Human malaria is caused primarily by 4 different species of Plasmodium namely; P. falciparum, P. vivax, P. malariae, and P. ovale. Of them P. vivax  (Pv) malaria is the second most common cause of malaria in the globe after P. falciparum (Pf) malaria (http://www.who.int/malaria/wmr2011/malaria2011). In South-East Asia region, India alone contributes 80% of malaria cases and in India malaria is contributed the most by Odisha state (World Health Organization, 2000). Both Pf and Pv are common in this part of India. Unlike falciparum malaria, severe forms of vivax malaria are uncommon, hence it is termed as “benign tertian” malaria. However, severe vivax malaria (SVM) has been described in Europe and China in the past, which was related to malnutrition and other concurrent disease (Warrell, 1993). There were few case reports of severe forms of vivax malaria till we made a prospective observational study on P. vivax malaria in 2002 from Odisha, Eastern India that showed about 11.2% of vivax malaria may present with complications like jaundice, anaemia, thrombocytopenia, pancytopenia, and cerebral malaria (Mohapatra et al., 2002). We also emphasized it as a warning signal and drug resistance may have a role. Within 10 years of speculation, SVM was found not only from India but also from other parts of the globe. From India it is mostly detected from North, North West, and Western part of India and outside India, it was reported from PNG, Indonesia, and Brazil (Kochar et al., 2009; Nadkar et al., 2012; Limaye et al., 2012; Genton et al., 2008; Tjitra et al., 2008; Andrade et al., 2010). In non-immune persons the symptoms may temporarily incapacitate the patients without any mortality. There were no deaths during an epidemic of vivax malaria in Sri Lanka in the year 1969 in which about half a million people affected (Warrell, 1993). However, recent reports from India and other parts of globe showed that vivax malaria not only manifest as severe form but also can cause death (Kochar et al., 2009; Nadkar et al., 2012; Limaye et al., 2012).

Further, the treatment of SVM is confusing. It has been recommended by WHO that SVM should be treated like severe falciparum malaria. Artesunate has been considered now as first line treatment for severe falciparum maIaria (World Health Organization, 2010). But there is no report regarding the efficacy of artesunate for treatment of SVM. Therefore, we have undertaken this research to study the clinical pattern, risk factors, outcome, and therapeutic efficacy of artesunate in SVM in a tertiary care centre. 

Results
Sub-study-1
During the sub-study-1 period 1188 diagnosed patients of malaria attended the hospital. Of them Pf, Pv, and mixed Pf & Pv malaria constituted 770 (64.8%), 300 (25.3%), and 118 (9.9%) respectively. Among them severe malaria was found in 541 (45.5%) cases, of which Pf, Pv, and mixed infection constituted 85.0% (n=460), 11.1% (n=60), and 3.9% (n=21) cases respectively. The number of severe malaria was significantly (p<0.001) more in Pf than Pv. Out of the patients of vivax malaria 20.0% (60 of 300) developed severe malaria. The observations of severe Pv malaria are presented in this study.

Among the 300 patients of Pv, there were 205 (68.3%) males and 95 (31.7%) females with a ratio of 2.6:1. Comparison of age distribution showed that the mean age of patients with severe malaria was 36.8±11.2 years compared to 28.5±8.5 years (p<0.001) of uncomplicated vivax malaria. Beyond the age of 40 years, SVM and UVM was found in 45.0% (n=27) and 29.2% (n=70) cases respectively (p<0.05) (Table 1). The clinical and baseline data were given in Table 2 and Table 3.
 

Table 1 Age and sex distribution

Table 2 Clinical presentation of severe and uncomplicated vivax malaria

Table 3 Base line characteristics of the study population

Irrespective of severity, fever was the most common clinical presentation of vivax malaria (Table 2). Intermittent fever with typical paroxysm was present in 277 (92.3%) cases whereas continuous fever was present in 23 (7.7%) cases. In addition to fever complaints like head ache, malaise, vomiting, abdominal pain were found in 196 (65.3%), 158 (52.6%), 152 (50.7%), 83 (27.6%) respectively.

