Unstable malaria in Sudan: the influence of the dry season. Clone multiplicity of Plasmodium falciparum infections in individuals exposed to variable levels of disease transmission.

Studies of infection and immunity to malaria often take little account of the fact that the amount of infectious challenge individuals receive is very variable. Classic studies in areas of holoendemic transmission showed that clinical immunity develops quite rapidly during childhood, although the processes through which increasing levels of resistance to infection are acquired are still not understood. However, holoendemic transmission is one end of the spectrum of malaria epidemiology and the development of clinical immunity is also affected by factors such as the infection rate and the local parasite species composition. An exceptionally simple type of malaria transmission occurs during the short, autumnal malaria outbreaks of the Sudanese sahel-savannah belt, where a sparse 200-500 mm of rain falls in 2-3 summer months, Plasmodium falciparum causes > 95% of malaria cases in most areas, and the entomological inoculation rate (EIR) is very low by African standards; thus the population dynamics of malaria parasites are less affected by super-infection. A comparison of certain features of parasite genetic diversity, particularly the average number of parasite clones present in infections in the Sudanese sahel and in malaria study sites with different levels of transmission, is presented. It is proposed that increasing EIRs are associated with progressively smaller increases in the average number of malaria parasite clones per host and the implications of this relationship for studies on malaria infection and immunity are discussed.     

Malaria in Afghan refugees in Pakistan

Prevalence of malaria in Afghan refugees in Pakistan is higher than in the local population. Malaria control officials in Pakistan hypothesized that Afghan refugees have brought a heavy load of malaria infections with them from Afghanistan, causing a serious setback to the malaria control programme in Pakistan. The purpose of this study was to test this hypothesis, because it is important regarding the selection of appropriate strategy for malaria control. The proposed hypothesis is rejected because of the following evidence against it: (i) a comparison of age-specific parasite rates of malaria in Afghan refugees and a nearby local population at Karachi indicated that Afghan refugees were susceptible to malaria even in later age-groups, while infections in the local population were limited to younger age-groups; (ii) a comparison of epidemiological trends of malaria in Afghan refugees and the local population in the North-West Frontier Province from 1979 to 1986 demonstrated that the rate of increase in the prevalence of malaria over the years was much higher in Afghan refugees than in the local population, a manifestation of low herd immunity in Afghan refugees. The most plausible alternate hypothesis is that Afghan refugees, being more susceptible, were at high risk of malaria infection in Pakistan rather than that they brought a high infection load with them from Afghanistan. Therefore, malaria control in Afghan refugee camps in Pakistan should be primarily based on preventive, rather than curative, measures.     

Unstable malaria in Sudan: the influence of the dry season. Malaria in areas of unstable and seasonal transmission. Lessons from Daraweesh.

Most studies of the natural history of Plasmodium falciparum infection have been performed in areas of stable malaria transmission and the acquisition of immunity to malaria in individuals who live in such areas is well documented. For the past 10 years, we have monitored host-parasite relationships in an area characterized by unstable and seasonal malaria of low transmission intensity. The work was performed in the village Daraweesh located in north-eastern Sudan 16 km from Gedaref town. The climate of the region is characterized by well-defined wet and dry periods with a short rainy season followed by a long dry season. In some years the rains fail and there is little precipitation even during the wet season. Malaria cases are rare in the dry season and during droughts. In years with rains, falciparum malaria sweeps through Daraweesh during the wet season and 20-40% of the entire population suffer at least 1 attack of malaria. All age-groups are affected, but the risk of getting a clinical attack is about twice as high in the age-group from 5 to 20 years as in adults aged above 30 years. Serological data and evidence obtained by polymerase chain reaction indicate that only about half of new blood-stage infections cause clinical disease. Together these findings suggest that many new infections are controlled immunologically and that individuals aged over 30 years are more successful in controlling infections than are teenagers. Parasite strains collected in Daraweesh are genotypically diverse and it is likely that the outcome of new P. falciparum infections depends on the preparedness of the host immune system to mount an attack against polymorphic or variable antigens expressed by the infecting parasite.     

