Dhanpat Kumar Kochar

Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite

Plasmodium vivax is geographically the most widely distributed cause of malaria in people, with up to 2.5 billion people at risk and an estimated 80 million to 300 million clinical cases every year--including severe disease and death. Despite this large burden of disease, P vivax is overlooked and left in the shadow of the enormous problem caused by Plasmodium falciparum in sub-Saharan Africa. The technological advances enabling the sequencing of the P vivax genome and a recent call for worldwide malaria eradication have together placed new emphasis on the importance of addressing P vivax as a major public health problem. However, because of this parasites biology, it is especially difficult to interrupt the transmission of P vivax, and experts agree that the available methods for preventing and treating infections with P vivax are inadequate. It is thus imperative that the development of new methods and strategies become a priority. Advancing the development of such methods needs renewed emphasis on understanding the biology, pathogenesis, and epidemiology of P vivax. This Review critically examines what is known about P vivax, focusing on identifying the crucial gaps that create obstacles to the elimination of this parasite in human populations.

An unexpected cause of fever and seizures

In June, 2007, a 27-year-old man was brought to our emergency department by ambulance, having regained consciousness after a generalised tonic-clonic seizure. He had been having fever, chills, and rigors, on alternate days, for the previous 8 days. He had no past history of convulsions, head injury, febrile convulsions during infancy, birth trauma, meningitis, encephalitis, or psychiatric illness. There was no other past medical history of note. Until he fell ill, he had been working in a jewellery shop in Surat, Gujarat—a city where both falciparum and vivax malaria are endemic. On examination, nothing abnormal was found. The patient’s full blood count was normal; biochemistry tests, including a blood glucose measurement, also gave unremarkable results. Electrocardiography, ophthalmoscopy, examination of the cerebrospinal fl uid, and CT of the head all showed nothing of note. However, examination of the blood fi lm showed trophozoites of Plasmodium vivax, at a density of 16 200 per μL (fi gure). A rapid diagnostic test (FalciVax, Zephyr Biomedical Systems, Goa, India) indicated the presence of parasite lactate dehydrogenase, specifi c to P vivax, and the absence of histidine-rich protein 2, specifi c to P falciparum. 6 h after he arrived, the patient had another generalised seizure. He was immediately given intravenous quinine, as per the WHO guidelines for severe vivax malaria; in addition, anticonvulsant drugs were given. Over the next 12 h, the patient had a total of eight generalised seizures, with intervals of 30–120 min, without regaining full consciousness. 48 h after treatment began, the fever subsided, and the patient became fully conscious. Further blood tests—for dengue fever, leptospirosis, and HIV—gave negative results; repeat CT of the head, and electroencephalography, showed nothing remarkable. PCR, which was done as described by Kochar and colleagues, confi rmed that the patient had been infected by P vivax, but not P falciparum. The patient was discharged 8 days after his arrival. When last seen, in August, 2007, he was entirely well. P falciparum is known to cause cerebral malaria, which can manifest with seizures. The parasite multiplies in red blood cells, which adhere to the walls of small blood vessels, causing reduced cerebral blood fl ow. P vivax is less likely than P falciparum to cause severe illness— indeed, the typical 48 h interval between fevers, and benign course, have led to vivax malaria being termed “benign tertian malaria”. Classically, P vivax has not been thought to cause cerebral malaria. However, it is now known that severe P vivax infection can cause cerebral malaria—although, to our knowledge, this is the fi rst case in which the cause of seizures has been confi rmed as P vivax alone. How P vivax causes cerebral malaria is unclear, but recent studies indicate that the mechanism may be similar to that triggered by P falciparum. Other causes of seizures in malaria include hypoglycaemia, hyponatraemia, lactic acidosis—and other illnesses, such as epilepsy.

