Review
Pathogenesis of malaria-associated acute respiratory distress syndrome

https://doi.org/10.1016/j.pt.2013.04.006Get rights and content

Highlights

  • Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a common and often lethal complication of malaria in adults.

  • New mouse models of MA-ARDS are useful to investigate the pathogenesis and therapy.

  • Inflammation with mononuclear infiltrates is prominent in human and mouse MA-ARDS.

  • Anti-inflammatory treatments are successful in mice but remain to be validated in patients.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an increasingly reported, often lethal, and incompletely understood complication of malaria. We discuss and compare the pathogenesis of MA-ARDS in patients and in different murine models, including recent models without cerebral involvement, and summarize the roles of different leukocyte subclasses, adhesion molecules, cytokines, and chemokines. In patients as well as in mice, severe edema and impaired gas exchange are associated with abundant inflammatory infiltrates consisting of mainly mononuclear cells and parasite sequestration, and the pathogenesis appears different from cerebral malaria (CM). Experimental anti-inflammatory interventions are successful in mice and remain to be validated in patients.

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

References (97)

  • N.H. Hunt et al.

    Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria

    Trends Immunol.

    (2003)
  • K. Srivastava

    Platelet factor 4 mediates inflammation in experimental cerebral malaria

    Cell Host Microbe

    (2008)
  • P.F. Piguet

    Role of the tumor necrosis factor receptor 2 (TNFR2) in cerebral malaria in mice

    Lab. Invest.

    (2002)
  • M. Fauconnier

    Protein kinase C-theta is required for development of experimental cerebral malaria

    Am. J. Pathol.

    (2011)
  • D. Togbe

    Murine cerebral malaria development is independent of Toll-like receptor signaling

    Am. J. Pathol.

    (2007)
  • N. Lacerda-Queiroz

    Platelet-activating factor receptor is essential for the development of experimental cerebral malaria

    Am. J. Pathol.

    (2012)
  • I.A. Clark

    TNF and Plasmodium berghei ANKA-induced cerebral malaria

    Immunol. Lett.

    (1990)
  • R. Lucas

    Respective role of TNF receptors in the development of experimental cerebral malaria

    J. Neuroimmunol.

    (1997)
  • N. Favre

    Role of ICAM-1 (CD54) in the development of murine cerebral malaria

    Microbes Infect.

    (1999)
  • B.R. Moore

    Plasmodium berghei: parasite clearance after treatment with dihydroartemisinin in an asplenic murine malaria model

    Exp. Parasitol.

    (2008)
  • W.R. Taylor

    Pulmonary manifestations of malaria: recognition and management

    Treat. Respir. Med.

    (2006)
  • A. Mohan

    Acute lung injury and acute respiratory distress syndrome in malaria

    J. Vector Borne Dis.

    (2008)
  • K.C. Nayak

    A study on pulmonary manifestations in patients with malaria from northwestern India (Bikaner)

    J. Vector Borne Dis.

    (2011)
  • K. Marsh

    Indicators of life-threatening malaria in African children

    N. Engl. J. Med.

    (1995)
  • M. English

    Deep breathing in children with severe malaria: indicator of metabolic acidosis and poor outcome

    Am. J. Trop. Med. Hyg.

    (1996)
  • M.A. Matthay et al.

    The acute respiratory distress syndrome: pathogenesis and treatment

    Annu. Rev. Pathol.

    (2011)
  • G.P. Maguire

    Lung injury in uncomplicated and severe falciparum malaria: a longitudinal study in Papua, Indonesia

    J. Infect. Dis.

    (2005)
  • C. Daneshvar

    Clinical and laboratory features of human Plasmodium knowlesi infection

    Clin. Infect. Dis.

    (2009)
  • T. William

    Severe Plasmodium knowlesi malaria in a tertiary care hospital, Sabah, Malaysia

    Emerg. Infect. Dis.

    (2011)
  • J.P. Hanson

    Fluid resuscitation of adults with severe falciparum malaria: effects on acid-base status, renal function, and extravascular lung water

    Crit. Care Med.

    (2013)
  • N. Valecha

    Histopathology of fatal respiratory distress caused by Plasmodium vivax malaria

    Am. J. Trop. Med. Hyg.

    (2009)
  • M.I. Duarte

    Ultrastructure of the lung in falciparum malaria

    Am. J. Trop. Med. Hyg.

    (1985)
  • G.G. MacPherson

    Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration

    Am. J. Pathol.

    (1985)
  • S. Punyagupta

    Acute pulmonary insufficiency in falciparum malaria: summary of 12 cases with evidence of disseminated intravascular coagulation

    Am. J. Trop. Med. Hyg.

    (1974)
  • J.G. Deaton

    Fatal pulmonary edema as a complication of acute falciparum malaria

    Am. J. Trop. Med. Hyg.

    (1970)
  • R.M. Feldman et al.

    Noncardiogenic pulmonary edema and pulmonary fibrosis in falciparum malaria

    Rev. Infect. Dis.

    (1987)
  • R. Kaushik

    Plasmodium vivax malaria complicated by acute kidney injury: experience at a referral hospital in Uttarakhand, India

    Trans. R. Soc. Trop. Med. Hyg.

    (2013)
  • N.M. Anstey

    Lung injury in vivax malaria: pathophysiological evidence for pulmonary vascular sequestration and posttreatment alveolar–capillary inflammation

    J. Infect. Dis.

    (2007)
  • P.A. Buffet

    Retention of erythrocytes in the spleen: a double-edged process in human malaria

    Curr. Opin. Hematol.

    (2009)
  • S. Handayani

    High deformability of Plasmodium vivax-infected red blood cells under microfluidic conditions

    J. Infect. Dis.

    (2009)
  • B.O. Carvalho

    On the cytoadhesion of Plasmodium vivax-infected erythrocytes

    J. Infect. Dis.

    (2010)
  • K. Chotivanich

    Plasmodium vivax adherence to placental glycosaminoglycans

    PLoS ONE

    (2012)
  • J. Cox-Singh

    Severe malaria – a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report

    Malar. J.

    (2010)
  • L. Schofield et al.

    Immunological processes in malaria pathogenesis

    Nat. Rev. Immunol.

    (2005)
  • A.G. Craig

    The role of animal models for research on severe malaria

    PLoS Pathog.

    (2012)
  • P.E. Van den Steen

    Immunopathology and dexamethasone therapy in a new model for malaria-associated acute respiratory distress syndrome

    Am. J. Respir. Crit. Care Med.

    (2010)
  • S. Epiphanio

    VEGF promotes malaria-associated acute lung injury in mice

    PLoS Pathog.

    (2010)
  • I.A. Clark

    Possible roles of tumor necrosis factor in the pathology of malaria

    Am. J. Pathol.

    (1987)
  • Cited by (73)

    • 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, Heliyon
      Citation 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 Immunopharmacology
      Citation 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 Toxicology
      Citation 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 Parasitology
      Citation 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].

    View all citing articles on Scopus
    *

    Current address: Cytokine Receptor Lab, Department of Medical Protein Research, Vlaams Instituut voor Biotechnologie, Ghent University, Albert Baertsoenkaai 3, 9000 Ghent, Belgium.

    View full text