Development of a transmission-blocking malaria vaccine: Progress,challenges, and the path forward

New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives.     

Genetic analysis of Plasmodium falciparum infections on the north-western border of Thailand

Genetic characterization of Plasmodium falciparum infections in north-western Thailand, a region of low transmission intensity (1 infection/person each year), has found a comparable number of parasite genotypes per infected person to regions with hyperendemic malaria. Clone multiplicity and parasite diversity were found to be homogeneous across 129 infected individuals comprising a range of age-groups (1.32 parasite genotypes; n = 98), patients (aged 2-16 years) with recrudescent infections (1.54; n = 13), and pregnant women (1.61; n = 18). Individuals belonging to groups with a high risk of infection, as deduced by clinical epidemiology, did not harbour a higher number of clones per infection, nor greater parasite diversity than low-risk groups. In fact, multiple genotype infections were as common in low-risk groups, suggesting that there is frequent transmission of polyclonal infections from a single inoculum, rather than superinfection. Such a polyclonal transmission system would enable generation of extensive parasite diversity by recombination, despite the low level of transmission. However, co-infection with P. vivax was associated with fewer P. falciparum genotypes per infection.     

Genotyping of Plasmodium falciparum infections by PCR: a comparative multicentre study

Genetic diversity of malaria parasites represents a major issue in understanding several aspects of malaria infection and disease. Genotyping of Plasmodium falciparum infections with polymerase chain reaction (PCR)-based methods has therefore been introduced in epidemiological studies. Polymorphic regions of the msp1, msp2 and glurp genes are the most frequently used markers for genotyping, but methods may differ. A multicentre study was therefore conducted to evaluate the comparability of results from different laboratories when the same samples were analysed. Analyses of laboratory-cloned lines revealed high specificity but varying sensitivity. Detection of low-density clones was hampered in multiclonal infections. Analyses of isolates from Tanzania and Papua New Guinea revealed similar positivity rates with the same allelic types identified. The number of alleles detected per isolate, however, varied systematically between the laboratories especially at high parasite densities. When the analyses were repeated within the laboratories, high agreement was found in getting positive or negative results but with a random variation in the number of alleles detected. The msp2 locus appeared to be the most informative single marker for analyses of multiplicity of infection. Genotyping by PCR is a powerful tool for studies on genetic diversity of P. falciparum but this study has revealed limitations in comparing results on multiplicity of infection derived from different laboratories and emphasizes the need for highly standardized laboratory protocols.     

Does population mixing measure infectious exposure in children at the community level?

Epidemiological studies focusing on the etiology of childhood chronic diseases have used population mixing as a proxy for the level of infection circulating in a community. We compared different measures of population mixing (based on residential migration and commuting) and other demographic variables, derived from the United Kingdom Census, with hospital inpatient data on infections from two Government Office Regions in England (Eastern and the West Midlands) to inform the development of an infectious disease proxy for future epidemiological studies. The association between rates of infection and the population mixing measures was assessed, using incidence rate ratios across census areas, from negative binomial regression. Commuting distance demonstrated the most consistent association with admissions for infections across the two regions; areas with a higher median distance travelled by commuters leaving the area having a lower rate of hospital admissions for infections. Deprived areas and densely populated areas had a raised rate of admissions for infections. Assuming hospital admissions are a reliable indicator of common infection rates, the results from this study suggest that commuting distance is a consistent measure of population mixing in relation to infectious disease and deprivation and population density are reliable demographic proxies for infectious exposure. Areas that exhibit high levels of population mixing do not necessarily possess raised rates of hospital admissions for infectious disease.     

