Complications in P. vivax Malaria

</em>Although P. vivax malaria is considered to be a benign malaria, it has been increasingly reported to cause various manifestations of severe disease, including thrombocytopaenia, cerebral malaria, and acute renal, hepatic and pulmonary dysfunctions, with some reports of deaths. With increasing reports of drug resistance, this indeed is a cause for concern. The underlying mechanisms of severe manifestations are not well understood. Prompt and effective treatment and case management should be the same as for severe and complicated falciparum malaria.

Baird et al point out that classifications of malaria in 1880s described only clinical malaria and that severity was not correlated with any particular species. They also point out that an autopsy report of P. vivax death was documented as early as 1901 and that patients of neurosyphilis, treated with P. vivax, had a mortality of >20%, and deaths occurred in areas where P. vivax was endemic.[1]

A systematic review and meta-analysis of clinical studies in severe vivax malaria since 1900 included a total of 77 studies with reported severe vivax malaria and 63 studies with no reported severe vivax malaria (totaling 46,411 and 6,753 vivax malaria patients, respectively). The 77 studies with reported severe vivax malaria were mainly from India (n = 33), USA (n = 8), Indonesia (n = 6), and Pakistan (n = 6). Vivax endemic countries not reporting severe vivax malaria beyond individual case reports included: the Greater Mekong Sub-region, China, North Korea, Bangladesh, Afghanistan, Middle East (except Qatar), the horn of Africa, and Madagascar. Only 17/77 reports were from before 2000. Vivax mono-infection was confirmed by PCR in 14 studies and co-morbidities were ruled out in 23 studies. Among the 77 studies reporting severe vivax malaria, severe thrombocytopenia (<50,000/mm3) was the most common “severe” manifestation (888/45,775 with pooled prevalence of 8.6%). The case fatality was 0.3% (353/46,411). Among the studies with and without reported severe vivax malaria patients, the pooled prevalence of the  most commonly reported severity signs were: severe thrombocytopenia (4.7%), severe anaemia (2%), hepatic dysfunction (2%), metabolic acidosis (0.5%), renal dysfunction (0.5%) and cerebral malaria (0.3%). Pooled mortality was 0.1%. Among 77 studies with reported severe vivax malaria patients, 43 reported hepatic dysfunction, 42 cerebral malaria, 37 deaths, 34 severe anaemia, 27 severe thrombocytopenia, 27 respiratory dysfunction, 24 abnormal bleeding/DIC, 20 renal dysfunction, 14 hypoglycaemia, 11 generalized seizures, 11 circulatory collapse/shock, 10 haemoglobinuria, and eight studies reported metabolic acidosis. Among these studies, the pooled prevalence of the five most commonly reported severity signs were: severe thrombocytopenia (8.6%), shock (5.1%), hepatic dysfunction (4.2%), severe anaemia (4%), and hypoglycaemia (1.8%) and pooled mortality was (0.3%). The report concluded that there has been a marked increase in reported cases of severe vivax in certain geographical regions of the P. vivax endemic world, which cannot be explained with the current understanding of the disease and warrants further study into its aetiology.[3]

Another systematic review and meta-analysis of high quality studies also found similar results. Eight studies (n = 27490) compared the incidence of SM between P. vivax infection and P. falciparum mono-infection; a comparable incidence was found in infants (OR: 0.45, 95% CI:0.04–5.68, I 2:98%), under 5 year age group (OR: 2.06, 95% CI: 0.83–5.1, I 2:83%), the 5–15 year-age group (OR: 0.6, 95% CI: 0.31–1.16, I 2:81%) and adults (OR: 0.83, 95% CI: 0.67–1.03, I 2:25%). Six studies reported the incidences of SA in P. vivax infection and P. falciparum mono-infection; a comparable incidence of SA was found among infants (OR: 3.47, 95%:0.64–18.94, I 2: 92%), the 5–15 year-age group (OR:0.71, 95% CI: 0.06–8.57, I 2:82%). This was significantly lower in adults (OR:0.75, 95% CI: 0.62–0.92, I 2:0%). Five studies (n = 71079) compared the mortality rate between vivax malaria and falciparum malaria. A lower rate of mortality was found in infants with vivax malaria (OR:0.61, 95% CI:0.5–0.76, I 2:0%), while this was comparable in the 5–15 year- age group (OR: 0.43, 95% CI:0.06–2.91, I 2:84%) and the children of unspecified-age group (OR: 0.77, 95% CI:0.59–1.01, I 2:0%).[4]

Several other reports of P. vivax malaria causing complications and deaths are now available. [5-25]

Limaye et al reported on 680 cases of which 23.8% had severe malaria and of these, one-thirds had P. vivax, P. falciparum and mixed infections respectively.[5] Sarkar D et al studied 900 cases of P. vivax and 22.2% (200) had severe disease, and 20% of these died (40/200).[6] Of the 922 cases studeid by Saravu K et al, 16.9% of P. vivax and 36.3% of P. falciparum had severe malaria; mortality in vivax and falciparum malaria was 0.34% and 2.21%; and parasite index was predictor of severe disease only in P. falciparum infections.[7] Zubairi AB et al reported on 139 with severe malaria, 80% of whom had P. vivax infection.[8]

The pathogenesis of complications of malaria is blamed on parasite biomass, ‘malaria toxin(s)’ and inflammatory response, cytoadherence and related resetting and sequestration, altered deformability and fragility of parasitized erythrocytes, endothelial activation, dysfunction and injury and altered thrombostasis.[2,26]

The parasite biomass is far greater in P. falciparum than P. vivax malaria; while P. falciparum invades RBCs of all ages, progressing to high parasite burden, P. vivax has a preference for infecting young RBCs, and therefore with a limited reproductive capacity, parasitemia in vivax malaria rarely exceed 2% of circulating RBCs and high parasite burden is not a feature of P. vivax infection. [2,26]