Characterization of Plasmodium vivax-associated admissions to reference hospitals in Brazil and India

BackgroundThe benign character formerly attributed to Plasmodium vivax infection has been dismantled by the increasing number of reports of severe disease associated with infection with this parasite, prompting the need for more thorough and comprehensive characterization of the spectrum of resulting clinical complications. Endemic areas exhibit wide variations regarding severe disease frequency. This study, conducted simultaneously in Brazil and India, constitutes, to our knowledge, the first multisite study focused on clinical characterization of P. vivax severe disease.MethodsPatients admitted with P. vivax mono-infection at reference centers in Manaus (Amazon - Brazil) and Bikaner (Rajasthan - India), where P. vivax predominates, were submitted to standard thorough clinical and laboratory evaluations in order to characterize clinical manifestations and identify concurrent co-morbidities.ResultsIn total, 778 patients (88.0% above 12xa0years old) were hospitalized at clinical discretion with PCR-confirmed P. vivax mono-infection (316 in Manaus and 462 in Bikaner), of which 197 (25.3%) presented at least one severity criterion as defined by the World Health Organization (2010). Hyperlactatemia, respiratory distress, hypoglycemia, and disseminated intravascular coagulation were more frequent in Manaus. Noteworthy, pregnancy status was associated as a risk factor for severe disease (ORu2009=u20092.03; 95% CIu2009=u20091.2-3.4; Pu2009=u20090.007). The overall case fatality rate was 0.3/1,000 cases in Manaus and 6.1/1,000 cases in Bikaner, with all deaths occurring among patients fulfilling at least one severity criterion. Within this subgroup, case fatality rates increased respectively to 7.5% in Manaus and 4.4% in Bikaner.ConclusionP. vivax-associated severity is not negligible, and although lethality observed for complicated cases was similar, the overall fatality rate was about 20-fold higher in India compared to Brazil, highlighting the variability observed in different settings. Our observations highlight that pregnant women and patients with co-morbidities need special attention when infected by this parasite due to higher risk of complications.

Burden and impact of Plasmodium vivax in pregnancy: A multi-centre prospective observational study

Background Despite that over 90 million pregnancies are at risk of Plasmodium vivax infection annually, little is known about the epidemiology and impact of the infection in pregnancy. Methodology and principal findings We undertook a health facility-based prospective observational study in pregnant women from Guatemala (GT), Colombia (CO), Brazil (BR), India (IN) and Papua New Guinea PNG). Malaria and anemia were determined during pregnancy and fetal outcomes assessed at delivery. A total of 9388 women were enrolled at antennal care (ANC), of whom 53% (4957) were followed until delivery. Prevalence of P. vivax monoinfection in maternal blood at delivery was 0.4% (20/4461) by microscopy [GT 0.1%, CO 0.5%, BR 0.1%, IN 0.2%, PNG 1.2%] and 7% (104/1488) by PCR. P. falciparum monoinfection was found in 0.5% (22/4463) of women by microscopy [GT 0%, CO 0.5%, BR 0%, IN 0%, PNG 2%]. P. vivax infection was observed in 0.4% (14/3725) of placentas examined by microscopy and in 3.7% (19/508) by PCR. P. vivax in newborn blood was detected in 0.02% (1/4302) of samples examined by microscopy [in cord blood; 0.05% (2/4040) by microscopy, and 2.6% (13/497) by PCR]. Clinical P. vivax infection was associated with increased risk of maternal anemia (Odds Ratio-OR, 5.48, [95% CI 1.83–16.41]; p = 0.009), while submicroscopic vivax infection was not associated with increased risk of moderate-severe anemia (Hb<8g/dL) (OR, 1.16, [95% CI 0.52–2.59]; p = 0.717), or low birth weight (<2500g) (OR, 0.52, [95% CI, 0.23–1.16]; p = 0.110). Conclusions In this multicenter study, the prevalence of P. vivax infection in pregnancy by microscopy was overall low across all endemic study sites; however, molecular methods revealed a significant number of submicroscopic infections. Clinical vivax infection in pregnancy was associated with maternal anemia, which may be deleterious for infant’s health. These results may help to guide maternal health programs in settings where vivax malaria is endemic; they also highlight the need of addressing a vulnerable population such as pregnant women while embracing malaria elimination in endemic countries.