Effectiveness of mosquito nets treated with a tablet formulation of deltamethrin for malaria control in a hyperendemic tribal area of Sundargarh District, Orissa, India

A village-scale trial on the efficacy of mosquito nets treated with a tablet formulation of deltamethrin (K-OTAB) against malaria in comparison to untreated nets or no net was conducted in Sundargarh District of Orissa, India, which is characterized by perennial transmission with Plasmodium falciparum accounting for more than 80% of malaria cases. Three villages with similar topographical and epidemiological situations were selected and randomly assigned to 3 arms of the study: treated net, untreated net, and no net. Distribution of nets, based on a sleeping pattern survey, was carried out to cover 100% of the population in treated-net and untreated-net villages. Longitudinal and cross-sectional surveys were conducted to measure malaria incidence, prevalence, and splenomegaly. Malaria incidence was reduced by 64.3% in the village with treated nets, 45.2% in the village with plain nets, and 21.4% in the control village without nets. Comparison of malaria incidence data after 1 year of intervention showed significant difference between villages with treated net vs. untreated net (P < 0.05) and treated net vs. no net (P < 0.005). The incidence of clinical attack rate due to P. falciparum was significantly lower in the population using treated nets than in those using untreated nets and no nets. However, no age-specific protective efficacy of treated nets or untreated nets was observed. A significant reduction occurred in spleen rate and parasite rate in children aged 2-9 years using treated nets or untreated nets. An overall significant reduction was found in parasite rate in the total population using treated and untreated nets as compared to nonusers.     

A mathematical model for Plasmodium vivax malaria transmission: estimation of the impact of transmission-blocking immunity in an endemic area.

We have developed a multi-state mathematical model to describe the transmission of Plasmodium vivax malaria; the model accommodates variable transmission-blocking/enhancing immunity during the course of a blood infection, a short memory for boosting immunity, and relapses. Using the model, we simulated the incidence of human malaria, sporozoite rates in the vector population, and the level of transmission-blocking immunity for the infected population over a period of time. Field data from an epidemiological study conducted in Kataragama in the south of Sri Lanka were used to test the results obtained. The incidence of malaria during the study period was simulated satisfactorily. The impact of naturally-acquired transmission-blocking immunity on malaria transmission under different vectorial capacities was also simulated. The results show that at low vectorial capacities, e.g., just above the threshold for transmission, the effect of transmission-blocking immunity is very significant; however, the effect is lower at higher vectorial capacities.     

Allelic variation of msp-3α gene in Plasmodium vivax isolates and its correlation with the severity of disease in vivax malaria

Malaria is a global socio-economic burden of which Plasmodium vivax contributes for about 70–80 million cases on an annual basis worldwide and 60–65% cases in India. Diversity observed in highly polymorphic Merozoite Surface Protein-3α (msp-3α) encoded by MSP-3 gene family, has been used efficiently for genotyping of P. vivax infection. This study aims to correlate the severity of clinical symptoms with parasite load, genotype of P. vivax and multiplicity of infection. Based on clinical symptoms classification, 31 (67.9%) out of 46 cases were found to be severe while 15 (32.6%) were non-severe and correlation of the severity of vivax infection with parasite load was not observed. Analysis of msp3-α allele genotype showed that out of 31 severe cases, 19 (61.2%) were single-clone infection cases whereas 12 (38.7%) were multi-clone infections. Similarly, out of 15 non-severe cases, 9 (60%) were single clone and 6 (40%) were multi-clone infections indicating the absence of a correlation between the multiplicity of infection and disease severity. Allele frequency observed was 65.9%, 23.4%, 23.4%, and 28.2% for allele A, B, C and D, respectively. An important finding was the greater distribution of allele D than alleles B and C, which has been reported as a rare allele otherwise. Further, of 13 cases with allele D, 76.9% (10/13) cases were severe. This study showed the absence of a correlation between the severity of clinical symptoms with parasite load and multiplicity of infection but at the same time drives a possibility of severe vivax malarial symptoms to have an association with the persistence of allele D in the population. This upon exploration can lead to the development of a target in detection of severe cases of malaria.     

