Changing Trends in<i>P. falciparum</i>Burden, Immunity, and Disease in Pregnancy

Mayor, Alfredo; Bardají, Azucena; Macete, Eusébio; Nhampossa, Tacilta; Fonseca, Ana Maria; González, Raquel; Maculuve, Sónia; Cisteró, Pau; Rosario, Maria; Campo, Joe; Valá, Anifa; Sigaùque, Betuel; Jiménez, Alfons; Machevo, Sónia; Fuente, Laura de la; Nhama, Abel; Luís, Leopoldina; Aponte, John J.; Acácio, Sozinho; Nhacolo, Arsénio; Chitnis, Chetan E.; Dobaño, Carlota; Sevene, Esperanza; Alonso, Pedro L.; Menéndez, Clara

doi:10.1056/nejmoa1406459

Cited by 62 publications

(71 citation statements)

References 38 publications

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“…Indeed, a recent study conducted in Mozambique showed a close relationship between antibody levels and the intensity of malaria transmission. Mayor et al (2015) showed convincing evidence that a decline in the prevalence of malaria documented in the study area was accompanied by reductions in levels of IgG antibodies not only against VAR2CSA, but also against non-pregnancy-specific malaria antigens. In pregnant women with MiP, this was associated with an increase in parasite densities and a higher adverse effect of P. falciparum infection on maternal haemoglobin levels and newborn weights (Mayor et al, 2015).…”

Section: Pathologies Other Than Cm: Mipmentioning

confidence: 67%

“…Mayor et al (2015) showed convincing evidence that a decline in the prevalence of malaria documented in the study area was accompanied by reductions in levels of IgG antibodies not only against VAR2CSA, but also against non-pregnancy-specific malaria antigens. In pregnant women with MiP, this was associated with an increase in parasite densities and a higher adverse effect of P. falciparum infection on maternal haemoglobin levels and newborn weights (Mayor et al, 2015). Although they also suggest that immunity may be regained as exposure increases, the findings of this study indicate that malaria control and elimination programmes could precede a resurgence of pregnancy-associated malaria pathologies.…”

Section: Pathologies Other Than Cm: Mipmentioning

confidence: 67%

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Severe malaria: what’s new on the pathogenesis front?

Wassmer

Grau

2017

International Journal for Parasitology

111

102

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Plasmodium falciparum causes the most severe and fatal form of malaria in humans with over half a million deaths each year. Cerebral malaria (CM), a complex neurological syndrome of severe falciparum malaria, is often fatal and represents a major public health burden. Despite vigorous efforts, the pathophysiology of CM remains to be elucidated, thereby hindering the development of adjunctive therapies. In recent years, multidisciplinary and collaborative approaches have led to groundbreaking progress both in the laboratory and in the field. Here we review the latest breakthroughs in severe malaria pathogenesis, with a specific focus on new pathogenetic mechanisms leading to CM. The most recent findings point towards specific parasite phenotypes targeting brain microvasculature, endothelial dysfunction and subsequent oedema-induced brain swelling.

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Section: Pathologies Other Than Cm: Mipmentioning

confidence: 67%

Section: Pathologies Other Than Cm: Mipmentioning

confidence: 67%

Severe malaria: what’s new on the pathogenesis front?

Wassmer

Grau

2017

International Journal for Parasitology

111

102

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“…These observations illustrate that sustained reduction in exposure to malaria infection leads to changes in mean age and presentation of disease [65]. Moreover, increases in parasite density and in the susceptibility to severe disease have been observed in children [66,67] and pregnant women [68] residing in areas where malaria has declined substantially. Overall, these studies suggest that, in highly endemic areas, measures that led to reductions of parasite transmission, and thus immunity, may lead to a change in both the burden and the clinical spectrum of disease.…”

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confidence: 82%

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

Galatas

Bassat

Mayor

2016

Trends in Parasitology

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115

122

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With malaria elimination back on the international agenda, programs face the challenge of targeting all Plasmodium infections, not only symptomatic cases. As asymptomatic individuals are unlikely to seek treatment, they are missed by passive surveillance while remaining infectious to mosquitoes, thus acting as silent reservoirs of transmission. To estimate the risk of asymptomatic infections in various phases of malaria elimination, we need a deeper understanding of the underlying mechanisms favoring carriage over disease, which may involve both pathogen and host factors. Here we review our current knowledge on the determinants leading to Plasmodium falciparum symptomless infections. Understanding the host-pathogen interactions that are most likely to affect transitions between malaria disease states could guide the development of tools to tackle asymptomatic carriers in elimination settings. Being AsymptomaticPeaceful coexistence with the infected host, rarely causing clinical symptoms, is a common but poorly understood phenomenon that occurs for many human pathogens [1]. Because such asymptomatic cases of infection occur without eventual overt symptoms, they do not come to clinical attention, thus representing a large hidden reservoir of active infection that permits their persistence and eventual spread to other human hosts. This is the case for many malaria infections in semi-immune individuals from endemic areas, which commonly cause a mild febrile illness or no apparent symptoms at all, while keeping parasite numbers at low densities [2] (Box 1).Carriage of asymptomatic malaria (see Glossary) infections, being at the same time difficult to detect and to manage, has considerable implications for the design and use of malaria elimination strategies. Symptomless infections that persist during the dry season in areas of seasonal transmission have been suggested to seed the malaria outbreaks after annual rains when mosquitoes reappear [3]. Similarly, asymptomatic parasitemia may potentially contribute to persistence of transmission in low-transmission settings [4]. However, the precise contribution of asymptomatic malaria to transmission in areas that have achieved substantial reductions in the malaria burden remains a matter of debate [5], as is the assumption that detecting and targeting these individuals for radical treatment, as opposed to using mass drug administration approaches, would be an efficient and effective tactic. Moreover, eradication in Europe, North America, and other parts of the world using no better diagnostics than microscopy [6] suggest that key determinants of success might not be finding the last parasite. From a practical point of view, the proportion of asymptomatic infections in certain situations and phases of malaria elimination may impose the need for modifications of detection methods (active versus passive case detection) [7] if, for example, symptom-based surveillance at health facilities is insufficient and mass blood surveys are necessary to inform the design of elimination i...

