Clinical spectrum of Plasmodium vivax infection, from benign to severe malaria: A tertiary care prospective study in adults from Delhi, India.

OBJECTIVE: Plasmodium vivax infection has been recognized to be a cause of severe malaria in recent time. We report findings from a prospective observational study aimed at analyzing the clinical spectrum, complications, and outcome of patients infected with P. vivax malaria.
MATERIALS AND METHODS: The study was conducted in a tertiary care hospital of Delhi over a period of 2 years. All adults hospitalized with P. vivax malaria, confirmed on peripheral smear and/or rapid diagnostic test, were included in the study. The cases were categorized into uncomplicated and severe malaria groups according to WHO criteria. The clinical and biochemical profile of cases in each group were compared for determining the predictors of severe malaria.
RESULTS: One hundred and fifty consecutive cases of P. vivax monoinfection were included in the study. All patients had fever, and 63 (42%) developed severe malaria, while 87 (58%) were uncomplicated. Vomiting, abdominal pain, headache, altered consciousness, cough with breathlessness, icterus, and hepatosplenomegaly were more frequent in severe malaria. Severe malaria was associated with severe thrombocytopenia, leucopenia, raised serum bilirubin, elevated serum creatinine, and prolonged prothrombin time. Jaundice (54 patients) was the most common complication, followed by acute respiratory distress syndrome, spontaneous bleeding, metabolic acidosis, shock, renal failure, and cerebral malaria. Multiple complications were observed in 17 (26.9%) cases of severe malaria. Overall mortality of 1.33% was recorded. However, case fatality of 40% was observed in cases with evidence of multiorgan dysfunction.
CONCLUSION: P. vivax malaria has a varying clinical profile, from a relatively benign uncomplicated form to severe, even fatal disease. Certain clinical and laboratory parameters may serve as predictors of severe disease. Copyright:

INTRODUCTION

Plasmodium vivax is the most widespread human malaria, with 2.5 billion people at risk of infection.[1] In 2014, there were 2.14 million confirmed P. vivax cases globally, 18% of which occurred in India.[2] P. vivax continues to be an important cause of the malaria burden in India, accounting for approximately a third of all cases.

Urban malaria poses unique challenges to malaria control in India due to migration and rapid unorganized construction, making these areas prone to outbreaks with a surge in mortality. P. vivax accounted for 98% of all malaria cases under the urban malaria scheme in 2014.[2]

P. vivax malaria was conventionally considered a relatively benign form of the disease in comparison to falciparum malaria. However, there has been an increase in reports of severe and even fatal disease over the past 15 years, as observed in a systematic review of clinical studies of severe vivax malaria.[3]

This prospective study was conducted with the aim of exploring the diverse clinical manifestations of vivax malaria. Comparisons between the clinical and laboratory characteristics of uncomplicated and severe cases were made. The various complications of severe malaria and their clinical outcome were also analyzed.

MATERIALS AND METHODS

Study design

This prospective clinical observational study was carried out in the department of general medicine in a tertiary care hospital in New Delhi, India. The study was conducted over a period of 2 years from October 2013 to September 2015. Approval was obtained from the institutional ethics committee for conducting the study.

Study population

The study group included all adult patients (>12 years of age), admitted with the diagnosis of P. vivax malaria monoinfection. Cases with Plasmodium falciparum and mixed malarial infection or any other coinfection were excluded from the study.

Method of study

The diagnosis of malaria was made based on the detection of malaria parasites by conventional thick and thin peripheral blood films, stained with Giemsa stain, and rapid diagnostic tests (RDTs). The RDTs were based on detection of specific Plasmodium antigen, lactate dehydrogenase. The care start™ malaria parasite lactate dehydrogenase/histidine-rich protein 2 (pLDH/HRP2) combo (Pf/Pv) test was used. It consists of a conjugate pad dispensed with two monoclonal antibodies, which are specific to pLDH of P. vivax and HRP 2 of P. falciparum. Those patients who had monoinfection with vivax malaria as diagnosed by peripheral smear examination and/or RDT were included in the study group.

