Journal of Vector Borne Diseases

REVIEW ARTICLE
Year
: 2020  |  Volume : 57  |  Issue : 1  |  Page : 1--13

Severe malaria: Biology, clinical manifestation, pathogenesis and consequences


SN Balaji1, Rohitas Deshmukh2, Vishal Trivedi1,  
1 Malaria Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, India
2 Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India

Correspondence Address:
Dr Vishal Trivedi
Malaria Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology- Guwahati, Guwahati–781 039, Assam
India

Abstract

Every year, millions of people are infected with malaria, resulting in significant economic losses to the developing and developed nations. The malaria parasite pursues a complicated life cycle in an invertebrate, mosquito and vertebrate host with several distinct stages. In the human host, it invades the liver and red blood cells to complete its life cycle. It is surprising that not only these two organs are under pressure and exhibit functional abnormalities; a large number of clinical studies also support the notion that malaria parasite propagation in the host affects several other organs and modulates functional outcomes of individual cells. Moreover, patients recovered from severe malaria may suffer throughout their life from impairments in organ function such as loss of eyesight, kidney failure, and much more. Thus, malaria infection leads to several pathological outcomes involving different organs and individual cells in the host. The sole purpose of the present article was to give an overview of pathological outcomes during severe malaria along with their molecular mechanisms. A large proportion of deaths associated with disease is contributed by the pathological effect in host due to parasite propagation and toxicity of antimalarials or combination of both. Hence, there is a need, not only to develop antiparasitic agents but also to discover lead molecules to take care of pathophysiological effects in the host. This may help a beginner to get involved with the topic and initiate research work towards improving adjuvant therapy or avoiding serious complications.



How to cite this article:
Balaji S N, Deshmukh R, Trivedi V. Severe malaria: Biology, clinical manifestation, pathogenesis and consequences.J Vector Borne Dis 2020;57:1-13


How to cite this URL:
Balaji S N, Deshmukh R, Trivedi V. Severe malaria: Biology, clinical manifestation, pathogenesis and consequences. J Vector Borne Dis [serial online] 2020 [cited 2021 Apr 18 ];57:1-13
Available from: https://www.jvbd.org/text.asp?2020/57/1/1/308793


Full Text

 Introduction



Malaria is a deadly disease which infects over 219 million and kills around 0.4 million people annually[1]. Despite the annual decrease in malaria associated deaths, development of drug resistance in parasites and insecticide resistance in mosquitoes, along with climatic change contribute to the severe outcomes of the disease in developing and developed countries[1],[2],[3]. In humans, malaria is caused by five different species of Plasmodium, namely Plasmodium falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi[4]. Among them, P. falciparum is the most pathogenic species that accounts for 60–70% deaths. Malaria parasite completes its life cycle in two different hosts; invertebrate—Anopheles mosquitoes, and vertebrate—humans [Figure 1].{Figure 1}

The infection cycle starts with the bite of the Anopheles mosquito (vector) during the sucking of blood from the vertebrate host. In this process, the sporozoites present in the salivary gland of mosquito are being injected, and they quickly migrate towards liver to infect the hepatocytes. Mature merozoites are released from the hepatocytes to blood and each merozoite infects a new red blood cell (RBC) for multiplication[5],[6]. In RBC, merozoites undergo different stages such as rings, trophozoites and schizonts. The mature schizonts stage have 16–24 merozoites which come out of RBC through egress to infect new RBC to start a new cycle. The RBC stages are clinically critical as they are responsible for the symptoms and pathological outcomes in the host during the course of malaria infection[7],[8],[9]. The treatment of severe malaria involves the administration of various anti malarial drugs. But it has been reported that the recovered patients may suffer from deafening, loss of eyesight, kidney failure, etc. depending on the disease severity[1]. The major manifestation of severe malaria comprises of anaemia, acute renal failure, cerebral malaria, pulmonary edema, and/or bleeding.

Multiple organ failures and the cytotoxic effect of antimalarial drugs are the additional challenges in malaria control[10]. It indicates the necessity to develop safe and nontoxic antimalarial medicines, additional adjuvant therapies and also to reduce vector burden on the environment for controlling the disease spread. The present review discusses the impact of malaria on pathophysiology of different organs and its relationship with the appearance of disease conditions in the host. It also focuses on the consequences of severe malaria for better understanding as well as to improve the existing malaria therapies.

