Trends in Parasitology
ReviewPathogenesis of malaria-associated acute respiratory distress syndrome
Section snippets
Definition and occurrence of MA-ARDS
Malaria is a major health problem, with >650 000 deaths and 200 million clinical cases each year (www.who.org). Whereas most malaria infections are mild, complications may arise suddenly and cause the majority of deaths. Common complications are cerebral pathology, severe malarial anemia, placental malaria, and renal problems, but respiratory distress is also increasingly recognized as a complication with a poor prognosis 1, 2, 3. Different types of respiratory distress may be present in malaria
Pathophysiology of MA-ARDS in patients
Pulmonary edema in MA-ALI/ARDS is protein-rich and has a non-cardiogenic origin, as indicated by normal pulmonary capillary wedge pressure, an indicator for the function of the left ventricle 2, 12, 13. Hypoalbuminemia is often present and may contribute to the impairment of the Starling equilibrium in the lungs 12, 14. Fluid overload is also a severely aggravating factor and may occur upon rehydration [15]. Nevertheless, MA-ALI/ARDS also occurs in the absence of fluid overload. The main
Parasite species specific differences in MA-ALI/ARDS
The five malaria parasite species able to infect humans have been reported as causes of MA-ALI/ARDS (see Table S1 in the supplementary material online). Although the pathophysiology of MA-ARDS appears similar with the different parasite species, some clear differences exist. In particular, MA-ARDS with Plasmodium falciparum or P. knowlesi is often combined with other complications, such as renal failure, cerebral malaria (CM), and acidosis, and therefore has a worse prognosis than with
Mouse models of MA-ALI or MA-ARDS
Mouse models are particularly useful for the study of disease mechanisms and for testing possible interventions and treatments. Different mouse models of malaria are available, for example, for the study of CM, anemia, and antiparasite immunity 31, 32. These models were only used to a limited extent to study the pathogenesis of MA-ALI/ARDS, but recently new models for MA-ALI/ARDS have been introduced 33, 34, 35. In this section, we discuss the available models for MA-ALI/ARDS. The principal
Parasite sequestration in murine MA-ALI/ARDS
The precise mechanisms and pathways leading to ALI/ARDS in malaria-infected mice are not yet entirely understood, although the roles of several molecules are emerging. In general, sequestration of infected erythrocytes on the endothelium is regarded as highly important in malaria pathology, and P. falciparum is able to sequester in the lungs [18]. As documented with luciferase-expressing transgenic parasites, P. berghei ANKA sequesters or accumulates significantly in lungs and in umbilical fat
Role of inflammation in MA-ALI/ARDS
Besides sequestration, other parasite factors may be important for MA-ALI/ARDS. In comparison, ARDS induced by bacterial sepsis does not require sequestration of bacteria and is the consequence of an overactivated immune system by bacterial cell wall components, resulting in septic shock 7, 50. Although it is clear that malaria parasites are far less proinflammatory than bacteria, Plasmodium parasites may proliferate to larger numbers in the circulation and also cause inflammatory pathology,
Interventions and treatments
Currently used treatments for MA-ARDS patients have been reviewed and consist mainly of a combination of antimalarial drugs with mechanical ventilation support because no further adjunctive therapy is currently available 1, 2, 3. A few adjunctive treatments for MA-ARDS have been tested in mouse models and are summarized in Table 4.
An early study in murine MA-ARDS indicated a possible beneficial effect of phenoxybenzamine, an α-blocker and vasodilator. This is in line with the edema-promoting
Concluding remarks
MA-ARDS is a severe complication with poor prognosis. Although precise epidemiological data are lacking, this pathology occurs in a substantial number of adult patients and with different parasite species. The pathogenesis is mainly inflammatory and appears distinct from CM and also from non-malarial ARDS, because mononuclear cells, rather than neutrophils, are involved. Novel mouse models for this complication of malaria have been developed, which are suited for the study of the pathogenesis
Acknowledgments
The authors are grateful to Professor Jo Van Damme and to Natacha Lays for their continuous support and help for our malaria research. This study was supported by the Geconcerteerde OnderzoeksActies (GOA 2012/017 and GOA 2013/014) of the Research Fund of the KU Leuven and by the Fund for Scientific Research (F.W.O.-Vlaanderen). P.V.D.S. is a Research Professor of the KU Leuven and J.D. is a research assistant of the ‘Agentschap voor Innovatie door Wetenschap en Technologie’ (IWT), Belgium.
