Anaemia of acute malaria infections in non-immune 
patients primarily results from destruction of uninfected 
erythrocytes

Jakeman, G. N.; Saul, Allan; Hogarth, W. L.; Collins, William E.

doi:10.1017/s0031182099004564

Cited by 223 publications

(214 citation statements)

References 13 publications

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“…Although we do not explore any effects of immune responses here, we crudely mimicked these effects in simulations, and, as expected, the usual result was accelerated onset of catastrophic anemia (see supporting information). However, it should be clear that in their current form our models cannot resolve the debate about which factor is the major cause of sustained anemia in actual P. falciparum infections (3,18). Our results show that age-structured RBC susceptibility is an important, previously unappreciated determinant of malaria infection dynamics, to be considered in future work.…”

Section: Discussionmentioning

confidence: 88%

“…In some malaria patients a ''bystander'' effect may contribute to anemia: increased macrophage activity removes uninfected and infected RBCs, destroying perhaps 8.5 uninfected RBCs for each bursting infected RBC (18). Diserythropoesis may also contribute to anemia (17).…”

Section: Discussionmentioning

confidence: 99%

“…The particular mechanisms involved are still poorly understood (17), but one recent analysis reported an average 37% increase in RBC production in adult first-time P. falciparum patients (18). Here, we allow RBC production to match RBC depletion, up to a maximum of twice the basal rate (Eq.…”

Section: Compensatory Responses To Anemiamentioning

confidence: 99%

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Age-structured red blood cell susceptibility and the dynamics of malaria infections

McQueen

McKenzie

2004

Proc. Natl. Acad. Sci. U.S.A.

100

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Malaria parasites and immune responses in an infected human interact on a dynamic landscape, in which a population of replicating parasites depletes a population of replenishing red blood cells (RBCs). These underlying dynamics receive relatively little attention, but they offer unique insights into the processes that control most malaria infections. Here, we focus on the observation that three of the four malaria-parasite species that infect humans are restricted to particular age classes of RBC. We explicitly incorporate this observation in models of infection dynamics to distinguish common from species-specific pressures on host immune responses, and we find that age structuring has profound effects on the course of infection. For all four species conditions exist under which the parasites may persist at low densities, or may clear, even in the absence of an immune response. Catastrophic anemia can occur even with the two species that attack only the youngest RBCs, although only a small fraction of cells are parasitized at any point. Furthermore, with these two, compensatory erythropoetic responses in the host accelerate parasite population growth. A ''basic reproduction rate'' characterizes these differences in outcomes.M alaria in a human begins with an inoculum of Plasmodium parasites from an Anopheles mosquito. The parasites penetrate liver cells, multiply, then enter the bloodstream, and invade red blood cells (RBCs), where they again multiply and burst the cells, each releasing 8-32 ''merozoites'' that invade more RBCs and continue the cycle. Almost all malaria pathology is associated with this blood stage replication cycle; it leads to geometric growth in the parasite population and to fevers, anemia, and sometimes death in the host (1).Parasite population growth is usually constrained by host immune responses. Accordingly, most mathematical models of within-host dynamics have taken the general form of predatorprey models, with the predator a population of immune agents and the prey a population of Plasmodium (2). A few Plasmodium falciparum models attempt to relate the dynamics of the parasite population to those of its prey, the population of RBCs, but none incorporate RBC aging or age-structured susceptibility (3-7).RBC age appears to be a strong constraint on malaria parasites, however: susceptibility to Plasmodium vivax or Plasmodium ovale invasion is said to be restricted to the very youngest circulating age class of RBCs, the ''reticulocytes,'' and Plasmodium malariae invasion to the very oldest (8, 9). P. falciparum, the species responsible for almost all the 1-3 million deaths attributed to malaria each year, seems promiscuous with respect to its RBC targets (10). It is widely assumed that these age constraints explain why counts of parasitized RBCs rarely exceed 25,000 per l with P. vivax, P. ovale, or P. malariae, but may reach 500,000 and beyond with P. falciparum, and thus, in turn, why fatal anemia occurs only in P. falciparum infections (11).Most malaria infections are not fatal, but the...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Age-structured red blood cell susceptibility and the dynamics of malaria infections

McQueen

McKenzie

2004

Proc. Natl. Acad. Sci. U.S.A.

100

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“…Na malária por P. falciparum, ela teria decorrido do aumento exponencial da proporção de hemácias parasitadas 5 , acompanhado possivelmente da destruição aumentada de células não parasitadas por estresse oxidativo gerado, de forma aguda, em resposta ao parasita 26 . No segundo (P. malariae), ela teria sido resultado da cronicidade da infecção.…”

Section: Discussionunclassified

Diagnóstico tardio de malária em área endêmica de dengue na extra-Amazônia Brasileira: experiência recente de uma unidade sentinela no estado do Rio de Janeiro

Costa

Bressan

Pedro

et al. 2010

Rev. Soc. Bras. Med. Trop.