Organ specific complaints were present in all 60 patients of SVM which is more than UVM (p<0.001). Out of 60 cases of SVM, 46 (76.7%) had single complication and 14 (23.3%) had multiple complications. 24 (40.0%) patients had jaundice of which 17 (70.8%) as single and 7 (29.2%) as multiple complications. Hematological abnormality (n=24, 40%) as single organ dysfunction was found in 20 (83.3%) and as component of multiple complication in 4 (16.6%) cases. Of them anaemia , thrombocytopenia, and peripheral pancytopenia was found in  24 (100.0%), 11 (45.8%), and  6 (25.0%) cases respectively. However, severe anaemia (Hb<6.0 gm/dl) was present in 8 (33.3%) cases. It is notable that in spite of thrombocytopenia bleeding manifestations are uncommon and found only in 1 (1.7%) case. Neurological involvement was found in 14 (23.3%) cases. Convulsion was present in 2 (3.3%) cases of SVM. Respiratory distress was found in 6 (10.0%) cases of which 2 (33.3%) with single and 4 (66.6%) as a part of multiple complications. One patient had ARDS during treatment. Renal failure was present in 7 (11.7%) cases and all were as a part of multiple complications. Renal failure alone as a single organ involvement was not found in this series (Table 4). The mean malaria severity score (MSS) of SVM was 6.7 ¡À 2.6.
 

Table 4 Types of severe vivax malaria (n=60)

The diagnosis of malaria was made from peripheral blood smear and Immuno chromatographic Test (ICT) test. Out of 300 cases of Pv malaria 270 (90.0%) were diagnosed from PBS and rest 30 (10.0%) were diagnosed by ICT test. The mean parasitic count was 4300.7 ¡À 180.5/μL in UVM and 8756.3 ¡À 256.3/μL in SVM. The mean gametocyte count was 155.5 ¡À 15.5/μL in UVM and 170.8 ¡À13.9/μL in SVM (Table 3).

The mean interval of onset of fever to hospitalization is 3.2 ¡À 1.3 and 6.8 ¡À 2.8 days in UVM and SVM respectively. Patients of UVM used to seek treatment approximately 2 times earlier than SVM (p<0.05). Inappropriate and inadequate antimalarial drug was given to 68.3% (41of 60) patients of SVM compared to 33.3% (80 of 240) of UVM (p<0.001). Low BMI (<20) was found in 42 (70.0%) cases of SVM compared to 80(33.3%) in UVM (p<0.001). Associated infection was found in 35 (70.0%) cases of SVM that included Urinary tract infection, URTI, Pneumonia, and Enteric fever in 18 (51.4%), 7 (20.0%), 6 (17.5%), and 4 (11.4%) cases respectively. Co-morbidity was found in 15 (25.0%) cases of SVM.

There were 7 independent risk factors for development of  SVM. They were 1) Low BMI<20.0  (OR=1.9[95%CI 1.2-3.1], p=0.002), 2) High parasite count >8 000/uL (OR=1.8 [95%CI=1.1-2.8], p=0.01), 3) Age more than 40 years (OR=4.4[95%CI=1.4-14.3], p=0.02), 4) Fever to treatment interval>4.0 days OR=3.2 [95%CI=2.4-7.3], p=0.002), 5) Bad treatment history OR=3.6 [95%CI=2.4-7.3], p=0.002), 6) Associated infection OR=4.2 [95%CI=3.4-7.3], p=0.002), 7) co-morbid condition OR=3.8 [95%CI=2.8-5.3], p=0.001. Single risk factor was present in 11 (18.3%) cases and multiple risk factors was present in rest 49 (81.7 %) cases. Two, 3, and 4 risk factors were present in 25 (41.6%), 15 (25.0%), and 9 (15.0%) cases respectively.

The occurrence of vivax malaria (both for SVM and UVM) was more frequent (63.3%, 190 of 300) in rainy season i.e. from June to September than dry season (26.7%, 110 of 300, p<0.01). During rainy season total number of SVM and UVM were 40 (66.6%) and 150 (62.5%) and in dry seasons it was 20 (33.3%) and 90 (37.5%) respectively (p<0.01).

Sub-study-2
During sub-study-2 period 60 patients of SVM were treated with inj. artesunate. Adequate clinical and parasitological response was found in 58 (96.6%) cases. Early treatment failure was not found. One patient (1.6%) developed ARDS during the treatment. Therefore, it is considered as late treatment failure. Late parasitological failure was found in 1 (1.6%) patient.

In addition to inj. Artesunate, appropriate antibiotic was administered according to culture and sensitivity and before the report, inj. Ceftriaxone 1 gm IV was started empirically in patients with evidence of infection. Dialysis was done in 2 (33.3%) patients. 2 (33.3%) patients of severe anaemia received packed cell transfusion and 1 (1.6%) patient of thrombocytopenia with bleeding received one unit of platelet transfusion. Patients with convulsion were treated with inj. Phenytoin sodium. Mefloquine was administered along with Inj. Artesunate as a component of ACT. We did not encounter any adverse drug reaction during the treatment.

