Adherence to national malaria treatment guidelines in private drug outlets: a cross-sectional survey in the malaria-endemic Kisumu County, Kenya.

BACKGROUND: Malaria prevalence in Kenya is 6%, with a three-fold higher prevalence in western Kenya. Adherence to malaria treatment guidelines improves care for suspected malaria cases and can reduce unnecessary anti-malarial use. Data on adherence to guidelines in retail drug outlets (DOs) is limited, yet approximately 50% of people with fever access treatment first in these outlets. This study assessed adherence to the national malaria treatment guidelines among DOs in a high transmission area of Western Kenya. METHODS: In a cross-sectional survey of DOs in Kisumu Central and Seme sub-counties in 2021, DO staff were interviewed using structured questionnaires to assess outlet characteristics (location, testing services), staff demographics (age, sex, training), and health system context (supervision, inspection). Mystery shoppers (research assistants disguised as clients) observed malaria management practices and recorded observations on a standardized tool. Adherence was defined as dispensing artemether-lumefantrine (AL) to patients with a confirmed positive test, accompanied by appropriate medication counseling. Logistic regression was used to test for association between adherence to guidelines and DO-related factors. RESULTS: None of the 70 DOs assessed had a copy of the guidelines, and 60 (85.7%) were in an urban setting. Staff adhered to the guidelines in 14 (20%) outlets. The odds of adherence were higher among staff who had a bachelor's degree {odds ratio (OR) 6.0, 95% confidence interval (95% CI) 1.66-21.74}, those trained on malaria rapid diagnostic test (RDT) {OR 4.4, 95% CI 1.29-15.04}, and those who asked about patient's symptoms {OR 3.6, 95% CI 1.08-12.25}. DOs that had higher odds of adherence included those with functional thermometers {OR 5.3, 95% CI 1.46-19.14}, those recently inspected (within three months) by Pharmacy and Poisons Board (PPB) {OR 9.4, 95% CI 2.55-34.67}, and those with all basic infrastructure {OR 3.9, 95% CI 1.01-15.00}. On logistic regression analysis, recent PPB inspection {adjusted OR (AOR) 4.6, 95% CI 1.03-20.77} and malaria RDT-trained staff (aOR 4.5, 95% CI 1.02-19.84) were independently associated with adherence. CONCLUSION: Most outlets didn't adhere to malaria guidelines. Regular interaction with regulatory bodies could improve adherence. Ministry of Health should enhance private sector engagement and train DOs on RDT use.

Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial.

BACKGROUND: Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the comparative efficacy of prevention regimens is largely unknown. METHODS AND FINDINGS: We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited. CONCLUSIONS: In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted. TRIAL REGISTRATION: clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165.

Plasmodium falciparum importation does not sustain malaria transmission in a semi-arid region of Kenya.

Human movement impacts the spread and transmission of infectious diseases. Recently, a large reservoir of Plasmodium falciparum malaria was identified in a semi-arid region of northwestern Kenya historically considered unsuitable for malaria transmission. Understanding the sources and patterns of transmission attributable to human movement would aid in designing and targeting interventions to decrease the unexpectedly high malaria burden in the region. Toward this goal, polymorphic parasite genes (ama1, csp) in residents and passengers traveling to Central Turkana were genotyped by amplicon deep sequencing. Genotyping and epidemiological data were combined to assess parasite importation. The contribution of travel to malaria transmission was estimated by modelling case reproductive numbers inclusive and exclusive of travelers. P. falciparum was detected in 6.7% (127/1891) of inbound passengers, including new haplotypes which were later detected in locally-transmitted infections. Case reproductive numbers approximated 1 and did not change when travelers were removed from transmission networks, suggesting that transmission is not fueled by travel to the region but locally endemic. Thus, malaria is not only prevalent in Central Turkana but also sustained by local transmission. As such, interrupting importation is unlikely to be an effective malaria control strategy on its own, but targeting interventions locally has the potential to drive down transmission.

Relationship between changing malaria burden and low birth weight in sub-Saharan Africa: A difference-in-differences study via a pair-of-pairs approach.