Data were collected in a pro forma after obtaining informed consent from patients. The pro forma included demographic profile, detailed history, and general and systemic examination of the patients. Hematological and biochemical investigations were carried out which included complete blood count, erythrocyte sedimentation rate (ESR), random blood sugar, liver function test, renal function test, urine examination, prothrombin time, arterial blood gas analysis, and chest X-ray. G6PD screening test was also done. Other specific tests were done as per clinical judgment. Patients having coinfections with dengue, typhoid, leptospira, and viral hepatitis were excluded from the study after appropriate testing.

Malaria cases were categorized into uncomplicated and severe malaria in accordance with the WHO criteria for severe malaria.[4] All patients were treated according to WHO guidelines. Patients were followed up till discharge or death, and their clinical course, complications, and final outcome were recorded.

Statistical methods

Categorical variables were analyzed for association with severe malaria using Chi-square test. Continuous variables were compared between uncomplicated and severe malaria by Mann–Whitney U-test. P ≤ 0.05, with confidence interval of 95%, was considered as statistically significant. Statistical analysis was conducted using Epi Info™ 7 for Windows (public domain statistical software for epidemiology developed by Centers for Disease Control).

OBSERVATIONS AND RESULTS

A total of 150 admitted patients with peripheral smear and/or antigen-based RDT positive for P. vivax were included in the study.

Among the 150 cases studied, 91 (60.7%) were males and 59 (39.3%) were females. The male to female ratio was 1.54:1. The mean age was 35.61 years (range from 13 to 83 years). The predominant age group affected was between 21 and 40 years. There was no significant difference in the age of cases in the uncomplicated or severe malaria groups.

Fever was the presenting complaint in all 150 patients (100%). Other common symptoms in order of frequency were jaundice and vomiting seen in 54 (36%) cases each, followed by abdominal pain in 37, headache in 30, cough in 20, and breathlessness in 15 cases [Table 1]. Five cases presented with impaired consciousness and 1 had multiple convulsions. The symptoms of vomiting, abdominal pain, jaundice, headache, cough, and breathlessness were more frequent in severe malaria cases [Table 1]. Bleeding, petechiae, altered consciousness, and oliguria were found only in cases of severe malaria. The most frequent signs on physical examination were hepatomegaly in 74 (49.3%) and splenomegaly in 72 (48%) patients. Icterus, hepatomegaly, splenomegaly, and respiratory signs were more common in the severe malaria group as compared to uncomplicated malaria with P < 0.001 [Table 1].

Table 1

Comparison of clinical features of severe and uncomplicated malaria

Clinical features	Severe malaria (n=63)	Uncomplicated malaria (n=87)	Pa	Total number of patients (n=150), n (%)
Jaundice	54	0	<0.001	54 (36)
Vomiting	50	4	<0.001	54 (36)
Headache	21	9	0.001	30 (20)
Pain abdomen	33	4	0.001	37 (24.7)
Cough	16	4	<0.001	20 (13.3)
Breathlessness	14	1	<0.001	15 (10)
Bleeding	9	0	<0.001	9 (6)
Petechiae	4	0	<0.001	4 (2.7)
Altered consciousness	5	0	<0.001	5 (3.3)
Convulsions	1	0	<0.001	1 (0.7)
Oliguria	5	0	<0.001	5 (3.3)
Pallor	13	19	0.859	32 (21.3)
Icterus	54	0	<0.001	54 (36)
Splenomegaly	57	15	<0.001	72 (48)
Hepatomegaly	57	17	<0.001	74 (49.3)
Respiratory signs	18	1	<0.001	19 (12.7)
Days in hospital (median)	6.5	3.8	0.003b

aP value using the Chi-square test, bP value using the Mann-Whitney test

Profile of laboratory findings

The median hemoglobin in the study population was 11.6 g/dl. Severe anemia (hemoglobin <7 g/dl) was found in only 4 cases. There was no significant difference in the hemoglobin levels of cases with uncomplicated or severe malaria. G6PD deficiency was not found in any patient. Thrombocytopenia of <1.5 lack/mm3 was seen in 130 (86.67%) cases in our study. Cases in the severe malaria group had significantly lower platelet counts than those with uncomplicated malaria (P < 0.001). Severe thrombocytopenia (platelet <50,000/mm3) was observed exclusively in 54 (36%) cases of severe malaria. Most cases (105) had a normal leukocyte count. Leucopenia in 36 (24%) cases was found only in severe malaria. Raised ESR was also more frequently found in this group. Liver dysfunction in the form of serum bilirubin of more than 3 mg/dl was seen in 54 (36%) cases. Prothrombin time was prolonged in 58 patients. Severe malaria cases presented with significantly higher total bilirubin, creatinine, and prolonged prothrombin time [Table 2].

