Anaemia and malaria

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Term Occurence Count Dictionary
primaquine 1 infectiousdiseasesdrugs
pyrimethamine 1 infectiousdiseasesdrugs
quinine 5 infectiousdiseasesdrugs
syphilis 1 infectiousdiseases
blackwater fever 2 infectiousdiseases
cerebral malaria 2 infectiousdiseases
infectious disease 2 infectiousdiseases
malaria 231 infectiousdiseases

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Select Drug Character Offset Drug Term Instance
primaquine 44509 deficiency with febrile illnesses such as malaria or following ingestion of oxidants (notably radical cure primaquine regimens) [[127]].Post-artesunate haemolytic anaemiaThere are several reports, mainly from temperate
pyrimethamine 52424 gestation, or initial presentation at the antenatal clinic—whichever is later [[89]]. Sulfadoxine– pyrimethamine is the most widely used drug although this is increasingly challenged by resistance. The WHO recommends
quinine 20352 these younger circulating parasites which explains much of therapeutic superiority of artesunate over quinine in severe malaria, this deferred haemolysis of once infected erythrocytes may be regarded as the “price”
quinine 20855 erythrocytes, reticulocyte responses and plasma LDH in relation to anti-malarial drug treatment (artesunate or quinine ) in African children in Kinshasa, DRC, admitted to hospital with hyperparasitaemic falciparum malaria
quinine 31292 haemoglobin concentration following artesunate was less (a difference of 0.4 g/dL) than that following quinine [[70]] (Fig. 7). In contrast drug resistance is associated with increased anaemia both because of slow
quinine 44335 also occur in otherwise uncomplicated infections. Blackwater fever has historically been linked to quinine use, and it may occur in glucose-6-phosphate dehydrogenase deficiency with febrile illnesses such as
quinine 46181 probably reflects drug killing and then pitting of developed ring form parasites whereas background (and quinine associated) pitting may only occur for very young ring stages shortly after merozoite invasion with
Select Disease Character Offset Disease Term Instance
blackwater fever 35677 fulminant haemolytic anaemia which is usually associated with severe falciparum malaria or sometimes blackwater fever .Reduced microvascular perfusion resulting from cytoadherence and inter-erythrocytic adhesion.The first
blackwater fever 49782 feverBlackwater fever results from massive haemolysis sufficient to cause haemoglobinuria. The management of blackwater fever anaemia is with blood transfusion [[93]]. Anti-malarial treatment should not be withheld. Steroids are
cerebral malaria 39052 criterion for severe malaria. Inset is shown this same relationship in the subgroup of 2729 patients with cerebral malaria and the same parasitaemia rangeIn published series of children admitted to hospital with severe malaria
cerebral malaria 40149 [[112]–[117]] (Fig. 11). A similar pattern was observed in the subgroup of patients admitted with cerebral malaria (Fig. 11). There are many potential confounders which may explain this finding, but a causal association
infectious disease 6918 anaemiaPoor malaria control is often associated with weak health structures, and high prevalences of other infectious disease s and nutritional deficiencies, all of which contribute to anaemia. In Malawi, where transmission of
infectious disease 37085 malaria” definition still means that some anaemic children with incidental parasitaemia and another infectious disease (usually sepsis) may be diagnosed as having severe malaria. Thus the severe anaemia criterion encompasses
malaria 34 Title: Malaria JournalAnaemia and malaria Nicholas J. WhitePublication date (epub): 10/2018Publication date (pmc-release): 10/2018Publication date
malaria 402 erythrocytes and bone marrow dyserythropoiesis which compromises rapid recovery from anaemia. In areas of high malaria transmission malaria nearly all infants and young children, and many older children and adults have
malaria 423 dyserythropoiesis which compromises rapid recovery from anaemia. In areas of high malaria transmission malaria nearly all infants and young children, and many older children and adults have a reduced haemoglobin
malaria 598 adults have a reduced haemoglobin concentration as a result. In these areas severe life-threatening malaria l anaemia requiring blood transfusion in young children is a major cause of hospital admission, particularly
malaria 750 young children is a major cause of hospital admission, particularly during the rainy season months when malaria transmission is highest. In severe malaria, the mortality rises steeply below an admission haemoglobin
malaria 793 admission, particularly during the rainy season months when malaria transmission is highest. In severe malaria , the mortality rises steeply below an admission haemoglobin of 3 g/dL, but it also increases with higher
malaria 992 increases with higher haemoglobin concentrations approaching the normal range. In the management of severe malaria transfusion thresholds remain uncertain. Prevention of malaria by vector control, deployment of insecticide-treated
malaria 1055 normal range. In the management of severe malaria transfusion thresholds remain uncertain. Prevention of malaria by vector control, deployment of insecticide-treated bed nets, prompt and accurate diagnosis of illness
malaria 1205 insecticide-treated bed nets, prompt and accurate diagnosis of illness and appropriate use of effective anti- malaria l drugs substantially reduces the burden of anaemia in tropical countries.BackgroundMalaria is the most
malaria 1443 of man [[1]]. It is a major cause of anaemia in endemic areas, and in areas of higher transmission malaria is one of the most common reasons for blood transfusion. Six species of the genus Plasmodium infect
malaria 1596 transfusion. Six species of the genus Plasmodium infect humans commonly, and all cause anaemia. Most malaria attributable deaths and severe disease are caused by Plasmodium falciparum. The majority of fatalities
malaria 1844 Health Organization (WHO) has estimated that there were some 216 million cases and 445,000 deaths from malaria in 2016 [[2]]. A significant proportion of these deaths resulted directly or indirectly from anaemia.Epidemiology
malaria 1969 significant proportion of these deaths resulted directly or indirectly from anaemia.Epidemiology of malaria and anaemiaThe clinical consequences of malaria, and in particular the prevalence of anaemia, depend
malaria 2017 directly or indirectly from anaemia.Epidemiology of malaria and anaemiaThe clinical consequences of malaria , and in particular the prevalence of anaemia, depend on the intensity of malaria transmission (Fig. 1).