With treatment, the fever resolution time and parasitic clearance time was 48.2±25.6 hours and 48.2± 25.6 hours respectively. The recovery time of different organ dysfunctions were given in Table 5.
 

Table 5 Recovery of severe vivax malaria

Discussion 
Unlike severe falciparum malaria, severe vivax malaria (SVM) in adults is a less described entity (Warrell, 1993; Mohapatra et al., 2002; World Health Organization, 2000). The present one revealed that non-parasitological risk factors are important for development of SVM and Artesunate is an effective antimalarial drug for its treatment with good outcome.

The present study showed that vivax malaria was found in 25.3% (n=300) of total patients of malaria and of them 20.0% (60 of 300) developed severe malaria. The incidence of severe malaria due to Pv (11.1%) is less than Pf malaria (85.0%, p<0.001). The incidence of severe Pv malaria is variable in different studies showing a geographical variation of SVM. From Mumbai, the hospital incidence of severe vivax malaria was 66.8% (488 of 711, whereas from another hospital from Mumbai the percentage of vivax malaria was only 14. 8%) (Nadkar et al., 2012; Limaye et al., 2012). But in Eastern India still falciparum malaria is predominant species causing SVM (Mohapatra et al., 2002; Mohaptra, 2006).  In Papua New Guinea (PNG) and Indonesia it is more found in paediatric population whereas in India adult population is affected (Genton et al., 2008; Tjitra et al., 2008).

Apart from geographic heterogeneity, seasonal variation also influences the prevalence of Pv malaria. In this study area vivax malaria in general and SVM in particular occurred more in wet season than dry season. This seasonal variation may be due to relative abundance of the species in a geographical area (Mohapatra et al., 2012). Thus the incidence of SVM has been influenced both by geographical heterogeneity and seasonal variation.

The clinical pictures of SVM were different from UVM. Fever was present in majority of cases with typical paroxysm. However, in SVM nonfebrile complaints like head ache, abdominal pain and organ specific complaints are more common than UVM. The organ specific complaints are more because of severe malaria.

In the present study severe malaria was found in Pv malaria but it is about 8 times less than Pf mono infection (11.1% vs 85.0%, p<0.001). Thus severe malaria was higher in Pf malaria than Pv malaria. However, in a study from rural PNG, Pv is responsible for 21% of all cases severe malaria where as Pf and mixed infection for 71% and 5% respectively (Genton et al., 2008). 

All forms of severe malaria like cerebral malaria, anaemia, renal failure, jaundice, multi organ failure had been encountered in adult patients with SVM. Affection of different systems is also encountered in paediatric population. The study from PNG showed that neurological manifestation, anaemia, respiratory distress was found in 2.0%, 1.6%, and 5.1% respectively (Anstey et al., 2009). The increased risk of severe malaria in children has been attributed to higher overall parasite burden.

There are some distinct differences between Pv and Pf malaria which are responsible for the benign nature of Pv malaria. Firstly, Pv can only invade young red blood cells i.e. reticulocytes. Hence the density of parasites is lower than Pf  that invades all stages of RBCs causing high density of parasites (Gilles and Warrell, 1996). Secondly, the pyrogenic threshold of Pv is 150~200 parasites/µL which is much lower than that of Pf (1 500~2 000 /µL). Therefore, patients with Pv infection develop fever earlier than Pf mono infection resulting in early medical attention and treatment reducing the chance of development of severe disease (Mohapatra et al., 2012). Thirdly, resistance to drugs particularly, chloroquine is not commonly found in vivax malaria (Mohapatra et al., 2002; Tjitra et al., 2008). Fourthly, P. vivax does not sequester within the microvasculature of different internal organs (Gilles and Warrell, 1996). Therefore, the mechanisms of organ development in vivax malaria are debatable.

