17 0.05 0.05 0.12 Total mean costs 2.15 2.34 3.00 2.37 All estimates are based on an exchange rate of USD 1 = TSh 1,100. General costs = transport (USD 0.90)+consultation (USD 0.50)+RDT (USD 0.50) = USD 1.90. Drugs = ACT (USD 0.50−1.40)+antibiotics USD (0.30−0.90)+antipyretics (USD 0.05−0.20). Reattendance costs = transport (USD 0.90)+consultation (USD 0.50)+drugs (ACT, antibiotic+antipyretics = average USD 1.10) = USD 2.50. Discussion We found an overall 2-fold reduction in prescription of antimalarial drugs and reattendance of patients due to illness during the two-week follow-up period in the CD+RDT group compared with CD-alone group. Overall costs were, however, similar in the two groups despite a significant reduction of cost among the adult patients after RDT-aided diagnosis. Almost all enrolled fever patients in the CD-alone arm were considered and treated as malaria patients, resulting in high diagnostic sensitivity (99%) but low specificity (20%). This result follows the suggestion that fever alone may be a better criterion for malaria treatment than more complicated algorithms [4]. Studies on clinical diagnostic algorithms have shown that with weighting and scoring systems for clinical signs and symptoms may result in sensitivities of 70%–88% and specificities of 63%–82% [3], [4], [17], [27]. However, these methods may be too complicated to be effective under operational conditions, and the algorithms may be site- and context-specific [4]. Health workers learnt to use RDTs correctly with relative ease, confirming that the tests are simple to perform and interpret [11]. The estimated sensitivity (>100 parasites/µl of blood) is in line with WHO recommendations [10] and is also in accordance with a recent review concluding that the accuracies of the HRP2-based test in P. falciparum–endemic areas are normally high with a mean sensitivity of 93% [13]. The specificity in our study—88%—was similar to or lower than in some previous studies [12], [13], [15], [16], [19]. Especially under field conditions, heat and time stability could be an important impediment for the optimal use of RDTs for malaria, but according to the manufacturer Parachek Pf is expected to be stable at temperatures up to 40°C for up to two years. The use of confirmatory malaria diagnosis with RDT is expected to reduce the overuse of antimalarial drugs by ensuring that treatment is targeted to patients suffering from malaria infections as opposed to treating all patients with fever. Our findings confirm this expectation, although the impact of RDT-aided diagnosis will obviously be highly dependent on the malaria incidence (prevalence of malaria in fever patients) in a given situation. Importantly, in our study, the study nurses showed great confidence in the RDT results as a guide to choice of treatment, as did the patients. This is in contrast to the assumption that care providers, although willing to perform diagnostic tests, do not always comply with the results, especially when the result is negative [15], [20]. High adherence by prescribers in relation to RDT results was, however, also reported in a recent study conducted in mainland Tanzania [28]. We believe that the high compliance and confidence in the RDT in our study may result from a successful pre-study training, although local beliefs, behaviours, and treatment traditions may also account for discrepancies between our results and those of previous publications [15], [20]. We further realise that the study situation, supervision, and incentives provided to the nurses may also affect compliance, but we do not believe it has seriously biased our results. The incentive to the nurses was consistent with common practice for project participation in Zanzibar, but whereas it represented up to approximately a 65% increment of the ordinary salary it was not influenced or affected by performance. Our results obviously need to be confirmed before RDT can be more generally recommended, but we do believe they suggest that RDT use may be efficient if local diagnostic and treatment traditions are properly addressed. Fearing false negative test results and being aware that delays in providing effective treatment can be fatal for malaria patients is reported to be the main reason to prescribe antimalarial drugs despite a negative RDT result. Importantly, in our study, the patients with malaria detected by BS but non-detectable by RDT and therefore not treated with antimalarial drugs had relatively low parasite densities and no patients developed any severe malaria manifestations during the two week follow-up. This supports a general recommendation of consistence in not treating RDT negative patients. Re-testing will, however, obviously be required if the illness remains or aggravates. Our finding of a reduction in perceived illness during a two-week follow-up in the CD+RDT group of patients is critical. This was probably attributed to improved treatment of patients with fever not associated with malaria. More antibiotics were prescribed to the RDT-negative patients. The introduction of RDT and ACT thus provides an opportunity to improve the treatment of both malaria and bacterial diseases. We did consider the potential selection bias of the four health facilities; indeed, significant heterogeneity was observed with regard to the primary effect parameter. We do, however, assume this heterogeneity was at least partly accounted for by multilevel analysis and, since the RDT effect on drug prescriptions was quite large in each PHCU, it seems unlikely to be due to selection bias. The selection