Malaria-induced pathology is not limited to one organ

Clinical symptoms of malaria appear during the erythrocytic stage of the malaria parasites. Malarial fever elicits headaches, muscle aches, dry cough, nausea, vomiting, tiredness, etc. along with typical paroxysmal fever [Figure 2]a. A paroxysmal feature of malaria develops with the release of toxic by-products which initiates initial chillness followed by a sudden rise in the body temperature (fever). At advanced stages, manifestations may include severe anaemia, lactic acidosis, hypoxia, splenomegaly, liver diseases, kidney diseases, visual defects, cerebral malaria with neuronal damages, etc. [Figure 2]b. Untreated malaria may lead to coma before death[3],[11],[12]. Giga et al[13] observed anaemia (45%) as the predominant symptom of malaria, followed by convulsions (21%), cerebral malaria (16.4%) and hypotension (11.8%). But Mohanty et al[14] indicate cerebral malaria (52%) as the leading cause of the death in case of P. falciparum infection.{Figure 2}

Earlier, it was believed that the infection caused by P. vivax is clinically mild type and the parasite does not pass in the deep blood vessels of the organs. However, studies from specific geographical area suggest that P. vivax is also associated with severe clinical manifestations and even death[15],[16]. Vivax malaria primarily causes severe anaemia and related problems such as kidney failure, jaundice, respiratory distress, etc[17]. Plasmodium vivax infection (61%) is primarily responsible for the kidney problems in the host[18]. Recently, Mathews et al[19] studied the clinical spectrum of P. vivax infection in 150 patients in the Delhi region of India for 2 yr and observed that about 42% (63 patients) had signs of severe malaria. Plasmodium vivax exclusively resides in reticulocytes and is reported to show higher cytokine production, inflammatory response and endothelial activation as compared to P. falciparum infection. It was suggested that the higher level of CG content in the genome of P. vivax results in higher content of toll-like receptor 9-stimulating CpG motifs causing inflammatory response and cell activation[20].

Another study by Limaye[21] suggested that P. falciparum malaria leads to higher mortality, but differs in malaria pathology when compared with P. vivax. Mixed infection of P. falciparum and P. vivax is more severe than the individual infection. Malaria is also a major cause of death in pregnant women. Postpartum haemorrhage is the major cause of the maternal death during placental malaria[22].

Malaria-mediated pathological outcomes in the host and its mechanism

Plasmodium falciparum infection causes various adverse effects to the host and disturb the body homeostasis. Parasite metabolic wastes damage the host cell and organelle systems such as reticulo-endothelial systems, placenta, visual defects, etc. These effects are schematically depicted in [Figure 2] and discussed in the coming sections.

Severe anaemia

Anaemia is a clinical condition in which haemoglobin (Hb) level falls below 10 g/dl. Severe anaemia is very common during malaria where the level of Hb become <6 g/dl[11], haematocrit <15% in children <12 yr of age. In malaria patients, anaemia develops by following three mechanisms —(a) intravascular haemolysis, (b) increased clearance of malaria infected RBC (iRBC), and (c) decrease in RBC production through dysregulated erythropoiesis [Figure 3]. According to the World Health Organization (WHO), malaria is responsible for about 445,000 deaths per year and anaemia is directly or indirectly responsible for significant proportion of these deaths. Anaemia leads to low level of Hb and contributes to nutritional deficiencies, poor health structure and prevalence of other infectious diseases like bacterial, viral (HIV) and hookworm (intestinal helminth infection)[23],[24]. The incidence of malaria caused especially by P. vivax and P. falciparum is low in American and Asian countries, where the people receive entomological inoculation rate (EIR) of ≤1 per year. Contrastingly, in sub-Saharan Africa region and in low land New Guinea, the EIR has been reported up to 1000 per year. The high incidence of malaria is associated with severe anaemia and results in considerable morbidity and mortality[24].{Figure 3}

Blood transfusion is one of the primary treatment to combat with severe malarial anaemia. Scott et al[25] estimated that increase in Hb to 1 g/dl can reduce the risk of death by 24% (1.8 million) among children between 28 days to 5 yr. Phytochemicals have also been reported and exhibit antiparasitic activity and lowers severe anaemia in murine malaria. In an in vitro study, ursolice acid, betulinic acid, maslinic acid and oleanolic acid have been shown to have antimalarial activity against chloroquine-sensitive and chloroquine-resistant P. falciparum parasites[26],[27].