An assessment of low birthweight risk in primiparae as an indicator of malaria control in pregnancy

Malaria is an important environmental factor which reduces fetal growth in primiparae more than multiparae living under holoendemic conditions for malaria. This relates to greater susceptibility to malaria infection in first pregnancies. The relative risk for low birthweight (less than 2500 g) associated with primiparity is increased in malaria-endemic areas and significantly correlates with the malaria parasite rate at delivery in primiparae. Because of this association, the relative risk is proposed as an indicator to assess malaria control in pregnant women as well as in the community. The sensitivity and specificity of the relative risk for low birthweight in primiparae are calculated for 13 malarious and 15 non-malarious populations. The highest sensitivity and specificity is achieved at a relative risk of 1.7. Social and environmental variables which could alter the sensitivity of the estimate are discussed. Estimates of the population-attributable risk per cent of low birthweight due to malaria in primiparae are calculated and vary between 10% and 40% in endemic areas. The method is applied to observations from malaria-intervention studies in pregnancy in the Solomon Islands and Papua New Guinea and appears sensitive in these prospective studies to changes in malaria prevalence. Calculation of these estimates is straightforward and their use to assess malaria control measures in areas of high transmission has not been suggested previously, it could have wide epidemiological application and requires further field evaluation.     

State transition detection in the spatio-temporal incidence of malaria

Mosquito-borne disease spread might exhibit irregular epidemic fronts caused by ecological heterogeneity in the risk factors. To determine Plasmodium vivax infection spread in north-eastern Venezuela, we used the State Transition Index (STI) to detect the spatial locations of malaria incidence boundaries and their dynamics over time. Then, we evaluated the role of population size on disease persistence. Boundary locations of malaria were found to be highly spatially variable. Waves of infection were observed in the spatial mosaics of large and small nearby localities due to a strong asynchrony in the epidemic dynamics between both host populations. Our results suggest that the epidemic spatial diffusion follows a hierarchy from large, populated villages (with few or no seasonal parasite fadeouts) to smaller, less populated localities, where infection outbreak was irregular or disease dynamics showed frequent fadeouts. Our findings stress the importance of malaria surveillance and control in these larger communities.     

Malaria epidemiological trends in Italy

Based on the official reports received from local health laboratories, an epidemiological analysis of malaria cases reported in Italy from 1989 to 1992 is presented. A total of 1,941 cases were reported, 1,287 among Italians and 654 among foreigners. The incidence of cases was on average 500 per year with a maximum in 1990. A slight, but constant decrease of incidence of malaria cases was recorded in this period among Italian citizens (–21.5%), while the incidence among foreigners increased (+80%).Plasmodium falciparum accounted for 74.2% of total infections, followed byP. vivax (19%). The highest number of cases was imported from Africa (86.5%), followed by Asia, South America, and Oceania. 11 cases were contracted in Europe (transfusion, airport and cryptic malaria). 26 people died from malaria during the four years, with a fatality rate of 2.3% among Italians. Other epidemiological features concerning incidence in the different categories of travellers, countries of infection, clinical and therapeutic aspects of cases, are also discussed.     

Latest developments in the laboratory diagnosis of malaria

Malaria is the most important parasitic disease worldwide. With the advent of multidrug-resistant strains, it is highly important that the disease be diagnosed both early and accurately. For the diagnosis of malaria parasites, the thick blood film approach remains the gold standard. However, the use of that standard requires a microscope, stains, and a trained microscopist to interpret the films. The author describes the microscopical detection of the malaria parasite through the use of fluorochrome as well as the development of antigen detection tests to improve the laboratory diagnosis of malaria. Histidine-rich protein II (HRPII) is expressed by the asexual stages of Plasmodium falciparum. The detection of HRPII antigen appears to be a useful alternative diagnostic technique when microscopes are unavailable. However, a negative test result may indicate the presence of non-P falciparum malaria or that it is too early in the course of infection to detect parasites. One advantage of a parasite lactate dehydrogenase (pLDH) detection system is its ability to detect all 4 species of malaria and to diagnose both P. falciparum and P. vivax infections.     