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“…As the rest of the population, pregnant women living in areas of different malaria endemicity experience varying degrees of exposure to infection, which affects the acquisition of antimalarial immunity and determines the course of disease [1, 2]. Protective immunity to Plasmodium falciparum in pregnancy has been suggested to rely mostly on antibodies against VAR2CSA that block adhesion of infected erythrocytes to placental chondroitin sulphate A, and thereby prevent parasite sequestration in the placenta [3].…”

Section: Introductionmentioning

confidence: 99%

“…Here, we aimed to assess the variations in the clinical impact of P. falciparum infections and in host defences developed by pregnant women under different malaria transmission intensities. To achieve this, we compared the carriage of submicroscopic infections and antibodies against P. falciparum antigens as indicators of the level of parasitological immunity [1]. We assessed the correlation between health outcomes (haemoglobin levels and birthweight) and parasite densities at delivery for summarising tolerance [8], with a flat slope indicative of tolerance to infection.…”

Section: Introductionmentioning

confidence: 99%

Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities

Ndam

Mbuba

González

et al. 2017

BMC Med

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BackgroundResistance and tolerance to Plasmodium falciparum can determine the progression of malaria disease. However, quantitative evidence of tolerance is still limited. We investigated variations in the adverse impact of P. falciparum infections among African pregnant women under different intensities of malaria transmission.Methods P. falciparum at delivery was assessed by microscopy, quantitative PCR (qPCR) and placental histology in 946 HIV-uninfected and 768 HIV-infected pregnant women from Benin, Gabon, Kenya and Mozambique. Resistance was defined by the proportion of submicroscopic infections and the levels of anti-parasite antibodies quantified by Luminex, and tolerance by the relationship of pregnancy outcomes with parasite densities at delivery.Results P. falciparum prevalence by qPCR in peripheral and/or placental blood of HIV-uninfected Mozambican, Gabonese and Beninese women at delivery was 6% (21/340), 11% (28/257) and 41% (143/349), respectively. The proportion of peripheral submicroscopic infections was higher in Benin (83%) than in Mozambique (60%) and Gabon (55%; P = 0.033). Past or chronic placental P. falciparum infection was associated with an increased risk of preterm birth in Mozambican newborns (OR = 7.05, 95% CI 1.79 to 27.82). Microscopic infections were associated with reductions in haemoglobin levels at delivery among Mozambican women (–1.17 g/dL, 95% CI –2.09 to –0.24) as well as with larger drops in haemoglobin levels from recruitment to delivery in Mozambican (–1.66 g/dL, 95% CI –2.68 to –0.64) and Gabonese (–0.91 g/dL, 95% CI –1.79 to –0.02) women. Doubling qPCR-peripheral parasite densities in Mozambican women were associated with decreases in haemoglobin levels at delivery (–0.16 g/dL, 95% CI –0.29 to –0.02) and increases in the drop of haemoglobin levels (–0.29 g/dL, 95% CI –0.44 to –0.14). Beninese women had higher anti-parasite IgGs than Mozambican women (P < 0.001). No difference was found in the proportion of submicroscopic infections nor in the adverse impact of P. falciparum infections in HIV-infected women from Kenya (P. falciparum prevalence by qPCR: 9%, 32/351) and Mozambique (4%, 15/417).ConclusionsThe lowest levels of resistance and tolerance in pregnant women from areas of low malaria transmission were accompanied by the largest adverse impact of P. falciparum infections. Exposure-dependent mechanisms developed by pregnant women to resist the infection and minimise pathology can reduce malaria-related adverse outcomes. Distinguishing both types of defences is important to understand how reductions in transmission can affect malaria disease.Trial registrationClinicalTrials.gov NCT00811421. Registered 18 December 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0893-6) contains supplementary material, which is available to authorized users.

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Changing Trends inP. falciparumBurden, Immunity, and Disease in Pregnancy

Cited by 62 publications

References 38 publications

Severe malaria: what’s new on the pathogenesis front?

Severe malaria: what’s new on the pathogenesis front?

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities

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