Intravascular haemolysis

Intravascular haemolysis refers to the rupture of RBCs within the blood vessels [Figure 3]. During malaria, iRBC lysis releases merozoites which complete their life cycle by infecting fresh RBCs. The cyclic process leads to the reduction in RBCs in the blood and develop anaemia like condition. The iRBC lysis also release Hb derived products such as haemin, methaemoglobin (MetHb), degraded Hb peptides and malarial pigment haemozoin[28]. Metabolites released from iRBC are capable to generate free radicals and cause the oxidative damages to the blood cells. The Hb or its oxidation product MetHb, can damage RBC membrane following a nuclear fission model to enhance the RBC lysis several folds[29]. They also induce the nitric oxide (NO) synthesis by endothelium to contribute into additional oxidative stress. Tumour necrosis factor (TNF)-α is also involved in this process and increases the NO level in blood. Exposure to free radicals leads to the death of RBCs by oxidizing the RBC membrane lipids, proteins and inducing phosphatidylserine (PS) expression on RBC outer membrane[30],[31]. In a mice model, Dey et al[32] reported that the intravascular haemolysis during malaria damages the liver cells. The pro-oxidant molecule (haeme) released from rupture of RBC increases the oxidative load on liver cells, and activated NF-κB increases infiltration of neutrophils, upregulation of chemokines and intercellular adhesion molecules. The severity of haemolysis was positively correlated with the infiltration of the neutrophils and liver damage. Further, the study used deferoxamine (iron chelator) and N-acetylcysteine (anti-oxidant) in reversing the action and preventing the neutrophil infiltration, NF-κB activation and hepatic damage. Non-oxidative stress mediated RBC lysis during malaria is not pursued extensively. Complement mediated haemolysis was reported based on in vitro experiments, but it lacks in vivo support to draw fruitful conclusions[33],[34].

Clearance of red blood cells and infected red blood cells

In malaria, increased RBC clearance rate has been observed [Figure 3]. It may be due to the oxidative stress mediated RBC structural and functional changes, reduced deformability and PS externalization. The life span of RBC is ~120 days in healthy humans[35]. Old RBCs express different age-related markers (ARM) which can be used by macrophages to identify and phagocytose them in spleen, liver and bone marrow[36],[37]. Binding products on RBC surfaces also enhance the macrophagic clearance[36]. It has been reported that during malaria infection RBC expresses markers like rhoptry-associated protein-2 (RSP-2) and phosphatidylserine (PS). Macrophages recognizes the markers on iRBC membrane leading to the macrophagic clearances[36],[38],[39]. Altogether, the markers cause abnormal sequestration of RBCs in spleen and this condition leads to anaemia with reduction in RBC count in the blood.

Dysregulated erythropoiesis

Bone marrow is the prime site of production and maturation of erythropoietic cells. In the process of erythropoiesis, immature RBCs (reticulocytes) in bone marrow further develop and mature into RBC in blood vessels. Spleen and liver are also involved in the erythropoietic process as secondary sites[40]. The interference in erythropoietic process causes a reduction in RBC production, leading to drop in the RBC number in blood to develop anaemia [Figure 3]. Dyserythropoiesis (defective development of RBC) and ineffective erythropoiesis has been observed in human as well as murine Plasmodium infections. A microscopic examination of bone marrow of P. vivax infected patient showed erythroblasts at various stages of degradation[41]. Maggio-Price et al[42] characterized the changes in marrow haematopoietic stem cells in P. berghei-infected rodents. They observed reduction in burst forming unit-erythroid (BFU-E), colony forming unit-erythroid (CFU-E), erythroblasts and bone marrow cellularity in the infected mice after 24 h of infection.