of the four study sites was done to provide a relatively representative picture of both malaria epidemiology and previous use of RDT in Zanzibar. Since RDTs had already been introduced by MSF in some parts of Zanzibar we opted for including PHCUs both with previous experience (two sites) and without previous RDT use (two sites). Beside the previous RDT exposure, the selection of the four study sites was based on representing a common rural situation and representing both of the two major islands in Zanzibar, i.e. Unguja and Pemba (two PHCUs on each island). However, we do of course acknowledge that the choice of the four sites remains arbitrary and of low number and thus cannot be fully representative of an overall Zanzibar situation and even less so of an overall situation in sub-Saharan Africa, which indeed is very diverse itself with regard to epidemiology of malaria, cultural and behavioural aspects, health care structure, etc. With the understanding that four PHCUs is a very low number, we used a cross-over design of RDT versus non-RDT weeks within sites. The choice of RDT or non-RDT the first week was based on an allocation with one previous MSF/RDT site being in either arm and one non previous MSF/RDT similarly being in either arm. Still, we acknowledge that there may still be confounding effects with regard to health-seeking behaviour or even selection bias by study nurses on respective weeks by (a) patients/caretakers postponing health care attendance to a week with RDT or staff applying exclusion criteria on a CD week and instead request the patient to return on a RDT week, and/or (b) attending alternate PHCUs where RDT is performed. However, we assume that (a) is less realistic, considering that uncomplicated malaria requires urgent treatment and patients or their caretakers as well as health care workers are therefore not likely to wait and postpone treatment. We also do not believe (b) is realistic because systematic RDT use was not implemented outside study PHCUs at the time of the trial and the study sites were located far from each other. And indeed statistical analysis showed no significant difference between frequencies of fever patient attendance on RDT and non-RDT weeks. The only trend observed with regard to frequency of attendance was a tendency to a relative increase toward the later period of the study, compatible with increased malaria transmission. In summary, RDTs were well performed in peripheral health facilities with acceptable sensitivity and specificity for identifying malaria-attributable fever episodes. The RDT results were adhered to and did provide consistent and significant reduction in antimalarial treatment in parallel with an increase in prescribed antibiotics. This probably contributed to the significant reduction in reattendance due to illness during the two-week follow-up. Our results indicate that RDTs may represent an important tool for improved management of fever patients in peripheral health care settings in malaria-endemic areas, especially where ACT has been introduced for treatment of uncomplicated malaria. Supporting Information Text S1 Trial protocol. (0.15 MB DOC) Click here for additional data file. Text S2 CONSORT checklist. (0.06 MB DOC) Click here for additional data file.
Author and article information
Contributors
Lorenz von Seidlein: Role: Editor
Journal
Journal ID (nlm-ta): PLoS One
Journal ID (iso-abbrev): PLoS ONE
Journal ID (publisher-id): plos
Journal ID (pmc): plosone
Title:
PLoS ONE
Publisher:
Public Library of Science
(San Francisco, USA
)
ISSN
(Electronic):
1932-6203
Publication date Collection: 2013
Publication date
(Electronic):
4
September
2013
Volume: 8
Issue: 9
Electronic Location Identifier: e72912
Affiliations
[2
]Division of Global Health (IHCAR), Department of Public Health Sciences, Karolinska
Institutet, Stockholm, Sweden
[4
]Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg,
Gothenburg, Sweden
[5
]Centre for Applied Biostatistics, Sahlgrenska Academy, University of Gothenburg, Gothenburg,
Sweden
[6
]Department of Medicine, University of California San Francisco, San Francisco, California,
United States of America
Author notes
* E-mail:
deler.shakely@
123456ki.se
Conceived and designed the experiments: DS KE MIM BG KAB ASA AB AM. Analyzed the data: DS KE BAS UM MP AB AM. Wrote the paper: DS KE BAS UM MP AB AM. ICMJE criteria for authorship read and met: DS KE BAS MIM UM RO XW MP BG KAB ASA AB AM. Agreed with the manuscript’s results and conclusions: DS KE BAS MIM UM RO XW MP BG KAB ASA AB AM. Collected data/did experiments for the study: DS KE RO MIM BAS UM WX. Supervised the study: DS KE AM. Wrote the first draft of the paper: DS KE BAS AM. Contributed to the writing of the paper: DS KE BAS UM MP AB AM.
Article
Publisher ID: PONE-D-13-16744DOI: 10.1371/journal.pone.0072912
PMC ID: 3762850
PubMed ID: 24023791
SO-VID: e02d3928-3e84-4a21-872b-2bfbb24996a0
Copyright statement:
Copyright @
2013
License:
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.
History
Date
received
: 23
April
2013
Date
accepted
: 12
July
2013
Page count
Pages: 8
Funding
This study was funded by the ACT Consortium through an award from the Bill and Melinda
Gates Foundation to the London School of Hygiene and Tropical Medicine, and by the
Swedish International Development Cooperation Agency (Sida), Swedish Civil Contingencies
Agency (MSB) and Goljes Foundation. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Categories
Subject:
Research Article
ScienceOpen disciplines: Uncategorized
Data availability:
ScienceOpen disciplines: Uncategorized