Pulmonary pathology in pediatric cerebral malaria

Abstract

Respiratory signs are common in African children where malaria is highly endemic and, thus, parsing the role of pulmonary pathology in illness is challenging. We examined the lungs of 100 children from an autopsy series in Blantyre, Malawi, in many of whom death was attributed to P falciparum malaria. Our aim was to describe the pathological manifestations of fatal malaria, to understand the role of parasites, pigment, and macrophages, and to catalogue co-morbidities. From available patients which included 55 patients with cerebral malaria and 45 controls, we obtained 4 cores of lung tissue for immunohistochemistry and morphological evaluation. We found that in patients with cerebral malaria, large numbers of malaria parasites were present in pulmonary alveolar capillaries, together with extensive deposits of malaria pigment (hemozoin). The number of pulmonary macrophages in this vascular bed did not differ between patients with cerebral malaria, non-cerebral malaria and non-malarial diagnoses. Co-morbidities found in some cerebral malaria patients included pneumonia, pulmonary edema, hemorrhage, and systemic activation of coagulation. We conclude that the respiratory distress seen in patients with cerebral malaria does not appear to be anatomic in origin but that increasing malaria pigment is strongly associated with cerebral malaria at autopsy.

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…30 In contrast to the findings in the brain, features consistent with acute lung injury are frequently found in the pulmonary microvasculature at autopsy of both adult and pediatric patients with severe falciparum malaria. [31][32][33] The findings include edema, microthrombi and leukocyte infiltration. The microvessels are densely packed with IRBC.…”

The immunological balance between host and parasite in malaria

“…Regardless of differences in the cell type causing the obstruction, obstruction with associated hypoxia is present, as witnessed by the heterogeneous pattern of neuronal and perivascular hypoxia that is found scattered throughout the brain and that is significantly higher in brains of mice with CM compared to non-CM brains (Hempel et al 2011). Both iRBCs and inflammatory cells are present in the pulmonary microvasculature of mice and patients with MA-ARDS or CM (Franke-Fayard et al 2005;Mohan, Sharma and Bollineni 2008;Valecha et al 2009;Fonager et al 2012;Lacerda et al 2012;Milner et al 2013). Also in placentas of mice and P. falciparum-infected patients, high numbers of iRBCs and leukocytes accumulate in the intervillous maternal space and adhere to CSA at the syncytiotrophoblast surface rather than directly to the microvascular endothelial lining (Fried and Duffy 1996;Andrews and Lanzer 2002;Neres et al 2008;Mens, Bojtor and Schallig 2010).…”

Multiple Organ Dysfunction During Severe Malaria: The Role of the Inflammatory Response

“…Although there are few examples of leukocyte adhesion in the brain vasculature in the development of human cerebral malaria [62], necropsy in fatal cases of severe malaria reveals marked inflammatory cell infiltration in lung tissue [11]. Endothelium/leukocyte interactions in the lung differ from their interactions in the brain, likely due to differences in the BBB and the blood-air barrier tight junction compositions of the brain and lung endothelium.…”

“…In fact, the pathology observed in the lung tissue differs between adults and children. In children, few cases of pneumonia are observed [11], while an intense inflammatory cell infiltration is frequently noted [11,82]. Milner and coworkers hypothesize that ARDS in children is an indirect effect of the inflammatory response induced by CM because non-specific lung dysfunction is observed.…”

“…Beyond the three species cited above, Plasmodium malariae and Plasmodium ovale also affect multiple organs in children and adults, however with different intensity ( Table 1). The multi-organ dysfunction observed during severe malaria is associated with a systemic inflammatory response triggered by, among other factors, leukocyte adhesion to organ microvasculature, parasitized erythrocytes and production of inflammatory mediators [11,12]. Despite the morphological and biochemical differences among Plasmodium species, the mechanisms by which severe malaria develops appear to be similar.…”