Background: According to the World Health Organization (WHO), in 2018, an estimated 228 million malaria cases occurred worldwide with most cases occurring in sub-Saharan Africa. Scale-up of vector control tools coupled with increased access to diagnosis and effective treatment has resulted in a large decline in malaria prevalence in some areas, but other areas have seen little change. Although interventional studies demonstrate that preventing malaria during pregnancy can reduce the rate of low birth weight (i.e. child's birth weight <2500 g), it remains unknown whether natural changes in parasite transmission and malaria burden can improve birth outcomes. Methods: We conducted an observational study of the effect of changing malaria burden on low birth weight using data from 18,112 births in 19 countries in sub-Saharan African countries during the years 2000-2015. Specifically, we conducted a difference-in-differences study via a pair-of-pairs matching approach using the fact that some sub-Saharan areas experienced sharp drops in malaria prevalence and some experienced little change. Results: A malaria prevalence decline from a high rate (Plasmodium falciparum parasite rate in children aged 2-up-to-10 (i.e. PfPR2-10) > 0.4) to a low rate (PfPR2-10 < 0.2) is estimated to reduce the rate of low birth weight by 1.48 percentage points (95% confidence interval: 3.70 percentage points reduction, 0.74 percentage points increase), which is a 17% reduction in the low birth weight rate compared to the average (8.6%) in our study population with observed birth weight records (1.48/8.6 ≈ 17%). When focusing on first pregnancies, a decline in malaria prevalence from high to low is estimated to have a greater impact on the low birth weight rate than for all births: 3.73 percentage points (95% confidence interval: 9.11 percentage points reduction, 1.64 percentage points increase). Conclusions: Although the confidence intervals cannot rule out the possibility of no effect at the 95% confidence level, the concurrence between our primary analysis, secondary analyses, and sensitivity analyses, and the magnitude of the effect size, contribute to the weight of the evidence suggesting that declining malaria burden can potentially substantially reduce the low birth weight rate at the community level in sub-Saharan Africa, particularly among firstborns. The novel statistical methodology developed in this article-a pair-of-pairs approach to a difference-in-differences study-could be useful for many settings in which different units are observed at different times. Funding: Ryan A. Simmons is supported by National Center for Advancing Translational Sciences (UL1TR002553). The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Malaria infects around 230 million people each year, mostly in sub-Saharan Africa, and causes more than 400,000 deaths. Pregnant women are particularly susceptible to malaria. The parasite that causes malaria can sap the mother's iron stores and may starve the baby of nutrients. Babies born to infected mothers often have low birth weights, which can have lasting effects on their health and brain development. Previous studies suggest that preventing malaria in pregnant women using insecticide-treated bed nets or medications may improve birth outcomes. Successful efforts to prevent malaria have led to substantially fewer infections in sub-Saharan Africa. But success has been uneven with some communities continuing to have high rates of infection. These differences may allow scientists to better understand the community-level impact of falling rates of malaria on pregnancy outcomes in the real world. Heng et al. estimated that reducing malaria transmission minimises the number of infants born with low birth weights in communities in sub-Saharan Africa. In an observational study, they used data on more than 18,000 births in 19 countries in this region between 2000 and 2015 to assess the effects of declining malaria rates on birth weights. They found that a decrease of malaria prevalence is estimated to reduce the rate of low birth weight by 1.48%, which is a 17% reduction in the number of observed newborns with low birth weight in the study population. First-born infants appeared to benefit the most. This highlights that malaria interventions are beneficial for pregnant women and their newborns. Most analyses of the impact and cost-benefit of malaria control have ignored the potential advantages of malaria control on birth weight, and may thus undermine the benefits of malaria control. The approach used by Heng et al. may further be useful for other epidemiologists studying global health.

High-resolution micro-epidemiology of parasite spatial and temporal dynamics in a high malaria transmission setting in Kenya.

Novel interventions that leverage the heterogeneity of parasite transmission are needed to achieve malaria elimination. To better understand spatial and temporal dynamics of transmission, we applied amplicon next-generation sequencing of two polymorphic gene regions (csp and ama1) to a cohort identified via reactive case detection in a high-transmission setting in western Kenya. From April 2013 to July 2014, we enrolled 442 symptomatic children with malaria, 442 matched controls, and all household members of both groups. Here, we evaluate genetic similarity between infected individuals using three indices: sharing of parasite haplotypes on binary and proportional scales and the L1 norm. Symptomatic children more commonly share haplotypes with their own household members. Furthermore, we observe robust temporal structuring of parasite genetic similarity and identify the unique molecular signature of an outbreak. These findings of both micro- and macro-scale organization of parasite populations might be harnessed to inform next-generation malaria control measures.