malaria 2098 clinical consequences of malaria, and in particular the prevalence of anaemia, depend on the intensity of malaria transmission (Fig. 1). The main determinants of malaria transmission intensity are the density, longevity,
malaria 2155 prevalence of anaemia, depend on the intensity of malaria transmission (Fig. 1). The main determinants of malaria transmission intensity are the density, longevity, biting habits, and efficiency of the local mosquito
malaria 2624 child grows a disease controlling immunity develops such that by adolescence and adulthood nearly all malaria infections are asymptomatic. The prevalence of anaemia declines (Fig. 2). Thus, apparently healthy
malaria 2750 asymptomatic. The prevalence of anaemia declines (Fig. 2). Thus, apparently healthy individuals carry malaria parasites in their blood. These infections can persist for many months. This persistent asymptomatic
malaria 3095 parasitaemic individual may be caused by other infections. Meta-analyses of the relationship between malaria and anaemia are confounded by the non-specificity of parasitological diagnosis in high transmission
malaria 3592 infections—all of which contribute variably to anaemia [[10], [11]]. Thus, in higher transmission settings malaria increases the risk of anaemia in the entire population with the greatest impact in young children, and
malaria 3775 impact in young children, and in particular infants [[3]]. In lower transmission settings symptomatic malaria and resulting anaemia may occur at all ages, although it is children and pregnant women who are more
malaria 3936 it is children and pregnant women who are more likely to be anaemic. At all levels of transmission malaria (all species) is an important contributor to maternal anaemia during pregnancy, and poor birth outcomes
malaria 4067 important contributor to maternal anaemia during pregnancy, and poor birth outcomes [[13]]. Falciparum malaria is a direct cause of maternal mortality in lower transmission settings and an indirect cause by contributing
malaria 4240 settings and an indirect cause by contributing to anemia in higher transmissions settings [[14]]. Anti- malaria l drug resistance causing recrudescent infections increases the prevalence and the severity of malaria
malaria 4342 Anti-malarial drug resistance causing recrudescent infections increases the prevalence and the severity of malaria anaemia.Fig. 1Relationship of severe falciparum malaria manifestations to age at different levels of
malaria 4399 increases the prevalence and the severity of malaria anaemia.Fig. 1Relationship of severe falciparum malaria manifestations to age at different levels of malaria transmissionFig. 2Age patterns of average haemoglobin
malaria 4452 anaemia.Fig. 1Relationship of severe falciparum malaria manifestations to age at different levels of malaria transmissionFig. 2Age patterns of average haemoglobin concentrations in young children in Demographic
malaria 4638 children in Demographic and Health Surveys (DHS) from four African countries with moderate to high malaria transmission(Reproduced from Crawley J, with permission [[11]])Clinical patternsConstant, frequent,
malaria 4757 transmission(Reproduced from Crawley J, with permission [[11]])Clinical patternsConstant, frequent, year-round malaria reflects stable transmission. In the sub-Sahel region across Africa from Senegal to Sudan there is intense
malaria 4872 reflects stable transmission. In the sub-Sahel region across Africa from Senegal to Sudan there is intense malaria transmission, but this is largely confined to the 3–4 month rainy season. During this period young
malaria 5115 frequently present to hospitals and health centres with severe anaemia. In contrast in areas where malaria transmission is low, erratic, or focal (often termed unstable transmission), protective immunity from
malaria 5225 transmission is low, erratic, or focal (often termed unstable transmission), protective immunity from malaria is not acquired, and symptomatic malaria may occur at all ages. In such areas changes in environmental,
malaria 5266 (often termed unstable transmission), protective immunity from malaria is not acquired, and symptomatic malaria may occur at all ages. In such areas changes in environmental, economic, or social conditions, such
malaria 5466 conditions, such as heavy rains following drought or large population movements together with a breakdown in malaria control and prevention services (often resulting from conflict) can result in epidemics of malaria with
malaria 5565 malaria control and prevention services (often resulting from conflict) can result in epidemics of malaria with considerable mortality among all age groups [[1]]. Recent improvements in malaria control have
malaria 5652 epidemics of malaria with considerable mortality among all age groups [[1]]. Recent improvements in malaria control have reduced malaria transmission in many areas and increased heterogeneity in malaria epidemiology.
malaria 5681 considerable mortality among all age groups [[1]]. Recent improvements in malaria control have reduced malaria transmission in many areas and increased heterogeneity in malaria epidemiology. Unfortunately, there
malaria 5747 improvements in malaria control have reduced malaria transmission in many areas and increased heterogeneity in malaria epidemiology. Unfortunately, there is evidence that this recent progress has stalled, and malaria incidence
malaria 5845 in malaria epidemiology. Unfortunately, there is evidence that this recent progress has stalled, and malaria incidence in some parts of the tropics has started to rise again.In areas of moderate or high transmission
malaria 5960 incidence in some parts of the tropics has started to rise again.In areas of moderate or high transmission malaria infections (both P. falciparum and Plasmodium vivax) in pregnancy cause maternal anaemia, intrauterine
malaria 6462 steady rise in haemoglobin concentrations punctuated by acute reductions associated with symptomatic malaria infections [[11]] (Figs. 2 and 3).Fig. 3Estimated contributions of falciparum and vivax malaria to
malaria 6560 symptomatic malaria infections [[11]] (Figs. 2 and 3).Fig. 3Estimated contributions of falciparum and vivax malaria to severe anaemia in Papua. Shows adjusted population attributable fractions with 95% confidence bands
malaria 6823 species and by age(From Douglas et al. with permission [[9]])Concomitant contributors to anaemiaPoor malaria control is often associated with weak health structures, and high prevalences of other infectious diseases
malaria 7037 and nutritional deficiencies, all of which contribute to anaemia. In Malawi, where transmission of malaria is moderate to high and childhood malaria is very common, bacterial infections, HIV infection, hookworm
malaria 7079 which contribute to anaemia. In Malawi, where transmission of malaria is moderate to high and childhood malaria is very common, bacterial infections, HIV infection, hookworm and deficiencies in vitamins A and B12
malaria 7476 dehydrogenase (G6PD) deficiency] which provide some protection against the pathological consequences of malaria but themselves contribute to anaemia [[12], [16]]. Sickle cell anaemia is common in most of sub-Saharan
malaria 7682 sub-Saharan Africa (birth prevalence 1–2%) and is a major cause of severe anaemia, commonly provoked by malaria illness [[17]]. Patients with G6PD deficiency are also at increased risk of severe malarial anaemia
