Approval was taken from the ethical committee of the institute to conduct this study.

This was a descriptive, cross-sectional study, in which the discharge records of the children admitted at a tertiary care hospital in New Delhi (India) during May 2011 to October 2011, were examined retrospectively. All the acutely sick children admitted in the paediatric ward with a febrile illness of a duration of < 7 days and confirmed as P.vivax malaria by testing the peripheral smears and/or by rapid malaria antigen testing, were included in the study. However, all the children who were admitted with a febrile illness but were negative for the malaria test or those who were positive for P.Falciparum or a mixed infection and those who had other associated infections like enteric fever, urinary tract infections or proven meningitis/ encephalitis, were excluded from the study. The children from the out patients department with a positive malaria diagnosis were also excluded from the study. The case definition of severe malaria was made according to the WHO criteria.

The test results of P.vivax malaria for the study period of 6 months was collected from the haematology and the parasitology departments of the hospital. Accordingly, the case sheets and the discharge summary of these cases were collected from the Medical Records Department (MRD) by matching with the age and sex as per the laboratory results. The case sheets and the discharge summary sheets were examined in detail, to identify the clinical manifestations and the laboratory findings of these cases which were recorded on them.

The confirmation of malaria in these cases was done by using the RDT kit and/ or by testing the peripheral smears, which showed the trophozoites/ schizonts/ gametocytes stages of P.vivax.

The line list of these identified cases was prepared and it was entered into an MS Excel sheet. The data was validated for its completeness and correctness by randomly checking the case sheets, the line list with the data which was entered in Excel and also the time of the data compilation. The data was summarised by calculating the rates, ratios, proportions, means, standard deviations and the 95% confidence intervals. The Chi square test was applied to assess the significant difference between two qualitative variables.

In the year 2011, the total number of positive cases of malaria at all ages was 456 (inpatients and outpatients) at our study centre, among which, the positive cases were 261 (57.2%), the P. falciparum cases were 192 (42.1%) and 3 cases were of a mixed infection. The case sheet screening of 70 admitted sick children who were positive for malaria was done, out of which 16 were excluded due to the presence of other definitive diagnoses like enteric fever, meningitis, UTIs or an evidence of mixed infections. 54 children were included for a detailed study of the severe manifestations. A majority of the cases were from Delhi, 38 (70.4%) and 16 cases (29.6%) were from the neighbouring states of Haryana, Uttar Pradesh and Bihar. Most of the cases, 22 (40.7%) were under the age of 5 years , while 21 (38.9%) cases were between the ages of 6 to 10 years and 11 (20.4%) children were above the age of 10 years [Table/Fig-1]. The mean age was 6.7 + 4.1 years with a 95% confidence interval of 5.6–7.8 years. Among the total cases, 33 were boys (61.1%) and 21 were girls (38.9%) [Table/Fig-1].

All the cases presented with fever as the chief complaint, with a median duration of two days and the duration ranged from 1–3 days prior to their admissions. Hepatomegaly was present in 44 (81.5%) cases, with a mean size of 3.27±1.8 cm below costal margin (which ranged between 1 to 10 cm), while splenomegaly was present in 39 (72.2%) cases, with a mean size of 3.27 + 1.8 cm (which ranged between 1 to 9 cm). Among the study cases,the most common atypical presentations which were seen were severe thrombocytopaenia (platelet count < 20,000/ cumm) in 20 (37.0%) cases and jaundice with deranged liver functions in 14 (25.9%) cases. The other atypical presentations were abnormal bleeding in 10(18.5%) cases, impaired consciousness (GCS < 9) in 10 (18.5%) cases and severe anaemia in 8 (14.8%) cases. 6 (11.1%) children presented with hypotension, 4 (7.6%) with repeated convulsions, 3 (5.6%) with pulmonary oedema/ARDS and 3 (5.6%) with ascites. One case each showed haemoglobinuria, and pleural effusion [Table/Fig-2].

Thrombocytopaenia was the commonest unusual presentation in all the age groups. The other unusual manifestations were distributed similarly across all the age groups and the difference was not statistically significant [Table/Fig-3]. The pattern of the unusual presentations of P.vivax malaria in children was similar in both girls and boys, except that the proportion of girls (33.3%) with impaired consciousness was significantly (p < 0.05) more than that among boys (9.1%) [Table/fig-4].

There were similar patterns of presentation amongst the P.vivax malaria cases from Delhi and outside Delhi and the difference was not statistically significant [Table/Fig-5]. Among the 54 patients, all showed positivity when they were tested with the rapid malaria diagnostic kit for P.vivax . Positive peripheral smears which showed various stages of the parasite were present in approximately 40% (22) of the cases. The parasite load was available in 24% (13) of the children, which ranged from 200/μl to 41000/μl, with the highest counts being seen in the children who had multiple complications.

In the year 2011, the total number of positive cases of malaria in all ages were 456 (inpatients and outpatients) at our institute, among which the P.vivax positive cases were 261(57.2%), the P.falciparum cases were 192 (42.1%) and 3 cases were of a mixed infection. In India, the percentage of falciparum cases showed a rise from 38% in 1995 to 52% cases in [4], but the situation in different parts of the country vary and there are more number of P.vivax cases in the north-western areas like Delhi and the nearby areas as compared to the P.falciparum cases. Out of the four species, P.vivax and P. falciparum are responsible for most of the cases of malaria and the latter is responsible for the maximum number of cases of severe malaria and thereby, the increased mortality. The P.Vivax infection is considered as benign, without much consequences, but there are case reports which have emerged from around the world, which force us to notice the changing pattern in the severity of the P.vivax infection. The clinical profiles of 54 P.vivax positive children were studied, to look for the manifestations which are not usually seen in the cases of . Only scarce literature is available on the P.vivax infection which presents as severe complicated malaria, less so in the paediatric age group. A recent study which was done in Bikaner [12], India, a north-western area which is in proximity to our study centre, had a higher proportion of children 63.1% (65/103) who had P.vivax severe malaria than the children who had P.falciparum malaria 42.7% (79/185).