A longitudinal cohort study of malaria exposure and changing serostatus in a malaria endemic area of rural Tanzania.

BACKGROUND: Measurements of anti-malarial antibodies are increasingly used as a proxy of transmission intensity. Most serological surveys are based on the use of cross-sectional data that, when age-stratified, approximates historical patterns of transmission within a population. Comparatively few studies leverage longitudinal data to explicitly relate individual infection events with subsequent antibody responses. METHODS: The occurrence of seroconversion and seroreversion events for two Plasmodium falciparum asexual stage antigens (MSP-1 and AMA-1) was examined using three annual measurements of 691 individuals from a cohort of individuals in a malaria-endemic area of rural east-central Tanzania. Mixed-effect logistic regression models were employed to determine factors associated with changes in serostatus over time. RESULTS: While the expected population-level relationship between seroprevalence and disease incidence was observed, on an individual level the relationship between individual infections and the antibody response was complex. MSP-1 antibody responses were more dynamic in response to the occurrence and resolution of infection events than AMA-1, while the latter was more correlated with consecutive infections. The MSP-1 antibody response to an observed infection seemed to decay faster over time than the corresponding AMA-1 response. Surprisingly, there was no evidence of an age effect on the occurrence of a conversion or reversion event. CONCLUSIONS: While the population-level results concur with previously published sero-epidemiological surveys, the individual-level results highlight the more complex relationship between detected infections and antibody dynamics than can be analysed using cross-sectional data. The longitudinal analysis of serological data may provide a powerful tool for teasing apart the complex relationship between infection events and the corresponding immune response, thereby improving the ability to rapidly assess the success or failure of malaria control programmes.

Use of malaria RDTs in various health contexts across sub-Saharan Africa: a systematic review.

BACKGROUND: The World Health Organization recommends parasitological confirmation of malaria prior to treatment. Malaria rapid diagnostic tests (RDTs) represent one diagnostic method that is used in a variety of contexts to overcome limitations of other diagnostic techniques. Malaria RDTs increase the availability and feasibility of accurate diagnosis and may result in improved quality of care. Though RDTs are used in a variety of contexts, no studies have compared how well or effectively RDTs are used across these contexts. This review assesses the diagnostic use of RDTs in four different contexts: health facilities, the community, drug shops and schools. METHODS: A comprehensive search of the Pubmed database was conducted to evaluate RDT execution, test accuracy, or adherence to test results in sub-Saharan Africa. Original RDT and Plasmodium falciparum focused studies conducted in formal health care facilities, drug shops, schools, or by CHWs between the year 2000 and December 2016 were included. Studies were excluded if they were conducted exclusively in a research laboratory setting, where staff from the study team conducted RDTs, or in settings outside of sub-Saharan Africa. RESULTS: The literature search identified 757 reports. A total of 52 studies were included in the analysis. Overall, RDTs were performed safely and effectively by community health workers provided they receive proper training. Analogous information was largely absent for formal health care workers. Tests were generally accurate across contexts, except for in drug shops where lower specificities were observed. Adherence to RDT results was higher among drug shop vendors and community health workers, while adherence was more variable among formal health care workers, most notably with negative test results. CONCLUSIONS: Malaria RDTs are generally used well, though compliance with test results is variable - especially in the formal health care sector. If low adherence rates are extrapolated, thousands of patients may be incorrectly diagnosed and receive inappropriate treatment resulting in a low quality of care and unnecessary drug use. Multidisciplinary research should continue to explore determinants of good RDT use, and seek to better understand how to support and sustain the correct use of this diagnostic tool.

Changes in Malaria Epidemiology in Africa and New Challenges for Elimination.