It has been reported that severe malaria causes reduced erythropoiesis and is correlated with increased level of haemozoin, TNF-α, NO, NO-mediated apoptosis in CD34+ cells and reduced level of erythropoietin[43],[44],[45]. Haemozoin, also known as a malaria pigment was once considered as an inert material, but now reported to stimulate immune cells to release inflammatory cytokines. Phagocytosis of haemozoin by the immune cells like macrophages and monocytes results in dysregulation of innate inflammatory mediators. It inhibits the development of erythroid and is also responsible for reduced reticulocyte response[46],[47].

Abnormal level of cytokine causes release of hepcidin in the liver. Hepcidin is a hormone which regulates iron metabolism through its absorption and storage[48],[49]. Hyperhepsidinemia causes the reduction of intestinal iron absorption. On the other hand, hepcidin promotes the iron release from macrophages and leads to accumulation of iron in the liver. This process is known as iron delocalization and it causes hypoferremia to indirectly disturb the erythropoiesis in the bone marrow[50],[51],[52]. Reduction in the level of cytokine RANTES by haemin also impairs the erythropoiesis during malaria[53],[54],[55].

Phagocytosis of iRBC and haemozoin by macrophages causes release of macrophage migration inhibitory factor (MIF), a proinflammatory mediator. During malarial infection, MIF is believed to have a role in bone marrow suppression and inhibition of erythropoietin-dependent erythroid colony formation. Erythropoietic interfering factors during malaria was reviewed in more detail by Pathak and Ghosh[56].

Cerebral malaria

Cerebral malaria (CM) is defined as a serious neurological complication resulting from P. falciparum infection. It is one of the clinical criteria for severe malaria characterised with a Glasgow coma scale (GCS) score of <11 in adults and a Blantyre score of <3 in children. The CM is a leading cause of malaria mortality and it is estimated that CM due to P. falciparum infection is responsible for 20% of adult and 15% of children deaths. The children under the age of 5 yr who reside in high transmission areas have high chances of CM as compared to the adults[57].

Coma is the hallmark symptom during CM along with brain swelling, intracranial hypertension, retinal changes, brainstem signs, bleeding disorders and multi-organ failure[58]. In CM, age is an important factor and it has been observed that children and adults share only few common symptoms at initial time of infection of the disease. The symptoms include fever, convulsions, and neurological abnormalities along with coma[59]. The incidences of CM in children increase the mortality rate despite receiving the malarial chemotherapy. In adults, treatment with intravenous artesunate injection can delay or avoid death[60]. However, patients recovered from CM may suffer with different neurological difficulties such as blindness, ataxia, central hypotonia, cognition, motor function, behavioural changes and epilepsy throughout their life span[61].

The presence of methaemoglobin in the blood stream also potentiate the pathophysiology of CM. The methaemoglobin stimulated endothelium cells exhibit cytoadherence receptors CD36 and intercellular adhesion molecule 1 (ICAM1) on their cell surface which result in adherence of RBCs and contributing to the CM pathophysiology[62]. Post-mortem studies of CM patients showed parasite sequestration in the brain vessels, endothelial injury, blood brain barrier dysfunction and intracranial hypertension[63]. The iRBC sequestration was thought to have a great role in the development of CM. The possible events accountable for CM and associated pathology are given in [Figure 4]. The parasite adhesion protein, P. falciparum erythrocyte membrane protein-1 (PfEMP-1) present on iRBC interacts with ICAM-1 expressed on endothelial cells and allows the adherence of iRBC to the endothelial cell lining[64]. Adhesion of iRBC to endothelial cell promotes further adhesion of iRBC to endothelial lining and agglutination of blood cells in the sequestered area that leads to the blockage of the capillary. The infection of P. falciparum also leads to the activation and accumulation of macrophages, lymphocytes and monocytes at microvasculature. This results in generation of reactive oxygen species (ROS) and secretion of inflammatory cytokines (TNF, IFNγ and lymphotoxin) to produce inflammation and local damage to blood-brain barrier (BBB)[57]. By-products from iRBC also induce RBC aggregation under in vitro conditions and highlight this pathway to explain severe vascular blockage and complication during malaria[31],[65]. Blockage of the capillary develops hypoxia and hypoglycemic condition in the local area which leads to brain cell damage. Lactic acidosis condition further adds up to the cell damage.{Figure 4}