In the East Asian region, in the largest prospective study which was conducted in Papua, New Guinea and in Indonesia by Genton et al, over a period of 8 years (1997-2004), out of 9537 cases of all age groups with confirmed malaria, 6.2% had severe manifestations, most of them being children who were < 5 years. Among these, the proportion of the children with P.falciparum severe malaria was 11.7% and the proportion of severe malaria cases which were caused by P.vivax was 8.8%, which concluded that there was an increased number of children with P.vivax severe malaria [13].

In our study, the most common manifestation was thrombocytopaenia, which was reported in 90.2% of the cases and in about 37.0% children, severe thrombocytopaenia (<20,000/cumm) was present, with the lowest platelet count of 6000/cumm, which was probably the lowest count which was recorded among children in the literature [14–18]. There have been occasional reports of thrombocytopaenia with P.vivax malaria, either as an isolated or a more commonly associated complication [14–18]. Both a non-immunological destruction [19] as well as the immune mechanisms which involve the specific platelet-associated IgG antibodies that bind directly to the malarial antigen in the platelets, have been recently reported to play a role in the lysis of the platelets and in the development of thrombocytopaenia [20]. The elevated M-CSF (macrophage colony stimulating factor) levels in which are seen in malaria, on increasing the macrophage activity, may mediate platelet destruction in some cases [21]. An oxidative stress damage of the thrombocytes has also been implicated in the aetio-pathogenesis, based on the finding of low levels of platelet superoxide-dismutase and glutathione-peroxidase and the high platelet lipid peroxidation levels in malaria patients [22]. A clinically apparent, abnormal bleeding was seen in 18.5% (10) cases in the form of malena, haemetemesis, epistaxis, haematuria, petechiae and purpurae.

Icterus with deranged liver functions was present in 25.9% cases in our study, which was similar to the finding of a retrospective study which included all the age groups, which was done by Sharma and Khanduri, who reported deranged liver functions in 27% of the cases [23]. There were 18.5% (10) children who presented with impaired consciousness, with a GCS of ≤9. Out of 10 cases lumbar puncture was done in 80% (8) cases and it was found to be normal in all cases, except one case, which showed pleocytosis of 12 cells with 70% lymphocytes and protein levels of 50 mg/dl. This suggested a probable diffuse encephalopathy in all cases, except one, which showed an encephalitis like picture. Thapa et al., reported 2 cases of P.vivax cerebral malaria in 12 year old children at Calcutta, India [24]. Parakh et al., reported 6 children who were aged 1.5-11 years, who presented with severe P.vivax malaria. Among them, 3 had presented with cerebral malaria (), 2 with severe anaemia and 2 with abnormal KFT [25]. The altered sensorium in P.vivax malaria has been postulated to occur due to the occult mixed plasmodium infections, the metabolic changes, the reversible local microvascular dysfunction, endothelial activation and injury, and the microvascularthrombo-inflammatory responses. Besides these factors, age, the geographical profile, social factors and the genetics of the host play important roles in the pathogenesis of severe P.vivax malaria.

Severe anaemia was reported in 14.8% (8) cases, which may be due to recurrent bouts of haemolysis and dyserythropoiesis [26]. Besides, in vivax malaria, more number of non-infected RBCs are cleared from the circulation as compared to those in in falciparum malaria [27, 28]. The exact mechanism is not clear, but it has been postulated to be caused by the host immune mechanisms and the oxidative damage [29].

7.6% (4) cases had repeated convulsions. Hypoglycaemia was ruled out in all the cases as the cause of the seizures or the altered sensorium. Ozen et al., reported a case of P.vivax malaria which presented as status epilepticus [30]. Hypotension was observed in 11.1% (6) of the cases. None of the patients presented with ARF or multiorgan failure. Kaur and Gulati reported a case of P.vivax malaria which presented with fever, rash, a progressive deterioration of the renal function and uraemic encephalopathy [31].

Few patients (5.6%) presented with ARDS/ pulmonary oedema. The ARDS in vivax malaria probably results from the cytokine-related increases in the alveolar permeability and from the altered alveolar fluid clearance [32].

The exact pathophysiology of severe P.vivax malaria is not clear till date. The inflammatory response which occurs during the P.vivax infection is greater than that which is seen in the P. falciparum infection, with a similar or a greater parasite load [33]. The cytokine production which occurs during the infection is higher than that which is seen in the P. falciparum infection [34]. We could not draw comparisons between the proportions of se vere malaria and P.vivax malaria, as only the sick vivax malaria cases were studied. Moreover, ours was a retrospective, record based study, which nevertheless highlighted the occurrence of the severe manifestations in P.vivax malaria.

Plasmodium vivax is emerging as an important cause of severe /complicated malaria and it should no longer be considered entirely benign. There is a need to further study and clarify the pathophysiology, virulence factors and the molecular mechanisms which are involved in P.vivax malaria.