Although the burden of Plasmodium falciparum malaria is gradually declining in many parts of Africa, it is characterized by spatial and temporal variability that presents new and evolving challenges for malaria control programs. Reductions in the malaria burden need to be sustained in the face of changing epidemiology whilst simultaneously tackling significant pockets of sustained or increasing transmission. Large-scale, robust surveillance mechanisms that measure rather than estimate the actual burden of malaria over time from large areas of the continent where such data are lacking need to be prioritized. We review these fascinating developments, caution against complacency, and make the case that improving the extent and quality of malaria surveillance is vital for Africa as she marches on towards elimination.

Clinical and geographic patterns of rheumatic heart disease in outpatients attending cardiology clinic in western Kenya.

INTRODUCTION: Rheumatic heart disease (RHD) remains a leading cause of cardiovascular mortality in sub-Saharan Africa. Identifying high risk populations and geographic patterns of disease is crucial to developing RHD prevention and screening strategies in endemic areas. OBJECTIVES: To identify clinical and geographical trends in RHD throughout western Kenya METHODS: We conducted a retrospective chart review of all patients <50years old attending adult cardiology clinic at a national referral hospital in western Kenya. Demographic information, residential location and cardiac history were collected. We mapped the spatial distribution of cardiac disease rates and analyzed the effect of distance from the hospital on RHD status. RESULTS: Two-thirds (64%) of cardiology clinic patients <50years old (n=906) had RHD. RHD patients were younger (26 vs. 33years, p<0.001) and more often female (69% vs. 59%, p=0.001) than non-RHD patients. Global clustering of disease rates existed within 200km of the hospital with significant clustering of the RHD and non-RHD rate difference surrounding the hospital (Moran's I: 0.3, p=0.001). There was an interaction between ethnicity and distance from the hospital such that the odds of RHD decreased with further distance for Nilotes, but the odds of RHD increased with further distance for non-Nilotes CONCLUSION: Most adult cardiology patients treated at a national referral hospital in western Kenya have RHD. Young people and females are commonly affected. Ethnicity and distance to the hospital interdependently affect the odds of RHD. Future studies in this area should consider the impact of ethnic predisposition to RHD.

Q Fever, Scrub Typhus, and Rickettsial Diseases in Children, Kenya, 2011-2012.

To increase knowledge of undifferentiated fevers in Kenya, we tested paired serum samples from febrile children in western Kenya for antibodies against pathogens increasingly recognized to cause febrile illness in Africa. Of patients assessed, 8.9%, 22.4%, 1.1%, and 3.6% had enhanced seroreactivity to Coxiella burnetii, spotted fever group rickettsiae, typhus group rickettsiae, and scrub typhus group orientiae, respectively.

Etiology of pediatric fever in western Kenya: a case-control study of falciparum malaria, respiratory viruses, and streptococcal pharyngitis.

In Kenya, more than 10 million episodes of acute febrile illness are treated annually among children under 5 years. Most are clinically managed as malaria without parasitological confirmation. There is an unmet need to describe pathogen-specific etiologies of fever. We enrolled 370 febrile children and 184 healthy controls. We report demographic and clinical characteristics of patients with Plasmodium falciparum, group A streptococcal (GAS) pharyngitis, and respiratory viruses (influenza A and B, respiratory syncytial virus [RSV], parainfluenza [PIV] types 1-3, adenovirus, human metapneumovirus [hMPV]), as well as those with undifferentiated fever. Of febrile children, 79.7% were treated for malaria. However, P. falciparum was detected infrequently in both cases and controls (14/268 [5.2%] versus 3/133 [2.3%], P = 0.165), whereas 41% (117/282) of febrile children had a respiratory viral infection, compared with 24.8% (29/117) of controls (P = 0.002). Only 9/515 (1.7%) children had streptococcal infection. Of febrile children, 22/269 (8.2%) were infected with > 1 pathogen, and 102/275 (37.1%) had fevers of unknown etiology. Respiratory viruses were common in both groups, but only influenza or parainfluenza was more likely to be associated with symptomatic disease (attributable fraction [AF] 67.5% and 59%, respectively). Malaria was overdiagnosed and overtreated. Few children presented to the hospital with GAS pharyngitis. An enhanced understanding of carriage of common pathogens, improved diagnostic capacity, and better-informed clinical algorithms for febrile illness are needed.

High prevalence of malaria parasitemia and anemia among hospitalized children in Rakai, Uganda.

