COMMENTARY

Benign Tertian Malaria: How Benign Is It Today?

Dinesh Yadav & Jagdish Chandra & Ashok Kumar Dutta

Received: 13 May 2011 /Accepted: 15 June 2011 /Published online: 25 June 2011# Dr. K C Chaudhuri Foundation 2011

Malaria is a disease of global importance and afflicts morethan 90 countries and territories in the tropical and subtropicalregions. Malaria imposes great socio-economic burden onhumanity, and with six other diseases (diarrhea, HIV/AIDS,tuberculosis, measles, hepatitis B, and pneumonia), accountsfor 85% of global infectious disease burden. TheWorld HealthOrganization (WHO) estimates 3.3 billion people at risk,247 million malaria cases and one million estimatedannual malarial mortality worldwide [1]. Approximately2.48 million cases are reported annually from South-eastAsia, of which 75% cases are contributed by India alone.WHO has reported malaria mortality rate 15000 per yearfrom India; however, a recent study by million deathcollaborators suggest much higher annual malarial mor-tality in India (205,000 overall and 55000 in children<14 years age) [2].

Among cases with malaria, proportion of Plasmodiumvivax (Pv) and P. falciparum (Pf) varies in different parts ofIndia with 10–30% cases caused by Pf and remaining 70–90% by Pv in most parts of the country. A continued rise in Pfhas been reported recently and its proportion has graduallyrisen to nearly 50% of total cases in recent years [3].

Traditionally, infection with Pf is considered responsiblefor severe malaria and malarial mortality in literature. Verylittle information is available on the contribution of Pv to

severe disease. As the term “benign tertian malaria”implies, Pv malaria has usually enjoyed the status ofuncomplicated disease that runs a benign course and israrely fatal. Earlier studies from Thailand and Vanuatu inlast decade suggested a protective effect of Pv andsuggested that Pv co-infection with Pf may attenuateseverity of Pf malaria [4, 5]. However, there is growingevidence that Pv is responsible for a significant burden ofdisease worldwide. Recent studies from Papua NewGuinea, Indonesia and India have reported all complica-tions of severe malaria with Pv monoinfections as well [6–8]. These studies have shown that 21–27% of patients withsevere malaria have Pv monoinfection and clinical spec-trum of these cases is broad with an overall mortality of0.8–1.6% [9]. A study from Bikaner, in northwest India hasreported a much higher proportion (63.1%) of severemalaria contributed by Pv mono-infection in children. Inthis study, the proportion of severe malaria attributable to P.vivax was 67.4% in children <5 years of age compared with30.4% of P. falciparum and 2.2% (1/46) of mixed infection.Besides this, proportion of patients having severe manifes-tations, including severe anemia, thrombocytopenia, cerebralmalaria, acute respiratory distress syndrome (ARDS), hepaticdysfunction, renal dysfunction and abnormal bleeding wasalso significantly higher in association with Pv monoinfec-tion in 0–5 year age group. Also, Pv monoinfection wasreported almost equally serious to cause significant mortalityin comparison to Pf (case fatality rate of severe Pv was 3.9%versus 3.2% of severe Pf; P=1.0) [7]. This study furtherreaffirms the emergence of severe vivax malaria.

Complications in severe malaria are either sequestrationrelated, such as cerebral malaria, renal dysfunction, hepaticdysfunction and ARDS, or non-sequestration related, suchas anemia and thrombocytopenia [10]. Sequestration relatedcomplications were earlier reported in Pf infection only;however, clinical data provided by Kochar, et al. indicatesthat Pv infection can cause both sequestration related and

D. Yadav : J. Chandra :A. K. DuttaDepartment of Pediatrics, Lady Hardinge Medical Collegeand associated Kalawati Saran Children’s Hospital,New Delhi, India

J. Chandra (*)Lecturer’s Flat no 5, Lady Hardinge Medical College Campus,New Delhi 110001, Indiae-mail: jchandra55@gmail.com