malaria 7773 provoked by malaria illness [[17]]. Patients with G6PD deficiency are also at increased risk of severe malaria l anaemia [[18]]. Dissecting and quantitating the individual contributions of these various genetic factors
malaria 7891 [[18]]. Dissecting and quantitating the individual contributions of these various genetic factors to malaria anaemia overall is difficult.Relationship of anaemia to transmission intensityIn most of Asia and the
malaria 8010 overall is difficult.Relationship of anaemia to transmission intensityIn most of Asia and the Americas malaria transmission is low and seasonal. In Asia, the prevalences of P. falciparum and P. vivax malaria overall
malaria 8107 Americas malaria transmission is low and seasonal. In Asia, the prevalences of P. falciparum and P. vivax malaria overall are approximately equal [[2]]. In the Americas P. vivax predominates. In these areas people
malaria 8918 Africa. In such high transmission settings where everyone is infected, morbidity and mortality from malaria are considerable. Newborns have low birthweight and infant mortality is high [[1]–[6]]. Babies and
malaria 9259 often chronically anaemic with palpably enlarged spleens. There is an increased mortality both from malaria itself, and also indirectly from other infections which repeated malaria predisposes to. If the child
malaria 9332 increased mortality both from malaria itself, and also indirectly from other infections which repeated malaria predisposes to. If the child survives then by adulthood most malaria infections are asymptomatic.Contribution
malaria 9401 other infections which repeated malaria predisposes to. If the child survives then by adulthood most malaria infections are asymptomatic.Contribution of malaria to anaemiaThe best estimates of the causal contribution
malaria 9453 to. If the child survives then by adulthood most malaria infections are asymptomatic.Contribution of malaria to anaemiaThe best estimates of the causal contribution of malaria to anaemia in a particular setting
malaria 9520 are asymptomatic.Contribution of malaria to anaemiaThe best estimates of the causal contribution of malaria to anaemia in a particular setting come from randomized trials of malaria control interventions [[19],
malaria 9594 the causal contribution of malaria to anaemia in a particular setting come from randomized trials of malaria control interventions [[19], [20]]. A review of 29 community-based studies of insecticide-treated nets
malaria 9718 interventions [[19], [20]]. A review of 29 community-based studies of insecticide-treated nets (ITNs), anti- malaria l chemoprophylaxis, and insecticide residual spraying found that among children < 5 years exposed
malaria 9855 insecticide residual spraying found that among children < 5 years exposed to between 1 and 2 years of malaria control, mean relative risk for a haemoglobin concentration < 11 g/dL was 0.73 (95% CI 0.64–0.81),
malaria 10087 haemoglobin < 8 g/dL was 0.40 (95% CI 0.25–0.55) compared with the control groups not exposed to these malaria interventions [[20], [21]]. The WHO and the Roll Back Malaria (RBM) Partnership have recommended that
malaria 10251 Malaria (RBM) Partnership have recommended that anaemia be used as an additional indicator to monitor malaria burden at the community level as malaria control interventions are scaled up nationally. This recommendation
malaria 10292 that anaemia be used as an additional indicator to monitor malaria burden at the community level as malaria control interventions are scaled up nationally. This recommendation is based on results of an extensive
malaria 10481 results of an extensive review conducted by Korenromp et al. [[20]] showing that, in areas of stable malaria transmission, the prevalence of moderate-to-severe anaemia (haemoglobin < 8 g/dL) is a more sensitive
malaria 10622 moderate-to-severe anaemia (haemoglobin < 8 g/dL) is a more sensitive measure of a reduction in malaria exposure than parasite prevalence, and that it may respond more quickly than mortality as coverage of
malaria 10732 exposure than parasite prevalence, and that it may respond more quickly than mortality as coverage of malaria interventions, such as insecticide-treated bed nets (ITNs), malaria chemoprevention and indoor residual
malaria 10800 quickly than mortality as coverage of malaria interventions, such as insecticide-treated bed nets (ITNs), malaria chemoprevention and indoor residual spraying are scaled up [[20]–[22]]. In randomized controlled trials,
malaria 10991 randomized controlled trials, the impact of ITNs on anaemia was more pronounced than on the prevalence of malaria parasitaemia or on the incidence of clinical malaria.Improved control between 2000 and 2015 has resulted
malaria 11044 was more pronounced than on the prevalence of malaria parasitaemia or on the incidence of clinical malaria .Improved control between 2000 and 2015 has resulted in a reduction in malaria in high transmission areas,
malaria 11122 incidence of clinical malaria.Improved control between 2000 and 2015 has resulted in a reduction in malaria in high transmission areas, a substantial reduction in global malaria attributable mortality, and elimination
malaria 11192 has resulted in a reduction in malaria in high transmission areas, a substantial reduction in global malaria attributable mortality, and elimination of malaria from several countries [[2], [23], [24]].PathogenesisThe
malaria 11243 transmission areas, a substantial reduction in global malaria attributable mortality, and elimination of malaria from several countries [[2], [23], [24]].PathogenesisThe pathogenesis of malarial anaemia is multifactorial
malaria 11324 and elimination of malaria from several countries [[2], [23], [24]].PathogenesisThe pathogenesis of malaria l anaemia is multifactorial [[1], [25]–[34]]. Malaria is an intraerythrocytic parasite so there is
malaria 11825 approximately 90% of the acute anaemia resulting from a single infection. Parasitaemias in falciparum malaria commonly exceed 1% (of red cells parasitized), and in severe disease may exceed 10%. Plasmodium knowlesi
malaria 12014 10%. Plasmodium knowlesi may also cause hyperparasitaemia, but parasite densities in the other human malaria s very rarely exceed 2% [[1]]. In severe falciparum malaria there is a heavy parasite burden and anaemia
malaria 12073 but parasite densities in the other human malarias very rarely exceed 2% [[1]]. In severe falciparum malaria there is a heavy parasite burden and anaemia develops rapidly. The main contributor to this usually
malaria 12352 cells [[30], [35]–[37]]. The ratio of unparasitized red cells to parasitized red cells lost in acute malaria is even higher in P. vivax than in P. falciparum infections [[36]].The haemolytic anaemia of malaria
malaria 12453 malaria is even higher in P. vivax than in P. falciparum infections [[36]].The haemolytic anaemia of malaria is compounded by bone marrow dyserythropoiesis during and immediately after the acute illness [[28],
malaria 12661 [29], [38], [39]]. Bone marrow dyserythropoiesis persists for days or weeks following the start of malaria treatment in acute malaria. As a consequence reticulocyte counts are usually low in the acute symptomatic
malaria 12688 marrow dyserythropoiesis persists for days or weeks following the start of malaria treatment in acute malaria . As a consequence reticulocyte counts are usually low in the acute symptomatic phase of the disease