A metropolitan hospital in a non-endemic area provides a sampling pool for epidemiological studies on vivax malaria in Sri Lanka

An analysis of records of 494 malaria patients admitted to the General Hospital in Colombo (the capital of Sri Lanka where malaria transmission is not known to occur) from 1981 to 1984 is presented and compared with national malaria data from the entire country. The incidence of predominantly Plasmodium vivax malaria rose sharply over the 3 years; its species distribution and seasonal variation in patients in the General Hospital, Colombo (GHC) generally reflected the disease pattern in the country as a whole. The disease had spread from mainly the endemic dry zone to the non-endemic wet zone. Malaria patients at the GHC were mainly residents of Colombo who had acquired malaria during brief visits to endemic areas, and we have demonstrated how information from them can be used as a sampling method to obtain almost immediate epidemiological information from the whole country. Based on the histories of selected patients we deduced the incubation periods and possible relapse patterns of P. vivax infections in Sri Lanka. This study also provided an insight to the epidemiology of the disease in the city.     

深圳市2008-2012年疟疾监测与疫情流行特征分析

目的分析深圳市2008-2012年疟疾监测结果与疫情流行特点,为消除疟疾提供参考依据。方法整理深圳市2008-2012年"三热"病人血检监测及疟疾疫情报告资料,应用描述流行病学方法进行统计分析。结果 2008-2012年全市血检监测"三热"病人93 048人次,平均年血检率为1.7‰。5年累计报告疟疾170例,平均年发病率为0.31/10万。其中间日疟128例,输入性恶性疟42例。本地病例数逐年下降,至2011年后未再有本地病例报告;输入性疟疾119例,占病例总数的70%。按地区分,报告病例数前三位依次是龙岗区(86例)、罗湖区(35例)和宝安区(28例),其次为南山区(14例)和福田区(7例)。发病时间动态分布显示每年的6-10月为发病的高峰期。青壮年发病为主,20~39岁年龄段发病114例,占病例总数的67.1%。病例男女性别比为5.3:1。往来非洲、东南亚等疟疾高发地区的农民工群体和商务人员为高危人群。结论近年来深圳市疟疾疫情相对稳定,但输入性恶性疟增加,应加强监测与防控。实施以输入性疟疾防治为重点的干预措施取得良好效果。     

A prospective study of Plasmodium falciparum multiplicity of infection and morbidity in Tanzanian children

Several studies suggest that in individuals with substantial previous exposure to malaria, co-infection with multiple clones of Plasmodium falciparum can protect against subsequent clinical malaria attacks. Other studies, mainly of individuals with little previous exposure, found the converse relationship. To test whether acquisition of such cross-protection tracks the acquisition of clinical immunity in general, 610 Tanzanian children aged 0-6 years were enrolled in a nine-month prospective study of the risk of morbidity in relation to parasitological status and merozoite surface protein 2 genotypes on enrolment. Prevalence of parasitaemia and multiplicity of infection increased with age. In the first year of life, the incidence of clinical malaria was almost three times higher in children with parasites at baseline than in those without. In older children, baseline P. falciparum infections appeared to protect against both parasitaemic and non-parasitaemic fever episodes. In children aged less than three years, baseline multiple infection tended to be associated with higher prospective risk of clinical malaria than single infection while in children aged more than three years the converse was found, but these effects were not statistically significant. These results provide further evidence that relationships between asymptomatic malaria infections and clinical malaria change with cumulative exposure.     