 However, the later 3 factors seemed to alter recently. The delay in treatment due to inappropriate and inadequate drugs is a risk factor for development of severe disease. Thev drug resistance is also another important risk factor. Though chloroquine resistance has not been a problem for vivax malaria in India, in our earlier study we emphasized on the possibility of chloroquine resistance as a risk factor for SVM (Mohapatra et al., 2002). Multi drug resistance has been described as a factor for SVM in Indonesia (Tjitra et al., 2008). But recent studies showed that P. vivax infected erythrocytes may sequester within pulmonary microvasulature causing alveolar-capillary dysfunction (Anstey et al., 2009; Rogerson and Carter, 2008). Further P. vivax can induce enhanced inflammatory response. In all cases of ARDS with vivax malaria, the symptoms developed after antimalarial therapy raising the possibility of pulmonary inflammatory response to parasite killing. Thus the inflammatory and immunological response may play a significant role in pathophysiology of severe vivax malaria (Anstey et al., 2009).

The present study also showed that elderly age, low BMI, concurrent infections, high parasite count are also important risk factors for the development of severe disease. Majority patients of SVM belonged to 4th decade. Additionally, increased incidence of sever vivax malaria was found in paediatric population (Genton et al., 2008). Thus extremes of age are at risk of development of SVM (Mohapatra et al., 2002; Nadkar et al., 2012; Genton et al., 2008).

Associated infection is found to be a major risk factor of SVM. The common infections are urinary tract infection, upper respiratory tract infection, pneumonia, enteric fever. In addition to sequestration additional infection may play a role which was prevented by appropriate antibiotic therapy in our series. Therefore, in addition to parasitic killing, associated infection also has a major role to play for enhanced inflammatory response (Anstey et al., 2009). Associated disease may also contribute to the development of sever disease. Majority patients had diabetes mellitus, hypertension, and other metabolic abnormalities. As most patients are elderly, association of such non communicable disease are likely to present.
Low BMI is another risk factor for the development SVM. Severe vivax malaria had been described in the past in Europe, which was related to malnutrition and other associated diseases. Low BMI signifies under nutrition which may be responsible for sever disease. It may reduce the immunity increasing the chance of severity. Study from Brazil showed that patients of severe vivax malaria were younger, had short stay in the malaria endemic area, and less previous episodes of malaria signifying less immunity (Andrade et al., 2010).

Strain variation may play a role in severe disease. Cerebral vivax malaria has been reported occasionally particularly with long incubation period of  P. vivax multinucleatus in China (Warrell, 1993). In our series though we observed severe vivax malaria we could not able to identify the strain due to lack of facilities.

The present study showed that inj. artesunate is effective in the treatment of severe vivax malaria. The treatment of SVM has not been described clearly and there is also no study to compare our results. All the drugs that act against falciparum malaria also act against vivax malaria with exception sulfadoxine+pyrimethamine. In our study in 2002 we have treated all patients of SVM with Injection quinine and we got good response without any death (Mohapatra et al., 2002). After that WHO guideline for treatment of malaria published  in 2006 and suggested to treat patients of SVM as sever falciparum malaria (World Health Organization, 2006). Therefore, presently we treated such cases with Artesunate and found that it is effective  with adequate response in 96.6% of cases. This study also showed that in addition to antimalarial suitable antibiotic should be added for treatment of associated infection.

In the present series all patients of SVM recovered completely without a single death. In SVM the mortality was 9.0% and 1.8% in two different studies from Mumbai, India (Nadkar et al., 2012; Limaye et al., 2012). Low severity of the disease (assessed by MSS), detection and treatment of associated infection are the factors responsible for absence of mortality in our study.

One of the limitations of the study is the identification of the species by microscopy. It is known that this method largely misses co-infection. Since PCR method is costly and not yet accepted as a routine investigation for diagnosis and treatment of malaria, we used ICT test in addition to slide test for the diagnosis of vivax malaria and to exclude falciparum malaria. Most of the available studies have used only the slide test for the diagnosis of malaria (Nadkar et al., 2012; Limaye et al., 2012; Genton et al., 2008; Tjitra et al., 2008).

In conclusion, severe vivax malaria is an emerging recognized entity with multiple risk factors. The response to treatment with Artesunate is satisfactory with good outcome.

Material and Methods
This study was conducted in the Department of Medicine of V.S.S. Medical College, Burla, Odisha, as a part of our ongoing non-funded prospective observational study on malaria. The vivax, falciparum, and mixed malaria arm of the study had already been reported earlier that showed severe malaria in all the three groups (Mohapatra et al., 2002; Mohapatra and Das, 2009; Mohaptra, 2006; Mohapatra et al., 2012). The present one is the severe vivax malaria arm of the above study, in which data from March 2007 to February 2012 are included. It comprised of two parallel sub studies, i.e. one evaluating the risk factors and outcome (Study-1), and the other investigating the efficacy of Artesunate for treatment of severe vivax malaria (Study-2).

