Plasmodium falciparum

“ Abstract From which host did the most malignant human malaria come: birds, primates, or rodents? When did the transfer occur? Over the last half century, these have been some of the questions up for debate about the origin of Plasmodium falciparum, the most common and deadliest human malaria parasite, which is responsible for at least one million deaths every year. Recent findings bring elements in favor of a transfer from great apes, but are these evidences really solid? ”

“ Abstract Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. ”

“ In the genus Plasmodium, four species are traditionally regarded as human parasites: Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, and Plasmodium falciparum. These species are remotely related to each other, suggesting that adaptation to humans has occurred several times independently during the history of the genus. ”

“ Plasmodium vivax: a global health threat
Presently, 2.85 billion people globally are at risk of Plasmodium vivax malaria infection [1] . Worldwide the regional incidence of P. vivax has been increasing despite a decrease in Plasmodium falciparum cases [2] - [3] . The most geographically widespread of the six Plasmodium species that infect humans, P. vivax is a major health threat to huge populations throughout Asia, the Middle East and the Pacific [1] , where approximately 80 to 90% of the global P. vivax burden is concentrated [4] . ”

“ In conclusion, the recent data gathered from great apes in Africa have shown that a large diversity of Plasmodium species circulates among our relatives and have provided new insights into the evolutionary history of the malaria parasites of humans, particularly P. falciparum. These discoveries not only dramatically change our view on the evolution of the P. falciparum lineage, but also question the evolution and origin of the other human Plasmodium species (P. ovale, P. malariae, and P. vivax) . ”

“ In the spirit of Alexander, we propose that hemoglobinopathies may be nature's “Alexandrian solution” to the problem of understanding fundamental aspects of falciparum malaria. This bold slice through the Gordian knot of malaria pathogenesis represents a unique opportunity to isolate and identify the molecular correlates of falciparum malaria pathogenesis in humans in vivo, and to translate these findings into future interventions to prevent, treat, and eliminate this ancient and intractable scourge. ”

“ A national cross-sectional household survey was undertaken from December 2008 to January 2009. A finger prick blood sample was taken from randomly selected participants of all ages to examine for parasitaemia using rapid diagnostic tests (RDTs) and confirmed using Polymerase Chain Reaction (PCR) . Blood spots were also collected on filter paper and subsequently used to evaluate the presence of serological markers (combined AMA-1 and MSP-119) of Plasmodium falciparum exposure. Multivariate regression analysis was used to determine the risk factors for P. falciparum infection and/or exposure. ”

“ These genetic traits—including hemoglobin S (HbS) , hemoglobin C (HbC) , and α-thalassemia—are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait) . Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. ”

“ It is during this time that parasites sequentially invade and egress from their host RBCs and cause the signs and symptoms of malaria. While developing within the RBC, the parasite traffics proteins to the RBC surface that mediate binding to extracellular host receptors and enable the parasite to sequester in the placenta, brain, and virtually every other organ. The attenuation of malaria by repeated, sub-lethal P. falciparum infections suggests a significant role for adaptive immunity, but the targets of this attenuating immune response remain largely obscure. ”

“ Abstract Malaria represents a medical emergency because it may rapidly progress to complications and death without prompt and appropriate treatment. Severe malaria is almost exclusively caused by Plasmodium falciparum. The incidence of imported malaria is increasing and the case fatality rate remains high despite progress in intensive care and antimalarial treatment. ”

“ Malaria infection during pregnancy is a major public health problem in subtropical regions throughout the world. An estimated 125.2 million pregnancies occurred in areas with Plasmodium falciparum and/or Plasmodium vivax transmission in 2007, of which approximately 30.3 million occurred in Africa [1] , [2] . Of the five human malaria species, P. falciparum causes the most severe effects during pregnancy, and P. vivax is associated with maternal anaemia and low birth weight [3] , [4] . ”

“ Yuen, KY; et al. (2006) , Sensitive and inexpensive molecular test for falciparum malaria: detecting Plasmodium falciparum dna directly from heat-treated blood by loop-mediated isothermal amplification, vol. ”

“ Combining these estimates for all areas of transmission risk resulted in 451 million (95% credible interval 349–552 million) clinical cases of P. falciparum malaria in 2007. Almost all of this burden of morbidity occurred in areas of stable transmission. More than half of all estimated P. falciparum clinical cases and associated uncertainty occurred in India, Nigeria, the Democratic Republic of the Congo (DRC) , and Myanmar (Burma) , where 1.405 billion people are at risk. ”

“ Risk of Emergence: Human Invaded or Human Invader
The recent discovery of P. falciparum in bonobos [16] , chimpanzees [17] , and gorillas [15] , [17] as well as P. ovale, P. malariae, and P. vivax in chimpanzees, bonobos, and gorillas [16] , [17] , [31] , [32] highlights the risk of transfer of Plasmodium species from human to primates and vice versa. It is now urgent to identify the genetic and ecological factors that allow this group of pathogens to exploit a variety of host species. ”

“ Cross-sectional studies of children with hemoglobinopathies in Nigeria [94] , the Gambia [95] , Cameroon [96] , Gabon [97] , [98] , and Burkina Faso [99] have yielded inconsistent results, with some demonstrating higher seroreactivity to specific or variant surface P. falciparum antigens of heterologous parasites in HbAS children, and others reporting no differences. These findings were explored by measuring seroreactivity to a panel of 491 P. falciparum proteins in Malian children before and after a well-defined malaria transmission season [100] ”

