Ancient Plasmodium genomes shed light on the history of human malaria.

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.

The spatiotemporal distribution of historical malaria cases in Sweden: a climatic perspective.

BACKGROUND: Understanding of the impacts of climatic variability on human health remains poor despite a possibly increasing burden of vector-borne diseases under global warming. Numerous socioeconomic variables make such studies challenging during the modern period while studies of climate-disease relationships in historical times are constrained by a lack of long datasets. Previous studies have identified the occurrence of malaria vectors, and their dependence on climate variables, during historical times in northern Europe. Yet, malaria in Sweden in relation to climate variables is understudied and relationships have never been rigorously statistically established. This study seeks to examine the relationship between malaria and climate fluctuations, and to characterise the spatio-temporal variations at parish level during severe malaria years in Sweden 1749-1859. METHODS: Symptom-based annual malaria case/death data were obtained from nationwide parish records and military hospital records in Stockholm. Pearson (rp) and Spearman's rank (rs) correlation analyses were conducted to evaluate inter-annual relationship between malaria data and long meteorological series. The climate response to larger malaria events was further explored by Superposed Epoch Analysis, and through Geographic Information Systems analysis to map spatial variations of malaria deaths. RESULTS: The number of malaria deaths showed the most significant positive relationship with warm-season temperature of the preceding year. The strongest correlation was found between malaria deaths and the mean temperature of the preceding June-August (rs = 0.57, p < 0.01) during the 1756-1820 period. Only non-linear patterns can be found in response to precipitation variations. Most malaria hot-spots, during severe malaria years, concentrated in areas around big inland lakes and southern-most Sweden. CONCLUSIONS: Unusually warm and/or dry summers appear to have contributed to malaria epidemics due to both indoor winter transmission and the evidenced long incubation and relapse time of P. vivax, but the results also highlight the difficulties in modelling climate-malaria associations. The inter-annual spatial variation of malaria hot-spots further shows that malaria outbreaks were more pronounced in the southern-most region of Sweden in the first half of the nineteenth century compared to the second half of the eighteenth century.

VK210 and VK247 genotypes of Plasmodium vivax in anopheline mosquitoes from Brazilian Amazon.

Plasmodium vivax sporozoites are differenced by circumsporozoite protein. Studies on the circulation of P. vivax VK210 and P. vivax VK247 in anopheline mosquitoes are important to verify the adaptability of these parasites on mosquitoes in different locations and periods. This study aimed to describe and compare the distribution of these genotypes in anopheline mosquitoes from four states of the Brazilian Amazon. Epidemiological databases about CSP infections on mosquitoes from Pará (2000-2015), Amapá (2000-2010), Roraima (2000-2003 and 2009-2011) and Acre States (2012-2015) were used for analysis. A total of 895 specimens were found infected mainly by P. vivax VK210. We showed that the distribution of P. vivax VK247 changed over time in the main malaria vectors on the Brazilian Amazon. We note that A. darlingi was abundant in certain localities while A. albitarsis s.l. in anothers, which highlights the importance of entomological studies for the control of human malaria.

Tolerance May Be More Appropriate Than Immunity When Describing Chronic Malaria Infections.

Adults who have not grown up in a malaria-endemic area may experience severe malaria soon after entering a malarious area. Such mortality is usually limited to a short period of time (months), after which they are thought to be "immune." Such anti-disease immunity may be more accurately considered as tolerance. Malaria rates of British soldiers during the Second World War reflected their time with suppressed infections and the transmission levels. Black workers from non-endemic areas on the Panama Canal experienced higher initial mortality and infection rates than co-located white workers for Plasmodium falciparum, whereas the known genetic resistance of blacks to Plasmodium vivax reversed these rates. The ethnic differences observed in malaria rates may have more to do with acquired tolerance than genetic resistance. Long-term (years) sub-patent infections may maintain host tolerance, and elimination of malaria infections may place these adults at subsequent risk of severe malaria.

Epidemiology of Plasmodium vivax Malaria Infection in Nepal.