malaria 12870 symptomatic phase of the disease (Fig. 4). This accounts for the delayed erythropoietic response in acute malaria in low transmission settings. In such settings, the nadir of haemoglobin concentration in acute falciparum
malaria 12985 transmission settings. In such settings, the nadir of haemoglobin concentration in acute falciparum malaria is usually around 1 week after presentation with fever [[33]]. In acute vivax malaria the nadir in
malaria 13072 acute falciparum malaria is usually around 1 week after presentation with fever [[33]]. In acute vivax malaria the nadir in haemoglobin is earlier (usually after a few days) [[34]]. In contrast in higher transmission
malaria 13365 haemoglobin concentrations usually begin to rise immediately following the start of effective anti- malaria l treatment. In acute uncomplicated malaria, the resultant anaemia is worse in younger children, and
malaria 13408 to rise immediately following the start of effective anti-malarial treatment. In acute uncomplicated malaria , the resultant anaemia is worse in younger children, and those with protracted infections.Fig. 4The
malaria 13609 infections.Fig. 4The delayed reticulocyte response to anaemia in Thai adults with acute uncomplicated falciparum malaria [[28]]. Shows mean and SE values, and dashed line represents time to parasite clearance assessed by
malaria 13754 dashed line represents time to parasite clearance assessed by microscopyBone marrow dysfunction in malaria Dyserythropoiesis in malaria is thought to be related to intramedullary production of mediators which
malaria 13782 to parasite clearance assessed by microscopyBone marrow dysfunction in malariaDyserythropoiesis in malaria is thought to be related to intramedullary production of mediators which suppress erythropoiesis (proinflammatory
malaria 14181 long been observed that dyserythropoiesis and anaemia are associated with intramedullary deposition of malaria pigment (haemozoin). This is the obligatory by-product of intraerythrocytic malaria parasite haemoglobin
malaria 14265 intramedullary deposition of malaria pigment (haemozoin). This is the obligatory by-product of intraerythrocytic malaria parasite haemoglobin digestion (and thus haem detoxification). The haemozoin is expelled in the residual
malaria 14599 neutrophils and monocytes/macrophages. Indeed high proportions of peripheral blood monocytes containing malaria pigment reflect higher parasite burdens and are associated with anaemia in African children [[38], [39]].
malaria 15900 mediated peroxidation of PUFA, was shown to be an important mediator of this effect [[42], [43]].Severe malaria l anaemia in African children has been associated with the 238A TNF promoter genetic polymorphism and
malaria 16286 postulated to reflect the reduced ability of the Hp2-2 polymer to scavenge free haemoglobin-iron following malaria -induced haemolysis [[47]]. Serum erythropoetin levels are usually elevated in malarial anaemia, although
malaria 16372 haemoglobin-iron following malaria-induced haemolysis [[47]]. Serum erythropoetin levels are usually elevated in malaria l anaemia, although in some series it has been suggested that the degree of elevation was insufficient
malaria 16574 insufficient for the reduction in haemoglobin [[31], [32], [48]].Reduced red cell deformabilityIn severe malaria caused by P. falciparum or by P. knowlesi the entire red cell population becomes less deformable [[49]–[52]].
malaria 17059 erythrocyte deformability have not been identified with certainty, although there is evidence in acute malaria for increased oxidative damage which might compromise red cell membrane function and reduce deformability
malaria 17203 might compromise red cell membrane function and reduce deformability [[50], [53], [54]]. In simian malaria s, inversion of the erythrocyte membrane lipid bilayer in uninfected erythrocytes has been reported,
malaria 17592 haemoglobin (Hb) concentration reached during hospitalization in Thai patients with severe falciparum malaria (correlation coefficient 0.49, P = 0.002). When patients with a microcytic anaemia (MCV,80fL: red
malaria 17901 complement bindingThe role of red cell membrane bound antibody (i.e. Coombs’-positive haemolysis) in malaria l anaemia is unresolved. Some studies have shown increased red cell immunoglobulin binding in malaria,
malaria 18002 malarial anaemia is unresolved. Some studies have shown increased red cell immunoglobulin binding in malaria , whereas others have not [[56]–[58]]. In the presence of the malaria associated lowered clearance
malaria 18073 cell immunoglobulin binding in malaria, whereas others have not [[56]–[58]]. In the presence of the malaria associated lowered clearance threshold for splenic red cell removal (Fig. 6), increased antibody or
malaria 18684 clearance function for rigid erythrocytes associated with splenic enlargement in Thai adults with acute malaria [[61]]. Clearance curves of 51Cr-labelled heated autologous erythrocytes after intravenous injection
malaria 18941 detectable splenomegaly and 16 with palpable spleens (mean ± SD)The role of the spleenIn acute malaria the spleen reorganizes and enlarges rapidly. This results in increased clearance capacity and a lowered
malaria 20370 circulating parasites which explains much of therapeutic superiority of artesunate over quinine in severe malaria , this deferred haemolysis of once infected erythrocytes may be regarded as the “price” of the life-saving
malaria 20520 erythrocytes may be regarded as the “price” of the life-saving benefit. In higher transmission malaria endemic areas, where most malaria anaemia occurs, clinically significant post-artesunate delayed haemolysis
malaria 20554 the “price” of the life-saving benefit. In higher transmission malaria endemic areas, where most malaria anaemia occurs, clinically significant post-artesunate delayed haemolysis is rare [[70]] (Fig. 7). Fig. 7Reduction
malaria 20816 corresponding increases in pitted erythrocytes, reticulocyte responses and plasma LDH in relation to anti- malaria l drug treatment (artesunate or quinine) in African children in Kinshasa, DRC, admitted to hospital with
malaria 20957 quinine) in African children in Kinshasa, DRC, admitted to hospital with hyperparasitaemic falciparum malaria [[70]]Repeated malaria infections result in splenomegaly and, in some cases, hypersplenism. At its most
malaria 20980 children in Kinshasa, DRC, admitted to hospital with hyperparasitaemic falciparum malaria [[70]]Repeated malaria infections result in splenomegaly and, in some cases, hypersplenism. At its most extreme is a condition
malaria 21116 splenomegaly and, in some cases, hypersplenism. At its most extreme is a condition called “hyperreactive malaria l splenomegaly”, known in the past as “tropical splenomegaly”, in which there is massive splenomegaly,
malaria 21364 anaemia. Some cases progress to B cell malignancy. Untreated the mortality is high, but when caused by malaria , the splenomegaly resolves over weeks or months with effective malaria chemoprophylaxis [[71]–[73]].Iron
malaria 21435 is high, but when caused by malaria, the splenomegaly resolves over weeks or months with effective malaria chemoprophylaxis [[71]–[73]].Iron deficiencyThe interaction between iron and malaria is complex and