Glossary
- Acute lung injury
- diffuse heterogeneous lung injury characterized by hypoxemia (PaO2/FiO2 < 300 mm Hg), non-cardiogenic pulmonary edema, low lung compliance, and widespread capillary leakage.
- Alveolar–capillary membrane
- separation between air and blood in the lungs, formed by type 1 pneumocytes of the alveolar wall, the endothelial cells of the capillaries, and the interstitium, with a basement membrane between the two cell types.
- Alveolar edema
- leakage of plasma fluid in the interstitial tissue and
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High mobility group box-1 (HMGB-1) and its receptors in the pathogenesis of malaria-associated acute lung injury/acute respiratory distress syndrome in a mouse model
2021, HeliyonCitation Excerpt :In this study, the histopathological findings in the lung tissues of malaria-infected mice in the ALI/ARDS group showed alveolar thickening with capillary congestion, alveolar fibrin, alveolar oedema, alveolar haemorrhage and leukocyte accumulation in the alveolar sac, similar to the results of previous studies [23, 24, 25]. The key pathogenesis of MA-ALI/ARDS is associated with sequestration of parasitized red blood cells on the endothelium and exacerbation of the haemozoin-mediated inflammatory response, leading to apoptosis of endothelial and epithelial cells and resulting in impaired gas exchange and severe hypoxemia [26, 27]. As expected, the findings of the present study demonstrated that plasma concentrations of TNF-α, IFN-γ, IL-1 and IL-6 were significantly increased in malaria-infected mice in the ALI/ARDS group compared with those in the non-ALI/ARDS and control groups, which is consistent with previous studies showing elevated levels of cytokines in patients with malaria infection [28, 29] and in a mouse model of MA-ALI/ARDS [30, 31].
Monocyte Locomotion Inhibitory Factor confers neuroprotection and prevents the development of murine cerebral malaria
2021, International ImmunopharmacologyCitation Excerpt :When complicated, the infection progresses to severe malaria. Anemia, respiratory distress and cerebral malaria (CM) are the primary manifestations of malaria-derived fatalities, and the vast majority of complicated infections are produced by P. falciparum [3,4]. Approximately 1% of all P. falciparum-infected patients develop CM; children below five years old and those without previously acquired immunity to infection are the most affected.
Long-term acrylamide exposure exacerbates brain and lung pathology in a mouse malaria model
2021, Food and Chemical ToxicologyCitation Excerpt :This indicates that ACR exposure is a risk factor for the development of meningitis in patients with malaria. The pathogenesis of ARDS, which is the major cause of malaria-related deaths during the progression of malaria infection, is not completely understood (Taylor et al., 2006; Van den Steen et al., 2013). To investigate the effect of long-term ACR exposure on the lung tissue of mice with malaria, the lung tissues of the uninfected, long-term ACR exposure, PbNK-infected long-term PBS exposure, and PbNK-infected long-term ACR exposure groups were subjected to histopathological analysis.
Hemozoin in Malarial Complications: More Questions Than Answers
2021, Trends in ParasitologyCitation Excerpt :Plasmodium infections may also lead to MA-ARDS, a lethal lung complication. This may occur with P. falciparum or Plasmodium vivax infection in adults, pregnant women, travelers, and residents of low-transmission areas [52]. MA-ARDS is also the main complication of Plasmodium knowlesi infection [52].
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Current address: Cytokine Receptor Lab, Department of Medical Protein Research, Vlaams Instituut voor Biotechnologie, Ghent University, Albert Baertsoenkaai 3, 9000 Ghent, Belgium.