Malaria is endemic in the southern plain of Nepal which shares a porous border with India. More than 80% cases of malaria in Nepal are caused by Plasmodium vivax. The main objective of this study was to review the epidemiology of P. vivax malaria infections as recorded by the national malaria control program of Nepal between 1963 and 2016. National malaria data were retrieved from the National Malaria program in the Ministry of Health, Government of Nepal. The epidemiological trends and malariometric indicators were analyzed. Vivax malaria has predominated over falciparum malaria in the past 53 years, with P. vivax malaria comprising 70-95% of the annual malaria infections. In 1985, a malaria epidemic occurred with 42,321 cases (82% P. vivax and 17% Plasmodium falciparum). Nepal had experienced further outbreaks of malaria in 1991 and 2002. Plasmodium falciparum cases increased from 2005 to 2010 but since then declined. Analyzing the overall trend between 2002 (12,786 cases) until 2016 (1,009 cases) shows a case reduction by 92%. The proportion of imported malaria cases has increased from 18% of cases in 2001 to 50% in 2016. The current trends of malariometric indices indicate that Nepal is making a significant progress toward achieving the goal of malaria elimination by 2025. Most of the cases are caused by P. vivax with imported malaria comprising an increasing proportion of cases. The malaria control program in Nepal needs to counter importation of malaria at high risk areas with collaborative cross border malaria control activities.

Molecular evaluation of pvdhfr and pvmdr-1 mutants in Plasmodium vivax isolates after treatment with sulfadoxine/pyrimethamine and chloroquine in Iran during 2001-2016.

The rising use of sulfadoxine/pyrimethamine (SP) in the treatment of chloroquine (CQ)-resistant Plasmodium falciparum has resulted in increased exposure to P. vivax isolates in Iran, where both species are being circulated. In this investigation, the frequency of pvdhfr and pvmdr-1 mutants was assessed in P. vivax strains during 2001-2016 after the introduction of SP/CQ in malarious areas of Iran. The P. vivax isolates (n, 52) were obtained from autochthonous samples in Southeast Iran during 2015-2016. The genomic DNA was extracted and examined using nested polymerase chain reaction-(PCR) and sequencing. Mutations were detected in pvdhfr codons P33L (21.2%), T61 M (25%), S93H (3.9%), and S117 T (1.9%) and 5 isolates showed double mutations (33 L/61 M, 7.7%; 33 L/117 T, 1.9%). No mutation was identified in pvdhfr codons F57 and S58. The pvmdr-1 1076 L mutation was detected in 93.3% of P. vivax isolates. The findings indicated that the frequency of three codons of pvdhfr F57/S58/S117 has decreased from 2001 (1.05%/7.0%/16.9%) to 2016 (0%/0%/1.9%). Genomic analysis of pvmdr-1 showed that the frequency of 1076 L has gradually increased from 2013 (93%) to 2016 (93.3%) (P > .05). The results demonstrated that P. vivax isolates are probably being exited under SP pressure, which reflects the appropriate level of training for field microscopists, as established by Iranian policymakers. Emergent pvdhfr codons 33L, 61M, and 93H should be noticed in plausible drug tolerance and treatment plans. The high prevalence of pvmdr-1 1076L mutation shows that efficacy of CQ combination with primaquine may be in danger of being compromised, however further investigations are needed to evaluate the clinical importance of CQ-resistant P. vivax isolates.

Genetic Spatiotemporal Anatomy of Plasmodium vivax Malaria Episodes in Greece, 2009-2013.

An influx of immigrants is contributing to the reemergence of Plasmodium vivax malaria in Greece; 1 persistent focus of transmission is in Laconia, Pelopónnese. We genotyped archived blood samples from a substantial proportion of malaria cases recorded in Greece in 2009-2013 using 8 microsatellite markers and a PvMSP-3α gene fragment and plotted their spatiotemporal distribution. High parasite genetic diversity with low multiplicity of infection was observed. A subset of genetically identical/related parasites was restricted to 3 areas in migrants and Greek residents, with some persisting over 2 consecutive transmission periods. We identified 2 hitherto unsuspected additional foci of local transmission: Kardhítsa and Attica. Furthermore, this analysis indicates that several cases in migrants initially classified as imported malaria were actually locally acquired. This study shows the potential for P. vivax to reestablish transmission and counsels public health authorities about the need for vigilance to achieve or maintain sustainable malaria elimination.

Malaria in the Americas: trends from 1959 to 2011.