malaria 21522 with effective malaria chemoprophylaxis [[71]–[73]].Iron deficiencyThe interaction between iron and malaria is complex and controversial. Iron deficiency is very common in malaria endemic areas. It causes anaemia
malaria 21594 interaction between iron and malaria is complex and controversial. Iron deficiency is very common in malaria endemic areas. It causes anaemia and in young children iron deficiency is associated with neurodevelopmental
malaria 21814 delay. Malaria does not cause iron deficiency, but iron deficiency does reduce the incidence of severe malaria [[74]]. Nevertheless, iron deficiency and malaria still often coincide in the same patient. Assessment
malaria 21864 iron deficiency does reduce the incidence of severe malaria [[74]]. Nevertheless, iron deficiency and malaria still often coincide in the same patient. Assessment of iron deficiency in acute malaria is confounded
malaria 21953 deficiency and malaria still often coincide in the same patient. Assessment of iron deficiency in acute malaria is confounded by the associated inflammatory response. In some areas, but not others, routine elemental
malaria 22096 inflammatory response. In some areas, but not others, routine elemental iron supplementation following malaria has been shown to promote recovery from anaemia [[75], [76]]. Secondary folate deficiency is less common.
malaria 22294 is less common. Neither iron nor folate supplementation reduce childhood mortality in areas of high malaria transmission. Much of the controversy has centred on whether iron (and folate) supplementation actually
malaria 22413 transmission. Much of the controversy has centred on whether iron (and folate) supplementation actually worsen malaria and increase malaria associated mortality. Some large prospective studies, notably a study conducted
malaria 22434 controversy has centred on whether iron (and folate) supplementation actually worsen malaria and increase malaria associated mortality. Some large prospective studies, notably a study conducted on Pemba island which
malaria 22608 study conducted on Pemba island which was stopped prematurely [[77]], have shown increased falciparum malaria morbidity and mortality in elemental iron supplemented children [[77]–[80]]. So is it good or bad
malaria 22773 children [[77]–[80]]. So is it good or bad to provide elemental iron supplementation to children in malaria endemic areas? The risk–benefit assessment, and thus the answer to this question, varies and so is
malaria 23443 proposed as a safer strategy than non-physiological elemental iron supplementation [[84]]. In acute malaria hepatocyte production of the key iron regulator hepcidin is increased. This reduces iron uptake, and
malaria 23684 Concentrations of serum ferritin, an acute phase reactant, are also raised. The redistribution of iron in malaria is considered a risk factor for supervening bacterial infections which are associated with malaria in
malaria 23783 malaria is considered a risk factor for supervening bacterial infections which are associated with malaria in endemic areas [[86]], and particularly with severe malarial anaemia.Diagnosis of malariaIn the clinical
malaria 23845 infections which are associated with malaria in endemic areas [[86]], and particularly with severe malaria l anaemia.Diagnosis of malariaIn the clinical assessment of anaemia a diagnosis of acute malaria requires
malaria 23875 associated with malaria in endemic areas [[86]], and particularly with severe malarial anaemia.Diagnosis of malaria In the clinical assessment of anaemia a diagnosis of acute malaria requires either demonstration of malaria
malaria 23941 severe malarial anaemia.Diagnosis of malariaIn the clinical assessment of anaemia a diagnosis of acute malaria requires either demonstration of malaria parasites in a thick or thin blood film, or a positive rapid
malaria 23982 malariaIn the clinical assessment of anaemia a diagnosis of acute malaria requires either demonstration of malaria parasites in a thick or thin blood film, or a positive rapid test (RDT). Microscopy or RDTs have a detection
malaria 24263 corresponds approximately with the pyrogenic density in non-immune subjects [[1]]. The RDTs for falciparum malaria usually identify histidine-rich protein 2 (PfHRP2) as the target antigen. PfHRP2 persists in pitted
malaria 24626 parasitaemia clears. The RDTs for P. falciparum are slightly more sensitive than those for P. vivax malaria . Using sufficient volume blood samples PCR methods can now detect parasite densities 1000 times lower
malaria 24977 they are too sensitive for the diagnosis of acute illness (i.e. their predictive value for identifying malaria as the cause of illness is poor). Serology maybe useful in assessing previous malaria exposure, but
malaria 25063 for identifying malaria as the cause of illness is poor). Serology maybe useful in assessing previous malaria exposure, but not in identifying the cause of an individual’s illness [[1], [89]]. However, in many
malaria 25188 in identifying the cause of an individual’s illness [[1], [89]]. However, in many cases in which malaria causes anaemia the acute infection has resolved or been treated. The epidemiological context is critical
malaria 25352 treated. The epidemiological context is critical to the assessment. In some cases, finding residual malaria pigment in peripheral blood monocytes provides a useful clue to recent infection.Definitions of anaemiaAs
malaria 25486 blood monocytes provides a useful clue to recent infection.Definitions of anaemiaAs the epidemiology of malaria coincides with the epidemiology of inherited red cell abnormalities, nutritional deficiencies and helminth
malaria 25908 variety of definitions of anaemia in general have been proposed, the most commonly used definitions in malaria studies, based on haemoglobin concentrations, are as follows.Mild anaemia ≤ 11 g/dLModerate anaemia
malaria 26929 haemoglobin to haematocrit slightly overestimates the haematocrit [[90], [91]].In 1810 patients with acute malaria who provided 3254 simultaneous measurements from various time points (ranging from day 0 to day 63),
malaria 27140 good fit was obtained using Haematocrit = 5.62 + 2.60 * Haemoglobin [[90]].In areas of high malaria transmission where malaria is a major contributor to anaemia in the first years of life the ratio of
malaria 27167 Haematocrit = 5.62 + 2.60 * Haemoglobin [[90]].In areas of high malaria transmission where malaria is a major contributor to anaemia in the first years of life the ratio of haemoglobin to haematocrit
malaria 27349 haemoglobin to haematocrit changes with age [[91]]. Clinical trials of therapeutic interventions in malaria usually report changes in haemoglobin or haematocrit, whereas large assessments of preventive interventions
malaria 27742 variably in epidemiological studies. For example, in a recent assessment of seasonal chemoprevention in malaria prevention moderate anaemia was defined as < 11 g/dL (and in this study severe anaemia was defined
malaria 28079 have also used the < 8 g/dL threshold). The majority of studies have used 5 g/dL to define severe malaria l anaemia.Clinical featuresUncomplicated malariaMalaria is an acute febrile illness. There are no specific
malaria 28127 majority of studies have used 5 g/dL to define severe malarial anaemia.Clinical featuresUncomplicated malaria Malaria is an acute febrile illness. There are no specific clinical features in uncomplicated infections.