Indian J Pediatr (April 2012) 79(4):525–527DOI 10.1007/s12098-011-0514-x

non-sequestration related complications of severe malaria[7]. The essential pathological feature of severe vivaxmalaria is sequestration of erythrocytes containing matureparasites in the deep vascular bed (cerebral malaria, renal,hepatic involvement, ARDS). P. vivax-related coma is alsoconsidered to be of systemic metabolic origin, but the exactpathological mechanism is still unknown [11]. The pre-sumed pathogenesis of cerebral malaria involves adherenceof parasitized red blood cells (particularly schizont-infectederythrocytes) to the cerebral vascular endothelium, leadingultimately to the impeding of cerebral blood flow. In somecases, other factors (e.g., agglutination of parasitizederythrocytes, fibrin microthrombi, altered rheologic proper-ties of the parasitized red cells, and vascular endothelialchanges) may also contribute to the microvascular obstruc-tion. New evidence also suggests that at molecular level,localized and generalized ischemic hypoxia may enhancecytokine-induced nitric oxide synthetase, resulting indetrimental nitric oxide generation [12]. Besides this, otherfactors such as convulsions, acidosis and hypoglycaemiamay also impair the consciousness.

ARDS has more commonly been reported in Pvcompared with Pf cases, as they have more severealveolar-capillary dysfunction. Sequestration of Pv infectederythrocytes in pulmonary microvasculature and greaterinflammatory response to a given parasite burden in Pv isprobably responsible for this alveolar-capillary dysfunction.Small airway obstruction, gas exchange alteration, in-creased phagocytic activity and accumulation of pulmonarymonocytes are the other suggested mechanisms for respi-ratory complications [13].

Liver abnormalities are relatively common finding insevere Pf malaria. However, significant liver functionderangements have recently been reported in Pv monoinfection as well. Besides hemolysis, cholestasis andhepatocellular injury also significantly contribute to thesepatients with “Malaria hepatitis” in Pv malaria and many ofthese patients present with various grades of hepaticencephalopathy [7].

Acute renal failure also occurs more frequently infalciparum malaria. However, ARF due to Pv monoinfec-tion was reported in 20.4% cases with Malarial ARF in arecent study from Varanasi in UP. The endothelial cytoad-herence, sequestration, increased whole blood viscosity andcapillary lumen obstruction by sticky cell aggregates togethercontributes to renal ischemia and acute renal failure. Variousnon-specific effects of infection like hemolysis, disseminatedintravascular coagulation, jaundice and hypovolemia mayalso contribute to ARF. The associated endothelial activationleads to the release of several vasoactive cytokines andmediators which leads to decreased systemic vascularresistance and eventual reduction in renal blood flow andconsequent renal ischemia [14].

Severe anemia, DIC and thrombocytopenia are consideredto be non-sequestration-related complications with multifac-torial etiology, e.g. hemolysis, reduced cell deformity oferythrocytes, decreased platelet survival and increased splenicuptake [11]. Profound thrombocytopenia is a well-recognizedcomplication of Pf malaria but has been less well describedin Pv malaria. A recent study from Venezuela, reportedthrombocytopenia in 58.9% cases with Pv malaria, with25.6% requiring platelet transfusions [15]. Another pediatriccase series from Bikaner, northeast India reported thrombo-cytopenia in 61.5% children with severe Pv monoinfectionand bleeding symptoms in 10.8% cases [7]. The mechanismof thrombocytopenia in malaria is not clearly known.Fajardo and Tallent demonstrated Pv within platelets byelectron microscopy and suggested a direct lytic effect of theparasite on the platelets [16]. Both non-immunologicaldestruction as well as immune mechanisms involvingspecific platelet-associated IgG antibodies that bind directlyto the malarial antigen in the platelets has been reported.These antibodies play a role in the lysis of platelets and thedevelopment of subsequent thrombocytopenia [17, 18].Oxidative stress damage of thrombocytes has also beenimplicated in the etiopathogenesis based on the finding oflow levels of platelet superoxide-dismutase and glutathione-peroxidase activity and high platelet lipid peroxidation levelsin malaria patients, when compared to those of healthysubjects [19].