“ Defining Malaria Incidence in Areas of Unstable P. falciparum Malaria Transmission
We estimate that almost one billion people were living in areas where P. falciparum transmission was unstable in 2007 [21] (Figure 2) . Defining annualized disease risk in these areas from empirical data is difficult, as epidemiological investigations for research or survey purposes are rare. Nevertheless, in computing disease burdens it is important to impute some measure of completeness of formal malaria reporting within these marginal, unstable transmission areas. ”

“ In East Asia and Oceania a similar pattern pertains today. In East Asia a remarkably high proportion (20-50%) of symptomatic infections with P. falciparum are followed by an infection with P. vivax [121] - [122] . In Ethiopia where early relapse rates in vivax malaria are much lower, this proportion is also lower; 7% [ [123] . The intervals between the onset of treatment for the acute P. falciparum infection and the subsequent P. vivax infection are very similar to the intervals between acute vivax malaria and the first relapse (Figure 20) . ”

“ Malaria is one of the world's most deadly diseases. Even though it is highly preventable and treatable, it causes approximately 881,000 deaths every year [1] , with nine out of ten deaths occurring in sub-Saharan Africa, and 85% of malaria-related deaths in children under five years of age. This is the equivalent of a child dying of malaria in Africa every 30 seconds [ [2] . The most serious forms of the disease are caused by the parasite Plasmodium falciparum ”

“ Yet in the indigenous population living in transmission areas a significant degree of immunity should have been gained (by both sexes) by early adulthood which reduces the number of relapses. Usually in endemic areas it is children who bear the brunt of malaria. This applies to both falciparum and vivax malaria when malaria is uncontrolled, but with increasing control falciparum declines more rapidly than vivax, and their epidemiology separates. The paucity of data from children may contribute to the low apparent relapse rates reported from the Indian sub-continent. ”

“ Punctate basophilia is quite common in malarial anaemias. Up to the present time the culturing of the parasite can scarcely be considered an aid to diagnosis as it is difficult to carry the development beyond one generation so that we do not get multiplication of parasites. In cases where confusion exists as to the nature of the [541] species of parasite present culturing would help as regards the possibility of noting the developmental stages of Plasmodium falciparum.
Blackwater Fever.—The same points which hold for malaria hold for blackwater fever. ”

“ Ollomo, B & Ayala, FJ (2010) , African great apes are natural hosts of multiple related malaria species, including Plasmodium falciparum., vol. 107, pp. 1458–1463, 20133889, pmid:20133889 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Krief, S; Escalante, AA; Pacheco, MA; Mugisha, L & Andre, C (2010) , On the diversity of malaria parasites in African apes and the origin of Plasmodium falciparum from bonobos., vol. ”

“ Because of the increase in global travel to and immigration of people from areas endemic for malaria, the incidence of imported cases of malaria in developed countries has risen. Approximately 10 000–30 000 travelers from industrialized countries are expected to contract malaria each year [ [3] . In addition, drug-resistant Plasmodium falciparum malaria continues to spread and at present involves almost all areas of the world. An increasing number of travelers are exposed to drug-resistant plasmodia. ”

“ HRP2 is present in Plasmodium falciparum only, whereas pLDH and aldolase, with some conserved and some variable epitopes, are present in all four major species causing human malaria. RDTs have the obvious advantage of requiring less training, being easily performed in remote or village settings, and putting most of the quality control responsibility in the hands of the manufacturer instead of the user. ”

“ As noted above, field evidence indicates that hemoglobinopathies do not impair parasite infection but instead attenuate malaria; this pattern suggests that protection from malaria syndromes is not mediated against the pre-erythrocytic stages of the P. falciparum life-cycle, and that hemoglobinopathies may influence the transition from parasite infection to disease. ”

“ In falciparum malaria, these innate immune responses are potently initiated through the activation of TLRs on leukocytes by both PfGPI [69] and hemozoin (the product of heme polymerization) [70] , [71] , as well as by microvascular inflammation caused by PfEMP1-mediated binding of iRBCs to endothelium (see above) [72] . In murine models, the outcome of malaria is sensitive to experimental manipulation of multiple host innate response molecules, such as tumor necrosis factor (TNF) , interferon-γ [73] , and erythropoietin [74] , suggesting their role in mediating differential infection outcome. ”

“ This is also supported by the rarity of finding patients or healthy subjects with gametocytes of both species in the blood at the same time. Development rates in the mosquito are also slightly different (P. vivax being more rapid) . Although space-time clustering of infections may occur in low transmission areas it is implausible that over 20% of P. falciparum inoculations would be associated with a separate P. vivax inoculation within one or two days, particularly when individuals receive on average less than one infectious bite per year. ”

“ During pregnancy, malaria infection with Plasmodium falciparum or Plasmodium vivax is related to adverse maternal health and poor birth outcomes. Diagnosis of malaria, during pregnancy, is complicated by the absence or low parasite densities in peripheral blood. Diagnostic methods, other than microscopy, are needed for detection of placental malaria. ”

“ Opportunities for further reducing uncertainty in clinical burden estimates by hybridizing alternative burden estimation procedures are also evaluated.
Please see later in the article for the Editors' Summary==Abstract== Editors' Summary
Background
Malaria is a major global public-health problem. Nearly half the world's population is at risk of malaria, and Plasmodium falciparum malaria—the deadliest form of the disease—causes about one million deaths each year. Malaria is a parasitic disease that is transmitted to people through the bite of an infected mosquito. ”

“ A study of the pharmacokinetics of AL during pregnancy, conducted in Thailand in 2004, also reported on the safety of AL [21] . In total, 13 women in the second and third trimesters of pregnancy received AL to treat recrudescent falciparum malaria after seven days of supervised quinine treatment. All were rapidly cured of their infection (median parasite clearance time was two days) . There were no reports of serious adverse events and all 13 women delivered live infants with no congenital abnormalities. ”