malaria 28388 associated with more severe clinical disease, the relationship is very variable [[1]]. In falciparum malaria there is sequestration of erythrocytes containing mature parasites in the microcirculation. This causes
malaria 29240 predominantly sequestered biomass usually have more mature trophozoites, many of which contain visible malaria pigment [[95]]. Significant sequestration does not occur in the other human malarias.Anaemia develops
malaria 29324 contain visible malaria pigment [[95]]. Significant sequestration does not occur in the other human malaria s.Anaemia develops rapidly in acute malaria so the majority of symptomatic patients have already lost
malaria 29367 Significant sequestration does not occur in the other human malarias.Anaemia develops rapidly in acute malaria so the majority of symptomatic patients have already lost at least 1 g of haemoglobin per decilitre
malaria 31642 factors for gametocytaemia in P. falciparum infections [[96], [97]], so in a context of worsening anti- malaria l drug resistance it is common to see patients (often children) who present with anaemia and patent gametocytaemia.Fig. 8Development
malaria 31858 gametocytaemia.Fig. 8Development of anaemia and subsequent recovery in Karen patients with acute falciparum malaria treated on the Thailand-Myanmar border [[33]]Anaemia may be regarded a clock of the infection, in that
malaria 32001 border [[33]]Anaemia may be regarded a clock of the infection, in that a patient presenting with acute malaria and a normal haematocrit (provided they are not dehydrated) cannot have been ill for many days. The
malaria 32139 (provided they are not dehydrated) cannot have been ill for many days. The cumulative impact of repeated malaria episodes was documented in detail during the malaria therapy era, which began nearly a century ago,
malaria 32192 for many days. The cumulative impact of repeated malaria episodes was documented in detail during the malaria therapy era, which began nearly a century ago, when malaria was used to treat neurosyphilis and also
malaria 32252 episodes was documented in detail during the malaria therapy era, which began nearly a century ago, when malaria was used to treat neurosyphilis and also in detailed volunteer studies conducted by the military [[98]–[102]].
malaria 32393 and also in detailed volunteer studies conducted by the military [[98]–[102]]. In volunteers given malaria whose infections were untreated, haemoglobin concentrations declined rapidly initially over 1 to 2 weeks,
malaria 32876 by fever) in causing anaemia. They showed how, with continued infection, tolerance to the infecting malaria parasites was induced, so that the inflammatory response subsided, and eventually effective erythropoiesis
malaria 33274 reached a nadir during the 5th week of illness but then rose despite continuing parasitaemiaSevere malaria Severe malaria is usually caused by P. falciparum, although P. knowlesi and occasionally P. vivax may
malaria 33288 nadir during the 5th week of illness but then rose despite continuing parasitaemiaSevere malariaSevere malaria is usually caused by P. falciparum, although P. knowlesi and occasionally P. vivax may also cause severe
malaria 33424 falciparum, although P. knowlesi and occasionally P. vivax may also cause severe disease [[93]]. Severe malaria is a multi-system disease. Cerebral malaria (a diffuse symmetrical encephalopathy causing coma) is specific
malaria 33468 occasionally P. vivax may also cause severe disease [[93]]. Severe malaria is a multi-system disease. Cerebral malaria (a diffuse symmetrical encephalopathy causing coma) is specific for P. falciparum infection, but kidney
malaria 33648 falciparum infection, but kidney injury, metabolic acidosis, and severe anaemia may occur in all the malaria s [[93]]. The pattern of vital organ dysfunction depends on age, pregnancy status, and, to a lesser extent,
malaria 33847 lesser extent, the level of transmission intensity [[93]]. Anaemia develops very rapidly in severe malaria . The initial most rapid decline in haematocrit observed in hospitalized patients reflects rehydration
malaria 34908 lactate-pyruvate ratio [[104]–[106]]. Tissue ischaemia is also caused directly by severe falciparum malaria ; the lactate-pyruvate ratio is also increased, and hyperlactataemia correlates strongly with outcome
malaria 35108 outcome (vide infra), but the pathogenesis is different [[93]]. In patients with severe falciparum malaria and a high parasite burden the reduction in tissue oxygen delivery results from microvascular obstruction
malaria 35445 [108]]. Thus, there are two overlapping causes of tissue hypoxia and hyperlactataemia which both occur in malaria :Severe anaemia which may result either from repeated uncomplicated infections with any of the malaria
malaria 35547 malaria:Severe anaemia which may result either from repeated uncomplicated infections with any of the malaria parasites, or a more fulminant haemolytic anaemia which is usually associated with severe falciparum
malaria 35656 parasites, or a more fulminant haemolytic anaemia which is usually associated with severe falciparum malaria or sometimes blackwater fever.Reduced microvascular perfusion resulting from cytoadherence and inter-erythrocytic
malaria 35874 inter-erythrocytic adhesion.The first of these responds rapidly to blood transfusion.Anaemia and outcome in severe malaria The relationship between haemoglobin concentration at presentation to hospital and outcome in falciparum
malaria 35986 relationship between haemoglobin concentration at presentation to hospital and outcome in falciparum malaria suggests that mortality rises sharply at levels below 3 g/dL (independent of other severe manifestations)
malaria 36185 manifestations) [[109], [110]] (Figs. 10, 11). Severe anaemia is a prominent feature of all severe malaria but in areas of high transmission, where severe disease is confined to the first few years of life,
malaria 36374 few years of life, it is the predominant manifestation [[3], [11]]. Consensus definitions of severe malaria have been agreed upon-which for the anaemia criterion is a haemoglobin below 5 g/dL in a patient with
malaria 36588 least 10,000 parasites/μL [[93]]. Patients who fulfil the anaemia criterion for severe falciparum malaria , but have no other manifestations of severe malaria (i.e. cerebral, renal, metabolic or pulmonary dysfunction)
malaria 36640 fulfil the anaemia criterion for severe falciparum malaria, but have no other manifestations of severe malaria (i.e. cerebral, renal, metabolic or pulmonary dysfunction) have a much better prognosis than patients