BACKGROUND: There is a paucity of data on malaria among hospitalized children in malaria endemic areas. We determined the prevalence, presentation and treatment outcomes of malaria and anemia among children in two hospitals in Rakai, Uganda. METHODS: Children under five years hospitalized in Kalisizo hospital or Bikira health center in Rakai district, Uganda between May 2011 and May 2012 were enrolled and followed-up until discharge, death or referral. Data were collected on social-demographic characteristics, current and past illnesses and clinical signs and symptoms. Blood smears, hemoglobin (Hgb) levels and HIV testing were performed from finger/heel prick blood. The associations between malaria infection and other factors were estimated using log-binomial regression to estimate adjusted prevalence risk ratios (aPRR) and 95% confidence intervals (CIs), controlling for clustering at health facilities. RESULTS: 2471 children were enrolled. The most common medical presentations were fever (96.2%), cough (61.7%), vomiting (44.2%), diarrhea (20.8%), and seizures (16.0%). The prevalence of malaria parasitemia was 54.6%. Children with malaria were more likely to present with a history of fever (aPRR 2.23; CI 1.18-4.24) and seizures (aPRR 1.12; CI 1.09-1.16). Confirmed malaria was significantly lower among girls than boys (aPRR 0.92; CI 0.91-0.93), HIV infected children (aPRR 0.60 CI 0.52-0.71), and children with diarrhea (aPRR 0.76; CI 0.65-0.90). The overall prevalence of anemia (Hgb<10 g/dl) was 56.3% and severe anemia (Hgb<6 g/dL) was 17.8%. Among children with severe anemia 76.8% had malaria parasitemia, of whom 93.1% received blood transfusion. Malaria associated mortality was 0.6%. CONCLUSION: There was a high prevalence of malaria parasitemia and anemia among inpatient children under five years. Malaria prevention is a priority in this population.

Developmental allometry and paediatric malaria.

WHO estimates that 80% of mortality due to malaria occurs among infants and young children. Though it has long been established that malaria disproportionately affects children under age five, our understanding of the underlying biological mechanisms for this distribution remains incomplete. Many studies use age as an indicator of exposure, but age may affect malaria burden independently of previous exposure. Not only does the severity of malaria infection change with age, but the clinical manifestation of disease does as well: younger children are more likely to suffer severe anaemia, while older children are more likely to develop cerebral malaria. Intensity of transmission and acquired immunity are important determinants of this age variation, but age differences remain consistent over varying transmission levels. Thus, age differences in clinical presentation may involve inherent age-related factors as well as still-undiscovered facets of acquired immunity, perhaps including the rates at which relevant aspects of immunity are acquired. The concept of "allometry" - the relative growth of a part in relation to that of an entire organism or to a standard - has not previously been applied in the context of malaria infection. However, because malaria affects a number of organs and cells, including the liver, red blood cells, white blood cells, and spleen, which may intrinsically develop at rates partly independent of each other and of a child's overall size, developmental allometry may influence the course and consequences of malaria infection. Here, scattered items of evidence have been collected from a variety of disciplines, aiming to suggest possible research paths for investigating exposure-independent age differences affecting clinical outcomes of malaria infection.

Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya.

BACKGROUND: As efforts to control malaria are expanded across the world, understanding the role of transmission intensity in determining the burden of clinical malaria is crucial to the prediction and measurement of the effectiveness of interventions to reduce transmission. Furthermore, studies comparing several endemic sites led to speculation that as transmission decreases morbidity and mortality caused by severe malaria might increase. We aimed to assess the epidemiological characteristics of malaria in Kilifi, Kenya, during a period of decreasing transmission intensity. METHODS: We analyse 18 years (1990-2007) of surveillance data from a paediatric ward in a malaria-endemic region of Kenya. The hospital has a catchment area of 250 000 people. Clinical data and blood-film results for more than 61 000 admissions are reported. FINDINGS: Hospital admissions for malaria decreased from 18.43 per 1000 children in 2003 to 3.42 in 2007. Over 18 years of surveillance, the incidence of cerebral malaria initially increased; however, malaria mortality decreased overall because of a decrease in incidence of severe malarial anaemia since 1997 (4.75 to 0.37 per 1000 children) and improved survival among children admitted with non-severe malaria. Parasite prevalence, the mean age of children admitted with malaria, and the proportion of children with cerebral malaria began to change 10 years before hospitalisation for malaria started to fall. INTERPRETATION: Sustained reduction in exposure to infection leads to changes in mean age and presentation of disease similar to those described in multisite studies. Changes in transmission might not lead to immediate reductions in incidence of clinical disease. However, longitudinal data do not indicate that reductions in transmission intensity lead to transient increases in morbidity and mortality.