Malaria has declined in recent years in countries of the American continents. In 2011, 12 of 21 endemic countries had already met their 2015 Millennium Development Goal. However, this declining trend has not been adequately evaluated. An analysis of the number of cases per 100,000 people (annual parasite index [API]) and the percentage of positive blood slides (slide positivity rate [SPR]) during the period of 1959-2011 in 21 endemic countries was done using the joinpoint regression methodology. During 1960-1979, API and SPR increased significantly and peaked in the 1980s. Since the 1990s, there have been significant declining trends in both API and SPR. Additionally, both Plasmodium vivax and P. falciparum species-specific incidence have declined. With the exception of two countries, such a collectively declining malaria trend was not observed in previous decades. This presents a unique opportunity for the Americas to seriously consider malaria elimination as a final goal.

Association of temperature and historical dynamics of malaria in the Republic of Korea, including reemergence in 1993.

Plasmodium vivax malaria reemerged in the Republic of Korea in 1993 after it had been declared malaria free in 1979. Malaria rapidly increased and peaked in 2000 with 4,142 cases with lower but variable numbers of cases reported through 2011. We examined the association of regional climate trends over the Korean Peninsula relative to malaria cases in U.S. military and Republic of Korea soldiers, veterans, and civilians from 1950 to 2011. Temperatures and anomaly trends in air temperature associated with satellite remotely sensed outgoing long-wave radiation were used to observe temporal changes. These changes, particularly increasing air temperatures, in combination with moderate rains throughout the malaria season, and distribution of malaria vectors, likely supported the 1993 reemergence and peaks in malaria incidence that occurred through 2011 by accelerating the rate of parasite development in mosquitoes and increased numbers as a result of an expansion of larval habitat, thereby increasing the vectorial capacity of Anopheles vectors. High malaria rates associated with a favorable climate were similarly observed during the Korean War. These findings support the need for increased investigations into malaria predictive models using climate-related variables.

[Malaria in endemic areas of Northern Italy and in the Italian context: remedies and substitutes in the nineteenth century medical practice]. / La malaria in aree ad elevata endemia del nord Italia e nel contesto italiano: rimedi e succedanei nella pratica medica dell'Ottocento.

Some areas of Northern Italy, especially Ferrara during the nineteenth century, represent privileged observatories regard to malaria, a disease that affected the poor, but did not spare the rich and powerful people. The so called Delta of the River Po, as well as the Maremma and other lowland areas in Italy, was particularly noted for its marshland environment (mosquito breeding grounds). Spared from Malaria because of the better hygienic conditions of the city that restricted the proliferation of anopheles, Ferrara represented an important study centre due to the presence of renowned physicians and scientists who exchanged knowledge and findings in the medical academies. Among these, Antonio Campana was very attentive to the latest scientific findings, and wrote about antimalarial remedies in his famous Ferrarese Pharmacopoeia. This paper analyses the main remedies listed in the various editions of Campana Pharmacopoeia since 1798 and particularly that of 1841, in the reports from the Accademia Medico Chirurgica di Ferrara and of Argenta physicians of the mid nineteenth century and in the Reports (1871 and 1876) from Alessandro Bennati, director of Arcispedale Santa Anna and concerned with hospital practice. Other printed documents referring to the town of Argenta are discussed.

Spatiotemporal dynamics and demographic profiles of imported Plasmodium falciparum and Plasmodium vivax infections in Ontario, Canada (1990-2009).