malaria 36898 [[93]]). Although most patients presenting with a parasite density of > 10,000 parasites/µL have malaria as the cause of their illness, this parasitaemia threshold for the “severe malaria” definition still
malaria 36983 > 10,000 parasites/µL have malaria as the cause of their illness, this parasitaemia threshold for the “severe malaria ” definition still means that some anaemic children with incidental parasitaemia and another infectious
malaria 37155 incidental parasitaemia and another infectious disease (usually sepsis) may be diagnosed as having severe malaria . Thus the severe anaemia criterion encompasses a broad range of presentations ranging from a fulminant
malaria 37374 with severe haemolytic anaemia to a sub-acute illness, often from recurrent or inadequately treated malaria , in which there has been progressive anaemia. The prognosis of the sub-acute presentation is much better
malaria 37883 presenting with acute multi-organ dysfunction [[110], [111]]. Thus the mortality associated with severe malaria l anaemia depends on many factors which include the degree of anaemia, age, transmission intensity, referral
malaria 38295 outpatients and hospitalized patients in Papua showing the substantially higher mortality of falciparum malaria with very severe anaemia compared with malaria caused by other Plasmodium species. Figures generated
malaria 38342 showing the substantially higher mortality of falciparum malaria with very severe anaemia compared with malaria caused by other Plasmodium species. Figures generated by multiple fractional polynomial regression analyses
malaria 38763 haemoglobin concentrations on admission and outcomes in 6451 adults and children with severe falciparum malaria studied in Africa and Asia between 1980 and 2015 who were admitted with a parasite density of > 10,000/μL.
malaria 38967 of > 10,000/μL. Below 5 g/dL (vertical blue dashed line) anaemia itself was a criterion for severe malaria . Inset is shown this same relationship in the subgroup of 2729 patients with cerebral malaria and the
malaria 39061 severe malaria. Inset is shown this same relationship in the subgroup of 2729 patients with cerebral malaria and the same parasitaemia rangeIn published series of children admitted to hospital with severe malaria
malaria 39165 malaria and the same parasitaemia rangeIn published series of children admitted to hospital with severe malaria anaemia (including those with other severity manifestations) mortalities range from 2.6 to 10.3%—while
malaria 39671 (Fig. 12).Fig. 12Time to death in children and adults admitted to hospitals in Asia and Africa with severe falciparum malaria Above a haemoglobin concentration of 5 g/dL other manifestations are required for a diagnosis of “severe
malaria 39797 concentration of 5 g/dL other manifestations are required for a diagnosis of “severe falciparum malaria ”. In a very large series of over 8000 adults and children with strictly defined severe falciparum
malaria 39905 malaria”. In a very large series of over 8000 adults and children with strictly defined severe falciparum malaria studied in Asia and Africa over the past 37 years mortalities rose with increasing admission haemoglobin
malaria 40158 [[112]–[117]] (Fig. 11). A similar pattern was observed in the subgroup of patients admitted with cerebral malaria (Fig. 11). There are many potential confounders which may explain this finding, but a causal association
malaria 40393 Interestingly in the large FEAST fluid bolus trial [[118]], which enrolled children with both severe malaria and sepsis, the 8-h mortality of patients with mild anaemia (defined in the trial as haemoglobin 7–9.9 g/dL)
malaria 41003 generally not warranted. But it does raise the possibility of a causal association in patients with severe malaria . If this were confirmed it would mean that mild anaemia reduces the probability of a fatal outcome in
malaria 41145 mean that mild anaemia reduces the probability of a fatal outcome in patients with severe falciparum malaria (and vital organ dysfunction). It does not mean that anaemia could be beneficial overall—indeed anaemia
malaria 41337 overall—indeed anaemia is clearly harmful—but that within the subgroup of patients with falciparum malaria who have developed vital organ dysfunction it is possible that anaemia protects against death. If a
malaria 42003 stress and shear rate respectively i.e. non-Newtonian fluid mechanics) which could be altered in severe malaria . Increasing haematocrit is associated with a linear increase in oxygen carriage but a non-linear increase
malaria 42575 markedly disrupted by sequestration. Cytoadherence, the fundamental pathological process in severe malaria which causes sequestration has been shown to be reduced by haemodilution. In an ex vivo system there
malaria 42924 to 30%, as a result of changes in shear rate [[122]]. The optimum haematocrit is not known in severe malaria , but red cell adherence to vascular endothelium, and to other erythrocytes is likely to lower it, and
malaria 43225 density of erythrocytes (i.e. anaemia) might improve microvascular perfusion in patients with severe malaria . If so that would increase oxygen delivery, until it was outweighed by the reduction in oxygen carriage.Alternatively
malaria 43632 vital organ dysfunction. The observed relationship between admission haematocrit and outcome of severe malaria might be explained entirely by other covariate relationships. Clearly this is an important question
malaria 44126 is extensive, the patient has a pale, slate-grey appearance. Blackwater fever may be part of severe malaria [[124]–[126]]. Death may occur from severe anaemia or from acute renal failure. Haemoglobinuria may
malaria 44444 use, and it may occur in glucose-6-phosphate dehydrogenase deficiency with febrile illnesses such as malaria or following ingestion of oxidants (notably radical cure primaquine regimens) [[127]].Post-artesunate
malaria 44783 anaemia occurring 1–3 weeks after parenteral artesunate treatment of hyperparasitaemic falciparum malaria . Most cases followed intravenous artesunate, although some were reported after intramuscular artemether,
malaria 45577 [[70]] (Fig. 7). Post-artesunate haemolytic anaemia has been attributed to the pitting of drug-damaged malaria parasites from infected erythrocytes [[67]]. These once-infected red blood cells (oi-RBC) have a much
malaria 45822 (7–14 days) compared with normal erythrocytes in healthy subjects (120 days) or in patients following severe malaria (44 days) [[66], [128]]. In the French series, a threshold of 180 once-infected erythrocytes/µL discriminated