Evaluating malaria attributable morbidity in endemic areas

There are no specific clinical signs or symptoms of malaria. Fever attacks, anemia, or signs of severity like coma or respiratory distress cannot easily be attributed to malaria in people who are infected most of the time. Ascribing clinical manifestations to malaria is problematic in populations that are regularly exposed to the transmission of human plasmodia. The more transmission is intense and regular, the higher the prevalence of asymptomatic infections. In areas of intense and perennial malaria transmission, more than 90% of the population may be infected and the simple detection of a plasmodial infection is not enough to attribute clinical manifestations to malaria. Naturally acquired anti-malaria immunity permitting asymptomatic infections is incomplete and temporary. It is an obstacle to the estimation of the malaria burden in endemic areas. The positive association between parasite density and fever allows the attribution of clinical attacks to malaria. The relationship between parasitaemia and the risk of fever is not continuous. An age- and endemicity-dependent threshold effect of parasite density has been demonstrated and can be used to distinguish clinical attacks due to malaria from others. Clinical diagnosis and evaluation of malaria are problematic in three situations: in public health to estimate the malaria burden for health services, in clinical research to evaluate treatments or prophylactic measures (drug, vaccine, anti-vectorial devices), and in basic research on pathophysiology, immunology or genetic susceptibility to clinical malaria. No one diagnostic definition nor procedure for detecting cases is adequate for all three purposes. Case detection may be passive (in health structures for example) or active (in population). The choice of methods for diagnosis and recruitment depends on the objectives and whether a "pragmatic" or "explicative" approach is used. The radical differences between these approaches are often unsuspected or ignored.     

Insecticide-treated materials for malaria control in Latin America: to use or not to use?

Studies on the protective efficacy of insecticide-treated materials (ITMs) in Plasmodium vivax endemic areas of Latin America have not yielded sufficient evidence for recommendation of their extensive use in the region. Therefore 2 randomized community trials have been conducted on the Pacific Coast of Nicaragua which analysed the minimum coverage of ITMs needed to be effective against malaria. For the characterization of the study area, epidemiological and entomological baseline surveys and household interview surveys were undertaken. Thereafter the communities were paired (6 pairs in the 1st year and 13 pairs in the 2nd year) according to 4-monthly reported malaria incidence rates, population size and bednet coverage, and then randomly allocated to intervention and control groups. In the intervention groups, bednets were impregnated with lambdacyhalothrin; in the control groups, people received general health education. Anopheles albimanus was found to be the main vector with marked indoor biting behaviour late in the evening. P. vivax (99%) clearly outweighed P. falciparum (1%) with low parasite prevalence rates in the asymptomatic general population (8%) and low parasite densities. The protective efficacy of ITMs varied according to the coverage achieved: protective efficacy was 68% in communities with an average ITM coverage of 50% (10 pairs); 31% in communities with an ITM coverage of 16-30% (4 pairs); and no protective efficacy in communities with ITM coverage below 16% (5 pairs). The comparison with other P. vivax endemic areas in Latin America showed that the vector's late biting behaviour and the indoor preference (where ITMs have a repellent effect) probably led to the favourable results in the study. In malaria endemic areas of Latin America, where P. vivax is predominant, studies on vector behaviour should be conducted in order to predict the impact of ITMs on malaria transmission.     

Relationship between malarial parasitaemia and symptoms of the disease: A review of the literature

The relationship between parasitaemia and the clinical manifestations of malaria is a highly complex subject, considered by the WHO Expert Committee on Malaria which met in September 1958 to warrant further investigation since it has an important bearing on the organization of eradication programmes. As a first step, the author has reviewed the existing literature on such aspects of malaria epidemiology as the prevalence of gametocytes at various stages of a malarial infection, the limit of infectiousness of the human host, the period of survival of the malaria parasite in man, and the development of immunity through repeated infection. From this study of the works published during the past 60 years, he concludes that much more information as to the role of asymptomatic parasitaemia in the transmission of malaria is required and suggests that it will best be obtained through a critical analysis of the data recorded during the eradication campaigns now under way in many countries.