Products released from iRBC causes inflammation and oxidative damages of the endothelium. Haemozoin or iRBC phagocytised macrophages secrete high level of matrix metalloprotease-9 (MMP-9) which can damage the basal lamina around the blood vessels and disrupt the blood brain barrier[46],[66],[67]. The MMPs further enhances the TNF-α and cytokine secretion by macrophages and lymphocytes. In CM, TNF-α, interleukins (IL-12, IL-6 and IL-10) play a critical role in disease development[68]. The role of TNF-α in ICAM-1 overexpression on endothelial surface has been studied in many laboratories. Elevated interleukins and chemokine levels are thought to play critical role in CM[61],[69]. The seizure during CM may be due to the kynurenic metabolites such as quinolinic acid and kynurenic acid. Quinolinic acid is an NMDA receptor agonist and excitotoxin which may have a role in neurological symptoms and complications[70]. Deregulation of Angiopoietin/Tie-2 system was observed in Ugandan children with CM and experimental model of murine[71], but molecular incidences were not explored. There are many unidentified factors involved in the development of CM and the neurological damage is still inconclusive.

The current antimalarial therapy targets specifically to the parasites alone and does not manage the inflammatory cascades. As a result, in spite of treatments, CM is still associated with 20–25% mortality rates. This challenge can be overcome by use of immune-modulators and antioxidants as an adjuvant therapy. Various molecules from synthetic and plant origin have been tested as adjuvant therapy for the management of CM. In instance, curcumin, a major constituent of Curcuma longa has been reported to exhibit antimalarial activity with IC50 value of 5–18 μM. In mice model, where the animal was infected with P. berghei, curcumin-arteether combination therapy prevents the CM and protects the animal from death[70],[72]. Vitamin D was also tested for modulating the proinflammatory response in the mice model infected with P. berghei. The mice supplemented with vitamin D showed a reduced death rate with integrated blood-brain barrier (BBB). The results suggest that vitamin D can be used as a supplement to reduce the severity of CM in malaria endemic regions[73].

Splenomegaly

Abnormal enlargement of the spleen is termed as splenomegaly and is common in severe malaria[11]. During clinical examination, the size of spleen denotes the intensity of the malaria. In malaria-endemic countries, hyper-reactive malarial splenomegaly (HMS) is a major cause of splenomegaly in severe malaria which is characterized by overproduction of IgM antibodies that results in haemolytic anaemia during pregnancy, rupture of spleen and is sometimes fatal. In spite of huge number of literature present on malaria very limited literature deals with HMS[74]. The schematic diagram to explain different biochemical processes leading to splenomegaly during malaria is given in [Figure 5]. Spleen has an important role in filtering the blood and removing aged RBCs, RBC-derived products and bacteria[75]. During malaria, uninfected RBCs and other blood cells undergo abnormal modification (including apoptotic marker expression) which reduces their lifespan. During malaria, immune complexes combine with activated complement C3b which can deposit complement receptor 1 (CR1) present on RBCs. Haemozoin also can enhance the C3b binding on RBC CR1 receptor independently. This event can elicit splenic clearance of uninfected RBC and adds up the work load on spleen leading to splenic infarction[33]. Red pulp macrophages recognize abnormal RBCs, products released from infected RBCs (Hb, MetHb, haemin and haemozoin) and they phagocytose them. The elevated level of cytokines, IgM levels during malaria may also have a role in splenomegaly but the links are not clear[33],[76]. The excessive turnover of RBCs (production and destruction) and toxic by-product released from iRBCs during malaria may lead to spleen dysfunction and splenomegaly.{Figure 5}

