Miriam K. Laufer

A research agenda for malaria eradication: basic science and enabling technologies

The Malaria Eradication Research Agenda (malERA) consultative group on Basic Science and Enabling Technologies present a research and development agenda for basic research required for malaria eradication.

Impact of HIV-Associated Immunosuppression on Malaria Infection and Disease in Malawi

BACKGROUND Human immunodeficiency virus (HIV) infection and malaria coexist in much of Africa. Previous studies differ in their findings on the interactions between the 2 infections. METHODS Adults living with HIV infection in Blantyre, Malawi, were enrolled in a longitudinal observational study from September 2002 to August 2004. Malaria blood smears were obtained monthly and for any illness suggestive of malaria. Complete evaluations of all illness episodes were conducted, regardless of malaria smear results. RESULTS The incidence of clinical malaria episodes was higher in participants with CD4 cell counts <200 cells/mm3 than in those with CD4 cell counts >500 cells/mm3. The trend was preserved when increasingly specific definitions of malaria disease were used. The prevalence of malaria infection was not associated with CD4 cell count. In per-visit analysis, lower CD4 cell counts were associated with higher incidences of pneumonia, sepsis, and tuberculosis but not of malaria. Severe malaria was rare, with only 3 cases in 591 person-years of observation. Parasite density and CD4 cell count were independent risk factors for fever. CONCLUSIONS Profoundly immunosuppressed adults with HIV infection require more-frequent treatment for uncomplicated malaria, but malaria infection and disease are less strongly associated with HIV-associated immunosuppression than are other opportunistic infections. Where malaria is common, the high incidence of fever found among immunosuppressed adults may lead to misclassification of illness episodes as malaria.

Return of Chloroquine-Susceptible Falciparum Malaria in Malawi Was a Reexpansion of Diverse Susceptible Parasites

The spread of drug-resistant Plasmodium falciparum malaria has been a major impediment to malaria control and threatens prospects for elimination. We recently demonstrated the return of chloroquine-susceptible malaria in Malawi after chloroquine use was abandoned. In this study, we trace the origins of chloroquine-resistant and chloroquine-susceptible parasites in Malawi by sequencing the P. falciparum chloroquine resistance transporter gene (pfcrt) and by genotyping microsatellites flanking this gene in isolates from infections that occurred in Malawi from 1992 through 2005. Malaria parasites from 2005 harbored the expected wild-type pfcrt haplotype associated with chloroquine susceptibility and have maintained high levels of diversity without linkage disequilibrium, which suggests that the return of chloroquine susceptibility is not the result of a back mutation in a formerly resistant parasite or a new selective sweep. Chloroquine-susceptible parasites that predominate in Malawi likely represent a reexpansion of the susceptible parasites that survived in the population despite widespread drug pressure in the region.

Dengue-Related Deaths in Puerto Rico, 1992–1996: Diagnosis and Clinical Alarm Signals

BACKGROUND Dengue, although endemic in Puerto Rico, is often not mentioned in the death certificates of decedents with laboratory results positive for dengue. Because confirmatory results are usually not available during hospitalization, we examined the utility of 2 instruments for diagnosis on the basis of clinical findings: the definition of dengue hemorrhagic fever (DHF) and the publicized (but unevaluated) clinical alarm signals for impending dengue shock. METHODS We studied data from all patients with laboratory test results positive for dengue who died (23 patients) and from the 8 patients whose death certificates listed dengue as a cause of death but whose laboratory test results were negative for dengue in Puerto Rico from 1992 through 1996. We examined hospital records to determine whether the clinical criteria for DHF were fulfilled and evaluated the incidence and timing of clinical alarm signals (intense, sustained abdominal pain; persistent vomiting; sudden change from fever to hypothermia; and marked restlessness or lethargy) and the hematocrit/hemoglobin ratio as an indicator of hemoconcentration. RESULTS A similar proportion of patients with laboratory test results positive for dengue (18 [78%] of 23) and negative for dengue (6 [75%] of 8) fulfilled the criteria for DHF. Clinical alarm signals were found only among patients with laboratory test results positive for dengue and were usually noted on the day that the patients condition deteriorated. The hematocrit/hemoglobin ratio identified 1 (6%) of 16 patients with dengue who had significant hemoconcentration. Important comorbidities were present in 16 (70%) of the patients with laboratory test results positive for dengue and in 4 (50%) of the patients with dengue-related deaths with laboratory test results negative for dengue. CONCLUSIONS Dengue-related deaths in Puerto Rico often occur in patients with comorbidities. Among such patients, the DHF definition and the hematocrit/hemoglobin ratio were not useful in identifying patients with laboratory test results positive for dengue. In contrast, the clinical alarm signals for shock supported the dengue diagnosis and should alert clinicians to the severity of the disease.