Sub-study-1
It is a prospective observational study in which adult patients of vivax malaria were included. The patients were grouped into uncomplicated vivax malaria (UVM) and severe vivax malaria (SVM). All patients of SVM were admitted to the indoor. On admission clinical work up was done in accordance with the proforma designed for the study. It also included history of antimalarial drugs consumed, body mass index (BMI), associated infections, and co-morbid conditions.

The diagnosis of vivax malaria was made with detection of asexual form of the parasite in the Giemsa stained peripheral blood smears (PBS). Parasite counts were expressed as numbers of asexual parasites per micro liter of blood and were calculated from the numbers of parasitized cells per 200 leukocytes in a thick film stained with Giemsa stain i.e. No. of parasites X total leukocyte count/200.

Severe malaria was diagnosed according to the guidelines of World Health Organization (2000). Earlier we did a longitudinal analysis to find out the criteria for definition of organ dysfunction of severe malaria and a scoring system for assessment of severity known as Malaria Severity Score (MSS) (Mohapatra and Das, 2009). Accordingly, we defined the organ dysfunction and assessed the severity by calculating MSS. The laboratory investigations done were: complete blood count (CBC), blood glucose, blood urea, serum creatinine, serum bilirubin, alanine-amino transferase (ALT), aspartate-amino transferase (AST), alkaline phosphatase and glucose-6-phosphate dehydrogenase (G-6-PD), serum sodium, and potassium. Lumbar puncture was done to study cerebrospinal fluid (CSF) in unconscious patient.

To find out the risk factors of development of SVM we have included all patients with different co-morbid conditions and investigate also for different infections. For detection of infections throat culture, urinalysis with culture, X-Ray chest PA view, Widal test were done.

Temperature was recorded and PBS was examined 12 hourly to determine fever resolution and parasitic clearance time. Patients who lost follow up were excluded from the study.

The study protocol was approved by the ethics committee and written informed consent was obtained from all the patients.

Sub-study-2
It is an open label and non-randomized trial. In this part of study we included the patients of SVM and treated with injection Artesunate 2.4 mg/kg at 0 h, 12 h, 24 h then once daily for 7 days or continued until they were able to tolerate drugs orally according to WHO guidelines (World Health Organization, 2010). Then mefloquine was given orally. Supportive treatment was given as per requirement. Oliguric acute renal failure  i.e. urine output <400 mL/24 hours associated with rising serum creatinine despite rehydration and a trial of diuretics; was treated with haemodialysis. Patients who developed adult respiratory distress syndrome were intubated and ventilated with positive end expiratory pressure if indicated.

Radical treatment was administered with primaquin 0.25 mg base/kg bw for 14 days to the patients without G6PD deficiency. Intermittent primaquin regimen of 0.75 mg/kg bw weekly for 8 weeks was given with supervision to patients with G6PD deficiency.

The outcomes of therapeutic efficacy of artesunate in SVM were assessed as per the WHO standard protocol for monitoring drug resistance for falciparum malaria (World Health Organization, 2003). Accordingly the therapeutic responses were grouped into four categories:

i) Early treatment failure (if the patient develops clinical and parasitological symptoms during the first 3 days of follow-up).

 ii) Late clinical failure (if symptoms develop during the follow-up period from day 4 to day 28 without meeting the criteria for early treatment failure).

 iii) Late parasitological failure (if only parasitemia reappear without any symptoms, in the period from day 7 to day 28).

 iv) Adequate clinical and parasitological response (absence of symptoms and parasitaemia on day 28 (World Health Organization, 2003; Mohapatra, 2009)).

Fever resolution time, parasitic clearance time, and recovery of individual organ dysfunction were determined in all cases of severe malaria. Complete resolution of organ dysfunction was defined when the patients have zero MSS (Mohapatra and Das, 2009).

Patients of uncomplicated vivax malaria were treated with oral chloroquine 25 mg base/kg bw given over 3 days+primaquin as described above for radical cure.

Patients were examined and assessed twice daily until full recovery. All patients were followed up for 28 days either at the out door or by  correspondence.

Analyses were performed with the use of SPSS software, version 10. Continuous data are presented as mean±SD if data were normally distributed. Unpaired data from two groups were compared by two sample t test. Distribution of categorical variables were compared with X² test and presented as absolute counts and percentage. A two-tailed probability value of <0.05 was considered statistically significant. CI was calculated at the 95% level. Univariate analysis was done for risk analysis.

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