Analyses of a case-control study among Afghan refugees in Pakistan find that a G6PD (glucose-6-phosphate dehydrogenase) “Mediterranean” type deficiency confers substantial protection against Plasmodium vivax malaria.

Objectives To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia.Design Analysisof nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study).Setting Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda.Participants 522 480 children and adults with acute febrile illness.Interventions Rapid diagnostic tests for malaria.Main outcome measures Proportions of patients for whom an antibiotic was prescribed in trial groups who had undergone rapid diagnostic testing compared with controls and in patients with negative test results compared with patients with positive results. A secondary aim compared classes of antibiotics prescribed in different settings.Results Antibiotics were prescribed to 127 052/238 797 (53%) patients in control groups and 167 714/283 683 (59%) patients in intervention groups. Antibiotics were prescribed to 40% (35 505/89 719) of patients with a positive test result for malaria and to 69% (39 400/57 080) of those with a negative result. All but one study showed a trend toward more antibiotic prescribing in groups who underwent rapid diagnostic tests. Random effects meta-analysis of the trials showed that the overall risk of antibiotic prescription was 21% higher (95% confidence interval 7% to 36%) in intervention settings. In most intervention settings, patients with negative test results received more antibiotic prescriptions than patients with positive results for all the most commonly used classes: penicillins, trimethoprim-sulfamethoxazole (one exception), tetracyclines, and metronidazole.Conclusions Introduction of rapid diagnostic tests for malaria to reduce unnecessary use of antimalarials—a beneficial public health outcome—could drive up untargeted use of antibiotics. That 69% of patients were prescribed antibiotics when test results were negative probably represents overprescription.This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings. It is often assumed that better disease specific diagnostics will reduce antimicrobial overuse, but they might simply shift it from one antimicrobial class to another. Current global implementation of malaria testing might increase untargeted antibiotic use and must be examined.

BackgroundVivax malaria remains a major cause of morbidity in the subtropics. To undermine the stability of the disease, drugs are required that prevent relapse and provide reservoir reduction. A 14-day course of primaquine (PQ) is effective but cannot safely be used in routine practice because of its interaction with glucose-6-phosphate dehydrogenase (G6PD) deficiency for which testing is seldom available. Safe and effective use of PQ without the need for G6PD testing would be ideal. The efficacy and safety of an 8-week, once weekly PQ regimen was compared with current standard treatment (chloroquine alone) and a 14-day PQ regimen.Methods and Principal Findings200 microscopically confirmed Plasmodium vivax patients were randomly assigned to either once weekly 8-week PQ (0.75mg/kg/week), once weekly 8-week placebo, or 14-day PQ (0.5mg/kg/day) in North West Frontier Province, Pakistan. All patients were treated with a standard chloroquine dose and tested for G6PD deficiency. Deficient patients were assigned to the 8-week PQ group. Failure was defined as any subsequent episode of vivax malaria over 11 months of observation. There were 22/71 (31.0%) failures in the placebo group and 1/55 (1.8%) and 4/75 (5.1%) failures in the 14-day and 8-week PQ groups, respectively. Adjusted odds ratios were: for 8-week PQ vs. placebo-0.05 (95%CI: 0.01-0.2, p<0.001) and for 14-day PQ vs. placebo-0.01 (95%CI: 0.002-0.1, p<0.001). Restricted analysis allowing for a post-treatment prophylactic effect confirmed that the 8-week regimen was superior to current treatment. Only one G6PD deficient patient presented. There were no serious adverse events.ConclusionsA practical radical treatment for vivax malaria is essential for control and elimination of the disease. The 8-week PQ course is more effective at preventing relapse than current treatment with chloroquine alone. Widespread use of the 8-week regimen could make an important contribution to reservoir reduction or regional elimination where G6PD testing is not available.Trial RegistrationClinicalTrials.gov NCT00158587

Objective To assess the accuracy of malaria diagnosis and treatment at primary level clinics in Afghanistan.Design Prospective observational study.Setting 22 clinics in two Afghan provinces, one in the north (adjoining Tajikistan) and one in the east (adjoining Pakistan); areas with seasonal transmission of Plasmodium vivax and Plasmodium falciparum.Participants 2357 patients of all ages enrolled if clinicians suspected malaria.Interventions Established (>5 years) microscopy (12 clinics in east Afghanistan), newly established microscopy (five clinics in north Afghanistan), and no laboratory (five clinics in north Afghanistan). All clinics used the national malaria treatment guidelines.Main outcome measures Proportion of patients positive and negative for malaria who received a malaria drug; sensitivity and specificity of clinic based diagnosis; prescriber’s response to the result of the clinic slide; and proportion of patients positive and negative for malaria who were prescribed antibiotics. Outcomes were measured against a double read reference blood slide.Results In health centres using clinical diagnosis, although 413 of 414 patients were negative by the reference slide, 412 (99%) received a malaria drug and 47 (11%) received an antibiotic. In clinics using new microscopy, 37% (75/202) of patients who were negative by the reference slide received a malaria drug and 60% (103/202) received an antibiotic. In clinics using established microscopy, 50.8% (645/1269) of patients who were negative by the reference slide received a malaria drug and 27.0% (342/1269) received an antibiotic. Among the patients who tested positive for malaria, 94% (443/472) correctly received a malaria drug but only 1 of 6 cases of falciparum malaria was detected and appropriately treated. The specificity of established and new microscopy was 72.9% and 79.9%, respectively. In response to negative clinic slide results, malaria drugs were prescribed to 270/905 (28.8%) and 32/154 (21%) and antibiotics to 347/930 (37.3%) and 99/154 (64%) patients in established and new microscopy arms, respectively. Nurses were less likely to misprescribe than doctors.Conclusions Despite a much lower incidence of malaria in Afghanistan than in Africa, fever was substantially misdiagnosed as malaria in this south Asian setting. Inaccuracy was attributable to false positive laboratory diagnoses of malaria and the clinicians’ disregard of negative slide results. Rare but potentially fatal cases of falciparum malaria were not detected, emphasising the potential role of rapid diagnostic tests. Microscopy increased the proportion of patients treated with antibiotics producing a trade-off between overtreatment with malaria drugs and probable overtreatment with antibiotics.

Abstract.Since 2010, the World Health Organization has been recommending that all suspected cases of malaria be confirmed with parasite-based diagnosis before treatment. These guidelines represent a paradigm shift away from presumptive antimalarial treatment of fever. Malaria rapid diagnostic tests (mRDTs) are central to implementing this policy, intended to target artemisinin-based combination therapies (ACT) to patients with confirmed malaria and to improve management of patients with nonmalarial fevers. The ACT Consortium conducted ten linked studies, eight in sub-Saharan Africa and two in Afghanistan, to evaluate the impact of mRDT introduction on case management across settings that vary in malaria endemicity and healthcare provider type. This synthesis includes 562,368 outpatient encounters (study size range 2,400–432,513). mRDTs were associated with significantly lower ACT prescription (range 8–69% versus 20–100%). Prescribing did not always adhere to malaria test results; in several settings, ACTs were prescribed to more than 30% of test-negative patients or to fewer than 80% of test-positive patients. Either an antimalarial or an antibiotic was prescribed for more than 75% of patients across most settings; lower antimalarial prescription for malaria test-negative patients was partly offset by higher antibiotic prescription. Symptomatic management with antipyretics alone was prescribed for fewer than 25% of patients across all scenarios. In community health worker and private retailer settings, mRDTs increased referral of patients to other providers. This synthesis provides an overview of shifts in case management that may be expected with mRDT introduction and highlights areas of focus to improve design and implementation of future case management programs.