Liver complication

About 2.5 to 62% of malaria patients suffer from the liver problems and develop clinical jaundice. The hepatocellular jaundice in severe malaria cases is referred as malarial hepatopathy which is characterized by increased level (about 3 folds than normal upper limit) of serum bilirubin and serum aminotransferases. Malarial hepatopathy is not common in such cases, but it still contributes into malaria mortality up to 2–5%. The schematic diagram to explain different biochemical and molecular pathways leading to liver damage during malaria is given in [Figure 6]. Parasite life cycle starts in the hepatocytes in humans and during this stage they modulate biochemical properties and increase stiffness of the infected hepatocytes[77]. Hepatocytic plasma membrane during sporozoite infection of the liver causes the secretion of the hepatocyte growth factor (HGF) which is known to involve in parasite infection into hepatocytes[78],[79],[80]. Interestingly, there is no remarkable liver pathophysiology during pre-erythrocytic malaria but haemolysis, congestion of hepatocytes, hepatocyte swelling, kupffer cell hyperplasia, deposition of haemozoin, and steatosis have been observed in autopsy of dead malaria patients[81],[82],[83],[84],[85].{Figure 6}

During the erythrocytic stage, the free Hb and haemin are being removed by the liver after binding with haptoglobin and haemopexin, respectively[86],[87]. Excess iRBC products oxidatively damage the cells present in microenvironment and lead them to apoptosis or lysis[88],[89]. The RBC released products along with parasitic antigens amplify the immune responses which lead to vascular dysfunction such as blockage, damage, iRBC sequestration, and haemolytic product accumulation in the liver. Accumulation of haemolytic products in the liver, causes severe damage to the hepatocytes through induction of apoptosis involving mitochondrial dysfunction, DNA fragmentation and oxidation of cytoskeleton proteins[32],[90],[91],[92]. Haemozoin also increases the secretion of cytokines from the macrophages and lymphocytes. The elevated levels of NF-κB and TNF-α in kupffer cell generate inflammatory response against hepatocytes during malaria. Hepcidin-mediated iron delocalisation in hepatocytes also damages the hepatocytes[51],[93]. Other mechanisms underlying in liver damage during malaria are still not clear[81],[94].

Guha et al[91] in a mice model reported that the oxidative stress-mediated by free radicals (OH*) was responsible for the death of hepatic cells via apoptosis. Therefore, they suggested that use of antioxidants (NAC, melatonin) and spin trap (TEMPO) can be used as an adjuvant therapy to prevent the mortality in severe malaria. Similarly, in order to improve liver functions and jaundice in severe malaria, ursodeoxycholic acid was also used as an adjunctive therapy along with intravenous artesunate[91],[92],[93],[94],[95].

Renal failure

Severe malaria develops acute kidney injury (AKI) in around 40% malaria patients and responsible for about 75% mortality in the endemic regions. Severe malaria is responsible for functional changes in glomeruli, tubules and interstitial region which arise mainly due to RBC abnormalities. In addition, proteinuria, haematuria, oedema and hypertension have been observed during malaria, especially with P. falciparum infection. During malaria, intravascular haemolysis activates endothelial cells, alter haemodynamics through the generation of oxidative stress, NO and pro-inflammatory cytokine, TNF-α. It leads to renal ischemia, acute tubular necrosis and acute interstitial nephritis[96]. Nephritis during malaria has showed involvement of INF-γ, IL-1α, IL-6 by altering levels of pro-inflammatory and anti-inflammatory cytokines[81],[97],[98]. Elevated level of IL-17 was observed in acute renal failure during malaria[99]. High parasitaemia causes stress to the kidney by various ways. Parasites-mediated lactic acidosis may overload the renal acid-base balance system. The iRBC sequestration and RBC rosetting in the blood vessels of kidney cause hypoxia, which affects the kidney cell activity[100]. IRBC sequestration further allows the deposition of parasites and malaria-related toxic products on the endothelial lining of kidney[101]. It results in endothelial damage as well as immune reactions in the kidneys. Altogether, they direct the kidney failure during malaria[98]. The treatment of kidney disease due to malaria includes use of antimalarial drugs along with fluid replacement and dialysis. In AKI, the association of dialysis in therapy among patients shows better outcome with 25% reduction in mortality and 30% increase in renal recovery[102].