Severe Pv malaria is thus an emerging entity, and thelongstanding belief that Pv is a non sequestering parasitemight need to be revisited. All the complications seen withfalciparum malaria are now reported with vivax as well.Further clinical studies and molecular research is requiredto understand emergence of severe manifestations in vivaxmono-infection.

References

1. World malaria report 2008. Geneva, Switzerland: World HealthOrganization; 2008. pp. 9–15.

2. Dhingra N, Jha P, Sharma VP, et al. Adult and child malariamortality in India: a nationally representative mortality survey.Lancet. 2010;376:1768–74.

3. Kumar A, Valecha N, Jain T, Dash AP. Burden of malaria in India:retrospective and prospective view. Am J Trop Med Hyg.2007;77:69–78.

4. Luxemburger C, Ricci F, Nosten F, et al. The epidemiology ofsevere malaria in an area of low transmission in Thailand. Trans RSoc Trop Med Hyg. 1997;91:256–62.

5. Maitland K, Williams TN, Newbold CI. Pv and Pf: biologicalinteractions and the possibility of cross-species immunity. Para-sitol Today. 1997;13:227–31.

6. Genton B, D’Acremont V, Rare L, et al. Pv and mixedinfections are associated with severe malaria in children: aprospective cohort study from Papua New Guinea. PLos Med.2008;5:881–9.

526 Indian J Pediatr (April 2012) 79(4):525–527

7. Kochar DK, Tanwar GS, Khatri PC, et al. Clinical features ofchildren hospitalized with malaria—a study from Bikaner,northwest India. Am J Trop Med Hyg. 2010;83:981–9.

8. Tjitra E, Anstey NM, Sugiarto P, et al. Multidrug-resistant Pvmalaria associated with high morbidity and mortality. PLoS Med.2007;5:e128. doi:10.1371/journal.pmed.0050128.

9. Price RN, Douglas NM, Anstey NM. New developments in Pvmalaria: severe disease and chloroquine resistance. Curr OpinInfect Dis. 2009;22:430–5.

10. Kochar DK, Das A, Kochar SK, et al. Severe Pv Malaria: A reporton serial cases from Bikaner in northwestern India. Am J TropMed Hyg. 2009;80:194–8.

11. Parakh A, Agarwal N, Aggarwal A, et al. Pv malaria: uncommonmanifestations. Ann Trop Pediatr. 2009;29:253–6.

12. Beg MA, Khan R, Baig SM, et al. Cerebral involvement in benigntertian malaria. Am J Trop Med Hyg. 2002;67:230–2.

13. Anstey NM, Handojo T, Pain MC, et al. Lung injury in vivaxmalaria: pathophysiological evidence for pulmonary vascular

sequestration and posttreatment alveolar-capillary inflammation.J Infect Dis. 2007;195:589–96.

14. Prakash J, Singh AK, Kumar NS, Saxena RK. Acute renal failure inplasmodium vivax Malaria. J Assoc Phys India. 2003;51:265–7.

15. Rodríguez-Morales AJ, Sánchez E, Vargas M, et al. Anemia andthrombocytopenia in children with plasmodium vivax malaria. JTrop Pediatr. 2005;52:49–51.

16. Fajardo LF, Tallent C. Malarial parasites within human platelets.JAMA. 1974;229:1205–7.

17. Looaresuwan S, Davis JG, Allen DL, et al. Thrombocytopenia inmalaria. Southeast Asian J Trop Med Public Health. 1992;23:44–50.

18. Yamaguchi S, Kubota T, Yamagishi T, et al. Severe thrombocytopeniasuggesting immunological mechanism in two cases of vivax malaria.Am J Hematol. 1997;56:183–6.

19. Erel O, Vural H, Aksoy N, et al. Oxidative stress of platelets andthrombocytopenia in patients with vivax malaria. Clin Biochem.2001;34:341–4.

Indian J Pediatr (April 2012) 79(4):525–527 527