P. vivax evokes a greater inflammatory response than P. falciparum, but the underlying mechanism(s) is not yet clear. P. vivax has a lower pyrogenic threshold, inducing fever at lower levels of parasitemia, and evokes a greater inflammatory response than that seen in P. falciparum infections with a similar or greater parasite biomass. Cytokine production during P. vivax infections is also higher than that in P. falciparum infections of similar parasite biomass. It is not known whether there are structural differences in the P. vivax GPI that make it more pyrogenic and whether greater concentrations of TLR9-stimulating motifs within P. vivax hemozoin account for greater pyrogenicity.[2] A cholesterol/triglyceride(s) containing lipid, proposed as a putative malaria toxin unique to P. vivax, has greater activity than GPI-like phospholipids and might also contribute to the pyrogenicity of P. vivax.[27]

Whereas P. falciparum-infected red cells adhere to capillary and postcapillary venular endothelium in the deep microvasculature (cytoadherence) and also to uninfected erythrocytes (rosetting), resulting in the sequestration of parasites in various organs, such phenomenon are not common in P. vivax infections. Although some studies have indicated that P. vivax-infected RBCs cytoadhere in vitro to chondroitin sulfate A and that P. vivax-infected RBCs might accumulate in the lung, the cytoadherence and/or sequestration of P. vivax-infected RBCs are less widespread and of lesser magnitude than that with P. falciparum. Rosetting and aggregation of leukocytes have also been reported in vivax malaria but their roles in pathophysiology are unknown.[2]

In contrast to P. falciparum, in which deformability of both infected and non-infected RBCs is impaired and red cells become rigid, the deformability as well as fragility of vivax-infected RBCs is increased. Increased deformability of P. vivax-infected RBCs makes sequestration and obstruction to blood flow unlikely, and might enable P. vivax to avoid destruction during passage through the splenic sinusoids. But the accompanying increase in fragility of both infected and non-infected RBCs may contribute to severe anemia in P. vivax malaria.[2,28]

Comparison between P. falciparum and P. vivax malaria
Problem P. falciparum P. vivax
Parasite Biomass ++++ +
Inflammation, cytokine response ++ ++++
Cytoadherence ++++ ?
Sequestration ++++ ?
Rosetting ++++ +
Red cell deformability Decreased deformability, rigid Increased deformability, fragile

Clinical Manifestations:

The clinical symptoms of fever, headache, nausea and vomiting in P. vivax may be incapacitating, particularly for those who are non-immune and suffering the infection for the first time.

CNS manifestations: Changes in behaviour, altered sensorium, seizures, cerebral malaria, cerebellar manifestations and ataxia, hemiparesis,  aphasia, psychosis, acute inflammatory demyelinating polyneuropathy and post-malaria neurologic syndrome causing bilateral facial paralysis have all been reported in P. vivax malaria and some of these cases have had multiorgan involvement.

Hepatic dysfunction: Hepatomegaly and non-specific hepatitis, with or without jaundice can occur in vivax malaria. Fever, jaundice, tender hepatomegaly, mild elevation in the levels of hepatic enzymes and bilirubin are observed. Liver biopsy in such cases has demonstrated brown malarial pigments in Kupffer’s cells, small to moderate sized granulomatous lesions with mononuclear infiltration and hepatocyte necrosis.

Liver function returns to normal shortly after antimalarial treatment.

Thrombocytopenia: Decrease in platelet counts can occur in vivax malaria, however, it is usually mild and bleeding does not occur.

Severe anemia: P. vivax can cause severe anemia, particularly when it is chronic and recurrent. Very rarely this can be life threatening or even fatal.

Rupture of spleen: Malaria is an important cause for spontaneous rupture of spleen. It is more common in vivax malaria than falciparum malaria and tends to occur in up to 0.7% of the patients.

Rupture occurs in acute, rapid, hyperplastic enlargement of spleen. It is rare in chronic malaria, despite massive enlargement. Rapid enlargement results in increased capsular tension and increased parenchymal friability.  Marked splenomegaly can occur even in low-grade parasitemia (50/ml) and it may persist for weeks or months after effective and complete treatment.

Patients present with abdominal pain, fever, tachycardia, prostration and rapidly developing anemia and hypotension. Some of these manifestations are seen in malaria itself and therefore splenic rupture can be easily missed. A degree of suspicion is required to differentiate the two conditions. Leukocytosis, severe anemia and hypotension are more in favour of splenic rupture. Ultra sound evaluation of abdomen and paracentesis of the abdomen can confirm the diagnosis.

Treatment includes replacement of fluid and blood, laparotomy and splenectomy.

Splenic rupture carries a high mortality of about 80% and this is partly attributed to lack of awareness and missed diagnosis.


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 © ©BS Kakkilaya | Last Updated: Oct 13, 2018

One Comment:

  1. Interesting study. If it weren’t for the association with malraia endemicity apparently attested in Africa and Europe, the pure gene evolution would point to a migration out of America (ancestral state) through East Asia to Europe and Africa (derived state). India is a bridge between the east and the West and a “swing” continent. Africa still preserves the original state in some pockets such as Madagascar, Horn of Africa and northwest Africa but overall it has shifted away from the original condition. But even with the malraia association in Africa and Europe this scenario would work.The map of Hbs distribution reminds me of Y-DNA YAP+ distribution, with Africa being heavy on YAP+ but with pockets of YAP-, Europe intermediary and Asia showing a strange small pocket of YAP+. India has Hbs, Tibetans and Andaman islanders have high frequencies of YAP+. America is devoid of YAP+ completely. There’s a parallelism here, I think.

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