Placental malaria

Placental malaria is another common complication observed in pregnant women infected with P. falciparum [Figure 7]. The compromised immune status in the first and third trimester of pregnancy makes women more susceptible to malaria infections. It had been reported that globally, pregnancy associated malaria (PAM) is accountable for 75,000–200,000 infant deaths per year[103]. Placental malaria leads to miscarriage, poor birth weight, neurological squeal and birth defects in newborn babies in severe cases. Placental malaria risk is higher in women with age below 25 yr and the onset of pregnancy, such as primiparity[104]. In placental malaria, phagocytic cells accumulate at the intervillous space to phagocytose iRBC. The TNF-α and IL-10 activate the macrophage to accumulate haemozoin, iRBC and induces leukocyte infiltration. It results in an increase of the thickness of trophoblast basement membrane to modulate the space between intervillous and perivillous. It results in a reduction of nutrient and oxygen transport across the placenta[105]. The role of elevated C5a during pregnancy may contribute in placental malaria through deregulated angiogenesis, the release of chemokine and cytokine[81]. Placental hormone human chorionic gonadotropin seems to promote malaria parasites.{Figure 7}

Malaria induced diabetes

Malaria mediated damages are not restricted to host organs, but also modulates the host metabolism. The metabolic modulation of the host is observed when there is an increased parasitic metabolism, resulting in altered immune responses and hormonal deregulation. Anaerobic metabolism of parasites directly influences the blood lactic acid level on the host. Parasitaemia level also directly correlates with TNF-α, interleukins and other cytokine level. Hormonal deregulation during malaria is yet unexplained, but the abnormal hormone level has been observed during placental malaria[106]. Elevated blood insulin level (hyperinsulinemia) during severe malaria has been reported in various studies[107],[108].

A recent study about the relation of type-II diabetes with malaria indicated that the incidence of type-II diabetes is increasing among malaria survivors[109]. Interestingly, type-II diabetes also increases the risk of malaria infection. Further, human insulin effects on mosquito indicate that it suppresses the NF-κB level in the mosquito to help the parasite survival in normal or starved mosquitoes[110],[111],[112]. Interestingly, hyperinsulinemia is often connected with hypoglycemia during malaria. During CM, hyperinsulinemia in conjugation with hyperglycemia cause more deaths than hypoglycemic condition alone[113],[114]. These interesting observations need to be explored for the connection between the interaction of insulin with parasites and its down-stream effects in disease development.

Malarial retinopathy

Malarial retinopathy is also one of the important consequences which has been observed in cases of severe malaria. Malarial retinopathy shows the cluster of some unique signs such as whitening of the retina, retinal haemorrhages, changes in ocular blood vessels to orange or white and papilledema. A number of cases of malaria retinopathy was reported in Africa, especially in children where they suffer from CM or severe malarial anaemia (SMA)[115],[116],[117],[118]. Lewallen et al[119] were the first to observe the unusual sign in the retina among the children suffering from CM in Malawi region by direct and indirect ophthalmoscopy. The cytoadherence properties of P. falciparum iRBC were well-established. The histopathology studies of eye show the sequestration of parasite-infected RBC within the ocular blood vessels by cytoadherence. The CM and SMA have been associated with the combination of retinal abnormalities[115]. The mortality rate and coma also correlate with severity of malarial retinopathy in African children suffering from CM, suggesting that the malarial retinopathy is correlated to the pathophysiology of malaria.

 Conclusion



Severe malaria is a global health problem in both endemic and non-endemic areas and is responsible for millions of deaths every year. The studies and results described in this review focused on the several pathological outcomes involving different organs and individual cells in the host due to malaria infection. It highlights the need of developing antiparasitic agents as well as discovering molecules to take care of pathophysiological effects in host. A large proportion of deaths associated with the malaria is contributed by the pathological effect in host due to parasite propagation and toxicity of antimalarials or combination of both. The present review will help the researchers to understand the pathophysiology of the malaria infection and its toxic effects on various organs. Moreover, it may also help the researchers to initiate research work towards improving adjuvant therapy or avoiding serious pathology. The work described in this review might lead to new possibilities for therapeutic interventions, which is urgently needed to reduce the morbidity and mortality of malaria.

Ethical statement: Not applicable.

Conflict of interest: None

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