We examined malaria cases reported to Ontario's public health surveillance systems from 1990 through 2009 to determine how temporal scale (longitudinal, seasonal), spatial scale (provincial, health unit), and demography (gender, age) contribute to Plasmodium infection in Ontario travellers. Our retrospective study included 4,551 confirmed cases of imported malaria reported throughout Ontario, with additional analysis at the local health unit level (i.e., Ottawa, Peel, and Toronto). During the 20-year period, Plasmodium vivax accounted for 50.6% of all cases, P. falciparum (38.6%), Plasmodium sp. (6.0%), P. ovale (3.1%), and P. malariae (1.8%). During the first ten years of the study (1990-1999), P. vivax (64% of all cases) was the dominant agent, followed by P. falciparum (28%); however, during the second ten years (2000-2009) the situation reversed and P. falciparum (55%) dominated, followed by P. vivax (30%). The prevalence of P. falciparum and P. vivax cases varied spatially (e.g., P. falciparum more prevalent in Toronto, P. vivax more prevalent in Peel), temporally (e.g. P. falciparum incidence increased during the 20-year study), and demographically (e.g. preponderance of male cases). Infection rates per 100,000 international travellers were estimated: rates of infection were 2× higher in males compared to females; rates associated with travel to Africa were 37× higher compared to travel to Asia and 126× higher compared to travel to the Americas; rates of infection were 2.3-3.5× higher in June and July compared to October through March; and rates of infection were highest in those 65-69 years old. Where exposure country was reported, 71% of P. falciparum cases reported exposure in Ghana or Nigeria and 63% of P. vivax cases reported exposure in India. Our study provides insights toward improving pre-travel programs for Ontarians visiting malaria-endemic regions and underscores the changing epidemiology of imported malaria in the province.

The activation of vivax malaria hypnozoites by infectious diseases.

The periodicity of vivax malaria relapses may be explained by the activation of latent hypnozoites acquired from a previous malarial infection. The activation stimulus could be the febrile illness associated with acute malaria or a different febrile infection. We review historical records to examine the association between relapses of Plasmodium vivax and febrile infectious diseases. In data from British soldiers in Palestine, epidemic falciparum malaria triggered a smaller epidemic of P vivax relapses only in those who had been extensively exposed to malaria previously. Relapses did not follow pandemic influenza infection. Evidence from three simultaneous typhoid and malaria epidemics suggest that typhoid fever might activate P vivax hypnozoites. Some data lend support to the notion that vivax malaria relapse followed febrile illness caused by relapsing fever, trench fever, epidemic typhus, and Malta fever (brucellosis). These observations suggest that systemic parasitic and bacterial infections, but not viral infections, can activate P vivax hypnozoites. Specific components of the host's acute febrile inflammatory response, and not fever alone, are probably important factors in the provocation of a relapse of vivax malaria.

1912-2012: a century of research on Plasmodium vivax in vitro culture.

The development of a continuous Plasmodium vivax blood cycle in vitro was first attempted 100 years ago. Since then, and despite the use of different methods, only short-term cultures have been achieved so far. The available literature has been reviewed in order to provide a critical overview of the currently available knowledge on P. vivax blood cycle culture systems and identify some unexplored ways forward. Results show that data accumulated over the past century remain fragmented and often contradictory, making it difficult to draw conclusions. There is the need for an international consortium on P. vivax culture able to collect, update, and share new evidence, including negative results, and thus better coordinate current efforts towards the establishment of a continuous P. vivax culture.

Experimental, therapeutic and natural transmission of Plasmodium vivax tertian malaria: scientific and anecdotal data on the history of Dutch malaria studies.

When Plasmodium vivax tertian malaria was prevalent in The Netherlands, the use of therapeutic malaria for the treatment of neurosyphilis patients presented an opportunity for biological studies of the parasite's behaviour, in healthy volunteers. One unexplained phenomenon was the long latency between natural exposure to a single infected mosquito and the appearance of clinical signs (average 8 months). Dutch studies with volunteers and syphilis patients, suggested that hundreds of sporozoites transmitted by several mosquito bites were enough to provoke an early attack, known from tropical vivax-malaria. Sporozoites appeared to be programmed either to delay their pre-erythrocytic development or to proceed to an early attack within three weeks. The number of infectious bites also determined the relapse rate and the number of relapses after a primary attack. Analyses of primary cases and relapses from the previous year were used to predict the incidence for the next year. These historic findings fit well with recent studies on genotyping of blood stages during primary attacks and relapses. External factors (i.e. the milieu inside the human host) may trigger hypnozoites to reactivate, but predetermined periods of latency should also be considered.

Morbidity in the marshes: using spatial epidemiology to investigate skeletal evidence for Malaria in Anglo-Saxon England (AD 410-1050).

