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Cytokine Arguments Missed in Understanding Severe Vivax Malaria

Posted by plosmedicine on 31 Mar 2009 at 00:27 GMT

Author: Ian Clark
Position: Professor, School of Biochemistry and Molecular Biology
Institution: Australian National University , Canberra
Additional Authors: Lisa M. Alleva
Submitted Date: July 03, 2008
Published Date: July 4, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

This commentary summarises the implications of the joint recognition, in two articles (Genton et al., Tjitra et al.) in the same number of the Journal, that vivax malaria in Papua New Guinea and West Papua is a much more severe disease than previously realised, approaching, and in some aspects surpassing, falciparum malaria. Of particular interest, the Venn diagrams in each article illustrate the novel finding that fatal illness associated with neurological changes is essentially as prevalent in vivax as in falciparum malaria. Previously this pathology was very much associated the latter illness.

These data provide an ideal opportunity to gain insight into the neurological disease caused by both Plasmodium vivax and Plasmodium falciparum. Unfortunately, this is largely missed in this commentary. Only an undefined systemic metabolic change, as well as cerebral vascular obstruction by sequestered infected erythrocytes (Tjitra et al.) are offered as mechanisms. A primary role for inflammatory cytokines is not countenanced, yet levels of these mediators have been known for many years to be increased in both vivax and falciparum malaria, and particularly associated with neurological changes [1-3], as well as in other diseases in which lung damage and anaemia coexist with neurological changes [4]. There is a considerable literature on mechanisms based on inflammatory cytokines, particularly those downstream from tumour necrosis factor (TNF), in many of these diseases, including malaria, for the anaemia [5] and respiratory distress syndrome [6] described in these two articles.

The recent description of TNF as necessary for normal synaptic activity [7] is consistent with a telling case report documenting the clinical picture of falciparum malaria in a non-immune adult chronically receiving Infliximab, a neutralising anti-TNF antibody [8]. It would have been useful if this approach had been discussed in either of the articles or the commentary. Rare reports of limited sequestration in vivax infections, now evoked to explain fatality, remained unremarked while the accepted pattern provided a tidy rationale for the respective benign or malignant natures of vivax and falciparum malaria. A primary role for vascular obstruction is increasingly questioned even in falciparum, where it is undoubtedly common, though not necessarily primary [9, 10].

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2. Wijesekera SK, Carter R, Rathnayaka L, Mendis KN (1996) A malaria parasite toxin associated with Plasmodium vivax paroxysms. Clin Exp Immunol 104: 221-227.
3. John CC, Panoskaltsis Mortari A, Opoka RO, Park GS et al. (2008) Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg 78: 198-205.
4. Clark IA, Alleva LE, Mills AC, Cowden WB (2004) Pathogenesis in malaria and clinically similar conditions. Clin Microbiol Rev 17: 509-539.
5. Scharte M, Fink MP (2003) Red blood cell physiology in critical illness. Crit Care Med 31: S651-S657.
6. Imai Y, Kuba K, Neely GG, Yaghubian Malhami R et al. (2008) Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133: 235-249.
7. Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440: 1054-1059.
8. Geraghty EM, Ristow B, Gordon SM, Aronowitz P (2007) Overwhelming parasitemia with Plasmodium falciparum infection in a patient receiving infliximab therapy for rheumatoid arthritis. Clin Infect Dis 44: e82-84.
9. Marsh K, Snow RW (1997) Host-parasite interaction and morbidity in malaria endemic areas. Philosoph Trans R Soc Lond 352: 1385-1394.
10. Clark IA, Alleva LM, Budd AC, Cowden WB (2008) Understanding the role of inflammatory cytokines in malaria and related diseases. Travel Medicine and Infectious Disease 6: 67-81.

No competing interests declared.