Relationship between exposure, clinical malaria, and age in an area of changing transmission intensity.

The relationship between malaria transmission intensity and clinical disease is important for predicting the outcome of control measures that reduce transmission. Comparisons of hospital data between areas of differing transmission intensity suggest that the mean age of hospitalized clinical malaria is higher under relatively lower transmission, but the total number of episodes is similar until transmission drops below a threshold, where the risks of hospitalized malaria decline. These observations have rarely been examined longitudinally in a single community where transmission declines over time. We reconstructed 16 years (1991-2006) of pediatric hospital surveillance data and infection prevalence surveys from a circumscribed geographic area on the Kenyan coast. The incidence of clinical malaria remained high, despite sustained reductions in exposure to infection. However, the age group experiencing the clinical attacks of malaria increased steadily as exposure declined and may precede changes in the number of episodes in an area with declining transmission.

Strain theory of malaria: the first 50 years.

From the 1920s to the 1970s, a large body of principles and evidence accumulated about the existence and character of 'strains' among the Plasmodium species responsible for human malaria. An extensive research literature examined the degree to which strains were autonomous, stable biological entities, distinguishable by clinical, epidemiological or other features, and how this knowledge could be used to benefit medical and public health practice. Strain theory in this era was based largely on parasite phenotypes related to clinical virulence, reactions to anti-malarial drugs, infectivity to mosquitoes, antigenic properties and host immunity, latency and relapse. Here we review the search for a definition of 'strain', suggest how the data and discussion shaped current understandings of many aspects of malaria and sketch a number of specific connections with perspectives from the past 30 years.

Fever in patients with mixed-species malaria.

BACKGROUND: Clinical symptoms of mixed-species malaria infections have been variously reported as both less severe and more severe than those of single-species infections. METHODS: Oral temperatures were taken from and blood slides were prepared for 2308 adults who presented at outpatient malaria clinics in Tak Province (Thailand) during May-August 1998, May-July 1999, and May-June 2001 with malaria infections diagnosed by 2 expert research microscopists, each of whom was blinded to the other's reports. RESULTS: In each year, temperatures of patients with mixed Plasmodium vivax-Plasmodium falciparum infections were higher than temperatures of patients with P. vivax or P. falciparum infections. In every mixed-species case, P. falciparum parasitemia was higher than P. vivax parasitemia, but patient temperature was not correlated with the parasitemia of either species or with the total parasitemia. CONCLUSIONS: Among adults who self-report to malaria clinics in western Thailand, patients with mixed P. vivax-P. falciparum infections have higher fevers than patients with single-species infections, a distinction that cannot be attributed to differences in parasitemia. This observation warrants more detailed investigations, spanning wider ranges of ages and transmission environments.

Gametocytemia in Plasmodium vivax and Plasmodium falciparum infections.

Two expert research microscopists, each blinded to the other's reports, diagnosed single-species malaria infections in 2,141 adults presenting at outpatient malaria clinics in Tak Province, Thailand, and Iquitos, Peru, in May-August 1998, May-July 1999, and May-June 2001. Plasmodium vivax patients with gametocytemia had higher fever and higher parasitemia than those without gametocytemia; temperature correlated with parasitemia in the patients with gametocytemia. Plasmodium falciparum patients with gametocytemia had lower fever than those without gametocytemia, but similar parasitemia; temperature correlated with parasitemia in the patients without gametocytemia. Hematologic data in Thailand in 2001 showed lower platelet counts in P. vivax patients with gametocytemia than in the P. vivax patients without gametocytemia, whereas P. falciparum patients with gametocytemia had similar platelet counts but lower red blood cell counts, hemoglobin levels, hematocrit levels, and higher lymphocyte counts than patients without gametocytemia.