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INTRODUçãO RESUMOIntrodução: A letalidade da malária na região extra-amazônica é cerca de 80 vezes maior do que na Amazônia, que concentra 99,8% dos casos do país. Em áreas de transmissão de dengue, como o Rio de Janeiro, o atraso no diagnóstico e tratamento da malária dos pacientes com febre, provenientes de áreas endêmicas de malária, pode ser, entre outros fatores, devido à confusão entre o diagnóstico das duas doenças pelos generalistas da rede de assistência médica. Neste trabalho, apresentamos as consequências do atraso diagnóstico em três pacientes com malária por Plasmodium falciparum; P. malariae e P. vivax, que, após o périplo habitual para tratamento de dengue, procuraram a nossa instituição onde foram corretamente diagnosticados e submetidos aos tratamentos adequados. Métodos: Descrição de três casos de malária diagnosticada tardiamente e encaminhados ao IPEC/ FIOCRUZ, entre os anos de 2007 e 2008. Resultados: uma brasileira proveniente de Moçambique, primo-infectada por P. falciparum, com malária diagnosticada após 6 dias do início da febre, morreu com malária cerebral e choque. Outro paciente com malária por P. malariae teve um curso grave e prolongado, mas ficou curado após o tratamento específico. A terceira paciente diagnosticada tardiamente apresentou malária por P. vivax adquirida na região de Mata Atlântica no Estado do Rio. Conclusões: Os profissionais de saúde do Rio devem ser treinados para aperfeiçoar a vigilância e o tratamento oportuno da malária e evitar desfechos mórbidos e fatais. Sugere-se que uma investigação de focos de malária autóctone em áreas de mata no estado seja realizada. Palavras-chaves: Malária. Dengue. Diagnóstico diferencial. Vigilância. ABSTRACT Introduction:The mortality of malaria in the extra-Amazon region is about 80 times higher than in the Amazon region, where malaria is concentrated (99.8% of cases). In areas of dengue transmission, delay in the diagnosis and treatment of malaria in patients with fever who reside in areas of malaria transmission can be due to the confusion between the clinical diagnoses of both diseases by nonspecialist doctors, among other factors. This work presents some of the consequences of delayed diagnosis in three patients with malaria by Plasmodium falciparum, P. malariae and P. vivax, who, after following the usual route for Dengue treatment, sought our institution, where they were correctly diagnosed and adequately treated. Methods: Description of three cases of malaria with delayed diagnosed malaria referred to the Outpatient Clinic for Acute Febrile Diseases, IPEC/FIOCRUZ-RJ, between 2007 and 2008. Results: A Brazilian from Mozambique, primo-infected with P. falciparum was diagnosed with malaria six days after the onset of fever and died of cerebral malaria and shock. Another patient with P. malariae malaria presented a severe and prolonged course, but was cured after specific treatment. A third patient, with delayed diagnosis of P. vivax malaria, acquired it in the Atlantic Forest region in the State of Rio. Conclusions: Health pr...

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“…We also describe the dynamics of RBCs entirely as a consequence of loss following infection by merozoites. This suggests that the role of bystander destruction of uninfected RBCs ( Jakeman et al 1999;Haydon et al 2003) may need to be reconsidered, at least for the initial dynamics of P. chabaudi infections of mice.…”

Section: Discussionmentioning

confidence: 99%

The dynamics of acute malaria infections. I. Effect of the parasite's red blood cell preference

2008

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What determines the dynamics of parasite and anaemia during acute primary malaria infections? Why do some strains of malaria reach higher densities and cause greater anaemia than others? The conventional view is that the fastest replicating parasites reach the highest densities and cause the greatest loss of red blood cells (RBCs). Other current hypotheses suggest that the maximum parasite density is achieved by strains that either elicit the weakest immune responses or infect the youngest RBCs (reticulocytes). Yet another hypothesis is a simple resource limitation model where the peak parasite density and the maximum anaemia (percentage loss of RBCs) during the acute phase of infection equal the fraction of RBCs that the malaria parasite can infect. We discriminate between these hypotheses by developing a mathematical model of acute malaria infections and confronting it with experimental data from the rodent malaria parasite Plasmodium chabaudi. We show that the resource limitation model can explain the initial dynamics of infection of mice with different strains of this parasite. We further test the model by showing that without modification it closely reproduces the dynamics of competing strains in mixed infections of mice with these strains of P. chabaudi. Our results suggest that a simple resource limitation is capable of capturing the basic features of the dynamics of both parasite and RBC loss during acute malaria infections of mice with P. chabaudi, suggesting that it might be worth exploring if similar results might hold for other acute malaria infections, including those of humans.

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Anaemia of acute malaria infections in non-immune patients primarily results from destruction of uninfected erythrocytes

Cited by 223 publications

References 13 publications

Age-structured red blood cell susceptibility and the dynamics of malaria infections

Age-structured red blood cell susceptibility and the dynamics of malaria infections

Diagnóstico tardio de malária em área endêmica de dengue na extra-Amazônia Brasileira: experiência recente de uma unidade sentinela no estado do Rio de Janeiro

The dynamics of acute malaria infections. I. Effect of the parasite's red blood cell preference

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