Relative Contributions of Macrovascular and Microvascular Dysfunction to Disease Severity in Falciparum Malaria

Hanson, Josh; Lam, Sophia W. K.; Mahanta, Kishore C; Pattnaik, Rajayabardhan; Alam, Shamsul; Mohanty, Sanjib; Hasan, Mohammad Rashedul; Hossain, Amir; Charunwatthana, Prakaykaew; Chotivanich, Kesinee; Maude, Richard J.; Kingston, Hugh; Day, Nicholas P. J.; Mishra, Saroj K.; White, Nicholas J.; Dondorp, Arjen M.

doi:10.1093/infdis/jis400

Cited by 67 publications

(73 citation statements)

References 31 publications

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“…8 Recent studies have shown that liberal fluid resuscitation does not improve acid-base balance and renal function in severe falciparum malaria, whereas inappropriate fluid replacement may exacerbate pulmonary edema. 10,11 Of importance, acute renal injury in severe falciparum malaria seems to result from pathological processes associated with parasitized erythrocytes sequestered in microcirculation. Although it is unknown whether macrovascular fluid depletion or microvascular sequestration of parasitized erythrocytes primarily contribute to acute renal injury in knowlesi malaria, artesunate treatment but not fluid resuscitation lead to rapid recovery of renal function in severe falciparum malaria.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is unknown whether macrovascular fluid depletion or microvascular sequestration of parasitized erythrocytes primarily contribute to acute renal injury in knowlesi malaria, artesunate treatment but not fluid resuscitation lead to rapid recovery of renal function in severe falciparum malaria. 10,11 Meanwhile, jaundice seems to be a common feature observed in renal failure in severe malaria and mainly stems from acute hemolysis that could further compromise renal function. 8,12,13 Despite the rarity of overt liver failure in malaria, transient disturbance of hepatic function is not uncommon.…”

Section: Discussionmentioning

confidence: 99%

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An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

Nakaviroj¹,

Kobasa²,

Teeranaipong³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract.A 58-year-old Thai man was infected with Plasmodium knowlesi in Chantaburi Province, eastern Thailand. In addition to pyrexia, the patient developed hypotension, renal failure, jaundice, and severe thrombocytopenia. The parasitemia at the time of admission was 16.67% or~503,400 parasites/μL. With artesunate treatment and supportive care, the patient recovered uneventfully. The occurrence of complicated knowlesi malaria in a low-endemic area underscores the risk of high morbidity from this simian malaria.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

Nakaviroj¹,

Kobasa²,

Teeranaipong³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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“…The blockage of small diameter vasculature may be directly observed in vivo in the retinal veins of children with CM, and in the mucous membranes of adults with CM [15,20]. Although there have been no studies directly observing cerebral blood vessels during life, post-mortem samples show high levels of sequestration in brain vasculature [12].…”

Section: Pathogenesismentioning

confidence: 99%

Pediatric Cerebral Malaria: A Scourge of Africa

et al. 2012

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Cerebral malaria, defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia, affects up to 1 million people per year, the vast majority of them being children living in sub-Saharan Africa. Despite optimal treatment, this condition kills 15% of those affected and leaves 30% of survivors with neurologic sequelae. The clinical diagnosis is hampered by its poor specificity, but the presence or absence of a malarial retinopathy in cerebral malaria has proven to be important in the differentiation of underlying coma etiology. Both antimalarials and intense supportive care are necessary for optimal treatment. As of yet, clinical trials of adjunctive therapies have not improved the high rates of mortality and morbidity. Survivors are at high risk of neurologic sequelae including epilepsy, neurodisabilities and cognitive–behavioral problems. The neuroanatomic and functional bases of these sequelae are being elucidated. Although adjunctive therapy trials continue, the best hope for African children may lie in disease prevention. Strategies include bednets, chemoprophylaxis and vaccine development.

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“…parasites that infect humans. Its ability to cytoadhere and sequester itself in the microvasculature can result in obstruction of blood flow and organ dysfunction, and these are key processes in the development of severe falciparum malaria (1).…”

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confidence: 99%

Infectivity of Plasmodium falciparum in Malaria-Naive Individuals Is Related to Knob Expression and Cytoadherence of the Parasite

et al. 2016

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j Plasmodium falciparum is the most virulent human malaria parasite because of its ability to cytoadhere in the microvasculature. Nonhuman primate studies demonstrated relationships among knob expression, cytoadherence, and infectivity. This has not been examined in humans. Cultured clinical-grade P. falciparum parasites (NF54, 7G8, and 3D7B) and ex vivo-derived cell banks were characterized. Knob and knob-associated histidine-rich protein expression, CD36 adhesion, and antibody recognition of parasitized erythrocytes (PEs) were evaluated. Parasites from the cell banks were administered to malaria-naive human volunteers to explore infectivity. For the NF54 and 3D7B cell banks, blood was collected from the study participants for in vitro characterization. All parasites were infective in vivo. However, infectivity of NF54 was dramatically reduced. In vitro characterization revealed that unlike other cell bank parasites, NF54 PEs lacked knobs and did not cytoadhere. Recognition of NF54 PEs by immune sera was observed, suggesting P. falciparum erythrocyte membrane protein 1 expression. Subsequent recovery of knob expression and CD36-mediated adhesion were observed in PEs derived from participants infected with NF54. Knobless cell bank parasites have a dramatic reduction in infectivity and the ability to adhere to CD36. Subsequent infection of malaria-naive volunteers restored knob expression and CD36-mediated cytoadherence, thereby showing that the human environment can modulate virulence. P lasmodium falciparum is the most virulent of the six Plasmodium sp. parasites that infect humans. Its ability to cytoadhere and sequester itself in the microvasculature can result in obstruction of blood flow and organ dysfunction, and these are key processes in the development of severe falciparum malaria (1).Parasite cytoadherence and sequestration are facilitated by parasite-encoded knoblike structures that first appear on early trophozoite-stage parasites and are formed beneath the plasma membrane of parasitized erythrocytes (PEs) (2). Cytoadherence to receptors in the deep vasculature prevents removal and destruction of the parasite by the mononuclear phagocytic system, especially the spleen. Higher knob densities have been reported on PEs collected directly from patients than on cultured PEs infected in vitro (3). Following in vitro cultivation of P. falciparum, knob formation on PEs varies in an isolate-dependent manner (3-5), ranging from a mild reduction in density to complete ablation. The major structural protein in knobs is the knob-associated histidinerich protein (KAHRP) (2, 6, 7). Deletion of the gene encoding KAHRP results in the loss of knobs (8, 9).P. falciparum isolates can lose the ability to adhere to tissue receptors in vitro (10). Loss of adherence is isolate dependent and can occur independently of whether the knob phenotype is retained (10). Cytoadherence involves an interaction between parasite ligands and tissue receptors, including CD36, on the vascular endothelium (11, 12). The principal parasite adh...

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Relative Contributions of Macrovascular and Microvascular Dysfunction to Disease Severity in Falciparum Malaria

Abstract: Vital organ dysfunction in severe malaria results primarily from sequestration of parasitized erythrocytes in the microvasculature rather than reduction in circulating blood volume and oxygen delivery.

Cited by 67 publications

References 31 publications

An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

Pediatric Cerebral Malaria: A Scourge of Africa

Infectivity of Plasmodium falciparum in Malaria-Naive Individuals Is Related to Knob Expression and Cytoadherence of the Parasite

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