Concerns over climate change and its potential impact on infectious disease prevalence have contributed to a resurging interest in malaria in the past. A wealth of historical evidence indicates that malaria, specifically Plasmodium vivax, was endemic in the wetlands of England from the 16th century onwards. While it is thought that malaria was introduced to Britain during the Roman occupation (AD first to fifth centuries), the lack of written mortality records prior to the post-medieval period makes it difficult to evaluate either the presence or impact of the disease. The analysis of human skeletal remains from archaeological contexts is the only potential means of examining P. vivax in the past. Malaria does not result in unequivocal pathological lesions in the human skeleton; however, it results in hemolytic anemia, which can contribute to the skeletal condition cribra orbitalia. Using geographical information systems (GIS), we conducted a spatial analysis of the prevalence of cribra orbitalia from 46 sites (5,802 individuals) in relation to geographical variables, historically recorded distribution patterns of indigenous malaria and the habitat of its mosquito vector Anopheles atroparvus. Overall, those individuals living in low-lying and Fenland regions exhibited higher levels of cribra orbitalia than those in nonmarshy locales. No corresponding relationship existed with enamel hypoplasia. We conclude that P. vivax malaria, in conjunction with other comorbidities, is likely to be responsible for the pattern observed. Studies of climate and infectious disease in the past are important for modeling future health in relation to climate change predictions.

[A history of malaria in modern Korea 1876-1945].

Although it is not certain when malaria began to appear in Korea, malaria is believed to have been an endemic disease from ancient times. It was Dr. H. N. Allen (1858-1932) who made the first description and diagnosis of malaria in terms of Western medicine. In his first year report (1885) of Korean Government Hospital he mentioned malaria as the most prevalent disease. Very effective anti-malarial drug quinine was imported and it made great contribution in treating malaria. After Japan had annexed Korea in 1910, policies for public health system were fundamentally revised. Japan assumed control of Korean medical institutions and built high-quality Western hospitals for the health care of Japanese residents. The infectious diseases which were under special surveillance were cholera, typhoid fever, dysentery, typhus, scarlet fever, smallpox, and paratyphoid fever. Among chronic infectious diseases tuberculosis and leprosy were those under special control. Malaria, however, was not one of these specially controlled infectious diseases although it was widely spread throughout the peninsula. But serious studies on malaria were carried out by Japanese medical scientists. In particular, a Japanese parasitologist Kobayasi Harujiro(1884-1969) carried out extensive studies on human parasites, including malaria, in Korea. According to his study, most of the malaria in Korea turned out to be tertian fever. In spite of its high prevalence, malaria did not draw much attention from the colonial authorities and no serious measure was taken since tertian fever is a mild form of malaria caused by Plasmodium vivax and is not so much fatal as tropical malaria caused by P. falciparum. And tertian malaria was easily controlled by taking quinine. Although the majority of malaria in Korea was tertian fever, other types were not absent. Quartan fever was not rarely reported in 1930s. The attitude of colonial authorities toward malaria in Korea was contrasted with that in Taiwan. After Japan had set out to colonize Taiwan as a result of Sino-Japanese war, malaria in Taiwan was a big obstacle to the colonization process. Therefore, a lot of medical scientists were asked to engage the malaria research in order to handle health problems in colonized countries caused by malaria. Unlike the situation in Taiwan, malaria in Korea did not cause a serious health problem as in Taiwan. However, its risk was not negligible. In 1933 there were almost 130,000 malaria patients in Korea and 1,800 patients among them died of malaria. The Japanese Government General took measures to control malaria especially during the 1930s and the number of patients decreased. However, as Japan engaged in the World War II, the general hygienic state of the society worsened and the number of malarial patients increased. The worsened situation remains the same after Liberation (1945) and during the Korean war (1950-53).

Simultaneous epidemics of influenza and malaria in the Australian Army in Palestine in 1918.

In October 1918, an Allied army (Egyptian Expeditionary Force) in Palestine experienced simultaneous epidemics of falciparum malaria and influenza during the cavalry campaign that defeated the Turkish Army. Malaria infection occurred 2 weeks after the advance of cavalry units into areas without environmental mosquito control. Pandemic influenza, now thought to be an A/H1N1 strain, struck at the same time. In the Egyptian Expeditionary Force of 315,000 soldiers, 773 died from malaria and 934 from influenza-pneumonia. Disease casualties outnumbered those due to combat by more than 37 to 1. Simultaneous infectious disease epidemics can cause mass casualties, capable of overwhelming any health service.