Patterns of chloroquine use and resistance in sub-Saharan Africa: a systematic review of household survey and molecular data

BackgroundAs a result of widespread chloroquine and sulphadoxine-pyrimethamine (SP) resistance, 90% of sub-Saharan African countries had adopted policies of artemisinin-based combination therapy (ACT) for treatment of uncomplicated malaria by 2007. In Malawi, cessation of chloroquine use was followed by the re-emergence of chloroquine-susceptible malaria. It was expected that introduction of ACT would lead to a return in chloroquine susceptibility throughout Africa, but this has not yet widely occurred. This observation suggests that there is continuing use of ineffective anti-malarials in Africa and that persistent chloroquine-resistant malaria is due to ongoing drug pressure despite national policy changes.MethodsTo estimate drug use on a national level, 2006-2007 Demographic Health Survey and Multiple Indicator Cluster Survey data from 21 African countries were analysed. Resistance data were compiled by systematic review of the published literature on the prevalence of the Plasmodium falciparum chloroquine resistance transporter polymorphism at codon 76, which causes chloroquine resistance.ResultsChloroquine was the most common anti-malarial used according to surveys from 14 of 21 countries analysed, predominantly in West Africa. SP was most commonly reported in two of 21 countries. Among eight countries with longitudinal molecular resistance data, the four countries where the highest proportion of children treated for fever received chloroquine (Uganda, Burkina Faso, Guinea Bissau, and Mali) also showed no significant declines in the prevalence of chloroquine-resistant infections. The three countries with low or decreasing chloroquine use among children who reported fever treatment (Malawi, Kenya, and Tanzania) had statistically significant declines in the prevalence of chloroquine resistance.ConclusionsThis study demonstrates that in 2006-2007, chloroquine and SP continued to be used at high rates in many African countries. In countries reporting sustained chloroquine use, chloroquine-resistant malaria persists. In contrast, a low level of estimated chloroquine use is associated with a declining prevalence of chloroquine resistance.

World Antimalarial Resistance Network I: Clinical efficacy of antimalarial drugs

The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed.The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed.

School-Age Children Are a Reservoir of Malaria Infection in Malawi

Malaria surveillance and interventions in endemic countries often target young children at highest risk of malaria morbidity and mortality. We aimed to determine whether school-age children and adults not captured in surveillance serve as a reservoir for malaria infection and may contribute to malaria transmission. Cross-sectional surveys were conducted in one rainy and one dry season in southern Malawi. Demographic and health information was collected for all household members. Blood samples were obtained for microscopic and PCR identification of Plasmodium falciparum. Among 5796 individuals aged greater than six months, PCR prevalence of malaria infection was 5%, 10%, and 20% in dry, and 9%, 15%, and 32% in rainy seasons in Blantyre, Thyolo, and Chikhwawa, respectively. Over 88% of those infected were asymptomatic. Participants aged 6–15 years were at higher risk of infection (OR=4.8; 95%CI, 4.0–5.8) and asymptomatic infection (OR=4.2; 95%CI, 2.7–6.6) than younger children in all settings. School-age children used bednets less frequently than other age groups. Compared to young children, school-age children were brought less often for treatment and more often to unreliable treatment sources. Conclusion: School-age children represent an underappreciated reservoir of malaria infection and have less exposure to antimalarial interventions. Malaria control and elimination strategies may need to expand to include this age group.

Resistance to Antimalarial Drugs: Molecular, Pharmacologic, and Clinical Considerations

One of the greatest obstacles to the control of malaria has been the spread of resistance to drugs used on a large scale. This review provides an update of the current understanding of the molecular basis for antimalarial drug resistance. Parasite intrinsic resistance is just one component that determines the in vivo efficacy of a drug. Human immune responses and pharmacologic properties play important roles in determining the clinical outcome of treatment. The emergence and spread of resistance also results from an interplay of these factors. Current efforts to characterize and deter resistance to new combination therapy are also discussed.

Submicroscopic malaria infection during pregnancy and the impact of intermittent preventive treatment

BackgroundMalaria during pregnancy results in adverse outcomes for mothers and infants. Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP) is the primary intervention aimed at reducing malaria infection during pregnancy. Although submicroscopic infection is common during pregnancy and at delivery, its impact throughout pregnancy on the development of placental malaria and adverse pregnancy outcomes has not been clearly established.MethodsQuantitative PCR was used to detect submicroscopic infections in pregnant women enrolled in an observational study in Blantyre, Malawi to determine their effect on maternal, foetal and placental outcomes. The ability of SP to treat and prevent submicroscopic infections was also assessed.Results2,681 samples from 448 women were analysed and 95 submicroscopic infections were detected in 68 women, a rate of 0.6 episodes per person-year of follow-up. Submicroscopic infections were most often detected at enrolment. The majority of women with submicroscopic infections did not have a microscopically detectable infection detected during pregnancy. Submicroscopic infection was associated with placental malaria even after controlling for microscopically detectable infection and was associated with decreased maternal haemoglobin at the time of detection. However, submicroscopic infection was not associated with adverse maternal or foetal outcomes at delivery. One-third of women with evidence of placental malaria did not have documented peripheral infection during pregnancy. SP was moderately effective in treating submicroscopic infections, but did not prevent the development of new submicroscopic infections in the month after administration.ConclusionsSubmicroscopic malaria infection is common and occurs early in pregnancy. SP-IPT can clear some submicroscopic infections but does not prevent new infections after administration. To effectively control pregnancy-associated malaria, new interventions are required to target women prior to their first antenatal care visit and to effectively treat and prevent all malaria infections.

Antimalarial drug resistance in Africa: key lessons for the future

Drug‐resistant parasites repeatedly arise as a result of widespread use of antimalarial drugs and have contributed significantly to the failure to control and eradicate malaria throughout the world. In this review, we describe the spread of resistance to chloroquine and sulfadoxine–pyrimethamine, two old drugs that are no longer used owing to high rates of resistance, and examine the effect of the removal of drug pressure on the survival of resistant parasites. Artemisinin‐resistant malaria is now emerging in Southeast Asia in a unique and unexpected pattern. We will review the most recent genomic and clinical data to help predict the behavior of resistance to new antimalarial medications and inform strategies to prevent the spread of drug‐resistant malaria in Africa in the future.