malaria 46451 synchronous elimination of these oi-RBC from the circulation 1 to 2 weeks after the start of anti- malaria l treatment results in haemolytic anaemia, which in some cases can be marked [[67]].ManagementSevere
malaria 46559 treatment results in haemolytic anaemia, which in some cases can be marked [[67]].ManagementSevere malaria Severe anaemia (haemoglobin < 5 g/dL) requires blood transfusion which can be life-saving [[129],
malaria 46779 The lower the haemoglobin the greater the need for transfusion. If there are other features of severe malaria such as acidotic breathing (respiratory distress) or coma, together with severe anemia then transfusion
malaria 47236 4 h, or 10mls/kg of packed cells (although this is often unavailable). In low transmission settings malaria treatment guidelines recommend transfusion in severe malaria if the haemoglobin is < 7 g/dL (haematocrit
malaria 47297 unavailable). In low transmission settings malaria treatment guidelines recommend transfusion in severe malaria if the haemoglobin is < 7 g/dL (haematocrit 20%), whereas in higher transmission settings the recommended
malaria 47510 recommended threshold is 5 g/dL (haematocrit 15%) [[93]]. The haemoglobin transfusion thresholds for acute malaria differ slightly from other WHO guidelines for the clinical use of blood. These recommend transfusion
malaria 48102 of these transfusion recommendations are based on solid evidence [[134]]. Transfusion thresholds in malaria were set intentionally slightly higher than for some other conditions [[135]] because haemoglobin concentrations
malaria 48254 for some other conditions [[135]] because haemoglobin concentrations usually fall rapidly in severe malaria . Thus, to avoid falling into the danger zone it has been thought better to order blood for transfusion
malaria 48578 observations have the disadvantage that many factors determine whether or not a patient with severe malaria receives a timely blood transfusion, and several of these factors could affect outcomes independently,
malaria 48787 independently, so prospective randomized trials are under way to try and answer these questions [[134]].The anti- malaria l treatment of choice for severe malaria is parenteral artesunate [[89], [93], [114], [116]]. When the
malaria 48827 under way to try and answer these questions [[134]].The anti-malarial treatment of choice for severe malaria is parenteral artesunate [[89], [93], [114], [116]]. When the patient can swallow reliably this should
malaria 49022 reliably this should be followed by a full course of an oral artemisinin-based combination therapy. Anti- malaria l treatment should not be delayed by transfusion.In areas where the HIV prevalence is high severe anaemia
malaria 49140 should not be delayed by transfusion.In areas where the HIV prevalence is high severe anaemia with malaria is more likely in HIV positive patients [[136]], and in high malaria transmission settings concomitant
malaria 49209 prevalence is high severe anaemia with malaria is more likely in HIV positive patients [[136]], and in high malaria transmission settings concomitant HIV exacerbates the anaemia that occurs in infancy after 3 months
malaria 49571 anaemia, and they also have an increased risk of dying in the following months [[10]]. Prevention of malaria reinfection with slowly eliminated anti-malarial drugs reduces these risks [[138]].Blackwater feverBlackwater
malaria 49619 dying in the following months [[10]]. Prevention of malaria reinfection with slowly eliminated anti- malaria l drugs reduces these risks [[138]].Blackwater feverBlackwater fever results from massive haemolysis
malaria 49846 haemoglobinuria. The management of blackwater fever anaemia is with blood transfusion [[93]]. Anti- malaria l treatment should not be withheld. Steroids are ineffective. Some cases result from oxidant haemolysis
malaria 50231 difficult to cross match. Acute kidney injury is an important complication.Anaemia in uncomplicated malaria A promptly treated discrete episode of malaria in a patient with a pre-morbid normal haemoglobin is unlikely
malaria 50277 is an important complication.Anaemia in uncomplicated malariaA promptly treated discrete episode of malaria in a patient with a pre-morbid normal haemoglobin is unlikely to result in clinically significant anaemia.
malaria 50455 result in clinically significant anaemia. It is the cumulative impact of repeated illness from recurrent malaria that is the main cause. In areas where P. vivax is endemic frequently recurring illness caused by repeated
malaria 50605 vivax is endemic frequently recurring illness caused by repeated relapse is the main contributor to malaria l anaemia in childhood [[8], [9]]. In areas where P. falciparum is endemic frequent infections or repeated
malaria 50842 anaemia. The prevalence of anaemia therefore increases with transmission intensity, and where anti- malaria l drug resistance compromises drug efficacy [[139]]. In areas of high transmission the greatest burden
malaria 51180 individual acute illness [[89]], but prevention of repeated or recurrent infection is the key to reducing malaria l anaemia at the community level.Malaria in pregnancyAnaemia is common in pregnancy in tropical regions.
malaria 51568 occur during the middle trimester in high transmission settings. Concomitant HIV infection exacerbates malaria l anaemia in pregnancy. High maternal parasitaemias are associated with fetal and newborn anaemia [[6]].
malaria 51980 achieved by chemoprophylaxis, although there is currently no satisfactory safe drug for falciparum malaria prevention. Chloroquine is regarded as safe in pregnancy and is still effective in preventing the non-falciparum
malaria 52101 Chloroquine is regarded as safe in pregnancy and is still effective in preventing the non-falciparum malaria s in most areas. The more widely used approach in higher transmission settings is intermittent preventive
malaria 52550 widely used drug although this is increasingly challenged by resistance. The WHO recommends that in malaria -endemic areas of Africa, intermittent preventive treatment with SP should be provided to all pregnant
malaria 52975 apart, with the objective of ensuring that at least three doses are received [[89]]. Pregnant women in malaria endemic areas should also receive iron and folate supplementation according to standard guidelines
syphilis 32283 during the malaria therapy era, which began nearly a century ago, when malaria was used to treat neuro syphilis and also in detailed volunteer studies conducted by the military [[98]–[102]]. In volunteers given

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