Table 2

Laboratory parameters of severe and uncomplicated malaria

Laboratory parameters	Median (IQR)		Pa
	Severe malaria (n=63)	Uncomplicated malaria (n=87)
Hemoglobin (g/dl)	11.6 (9.6-12.8)	11.8 (9.0-12.9)	0.678
Platelet count (×103/mm3)	35 (20-45)	100 (75-145)	<0.001
Total leukocyte count (x103/mm3)	3.7 (2.9-8.9)	7.4 (6.5-8.9)	0.56
ESR (mm in 1st h)	36 (11-45)	11 (9-13)	<0.001
Total bilirubin (mg/dl)	4.1 (3.4-5.1)	1.3 (0.9-1.7)	<0.001
Prothrombin time	20 (17.6-24.0)	12.8 (12.4-13.2)	<0.001
Creatinine (mg/dl)	1.0 (0.9-1.3)	0.9 (0.8-1.1)	<0.001

aP value using the Mann-Whitney test between severe and uncomplicated Plasmodium vivax malaria. IQR: Interquartile range, ESR: Erythrocyte sedimentation rate

The minimum duration of hospital stay was 2 days, and maximum duration of stay was 18 days. The median duration of stay in hospital was 6.51 days for severe malaria cases versus 3.85 for uncomplicated cases, the difference being statistically significant.

Severe malaria

Eighty-seven (58%) cases were classified as uncomplicated malaria. Sixty-three cases (42%) developed one or more manifestations of severe malaria. 46 cases had only a single complication, while 17 cases developed multiple complications.

Liver dysfunction in the form of jaundice was a common complication present in 54 cases. Acute respiratory distress syndrome (ARDS) was seen in 13 (8.67%) patients. These 13 patients required mechanical ventilation.

Significant bleeding was observed in 9 cases. Metabolic acidosis was seen in 8 (5.33%) cases. Hypoglycemia was not recorded in any case during the study. Acute kidney injury was seen in 5 (3.33%) cases, of which 4 required hemodialysis. Cerebral malaria, presenting with impaired consciousness, was seen in 5 (3.33%) cases and 1 of these cases had seizures [Table 3].

Table 3

Frequency of complications of severe malaria and association with mortality

Criteria	Number of cases (n=63, n (%))	Mortality	Case fatality rate (%)
Jaundice (bilirubin >3 mg/dl)	54 (85.7)	2	3.7
ARDS	13 (20.6)	2	15.3
Significant bleeding	9 (14.2)	1	11.1
Shock	4 (6.3)	2	50
Metabolic acidosis	8 (12.6)	2	25
Severe anemia	4 (6.3)	0	0
Hypoglycemia (<40 mg/dl)	0	0
Renal impairment (creatinine >1.5 mg/dl)	5 (7.9)	2	40
Cerebral malaria (impaired consciousness)	5 (7.9)	1	20
Multiple convulsions	1 (1.5)	0	0
Prostration	0
Single complication	46	0	0
Multiple complications	17	2	13.3
<3	12	0	0
>3	5	2	40

ARDS: Acute respiratory distress syndrome

Two patients died during the study period, both having evidence of severe malaria with multiorgan dysfunction. The mortality rate was 1.33% (2/150). The complications which were associated with higher rates of mortality were shock, renal impairment, metabolic acidosis, ARDS, and cerebral malaria [Table 3]. Mortality was also more likely in cases with multiple (3 or more) complications versus single or dual complications.

DISCUSSION

Severe malaria was conventionally associated with P. falciparum whereas P. vivax malaria was considered to be a benign form, with low morbidity and mortality. However, recent case reports and studies over the past few years have highlighted that severe disease, as well as mortality can be observed with P. vivax malaria.[567891011121314] Therefore, in this prospective observational study, we explored the diverse clinical profile of P. vivax malaria, ranging from uncomplicated cases to severe even fatal disease. The spectrum of clinical manifestations and complications of vivax malaria were analyzed.

In our study, 60.7% cases were males, and the male to female ratio was 1.54:1. A greater proportion of adult males affected by vivax malaria were also reported in studies done at Aligarh and Goa.[1315] Most of the cases (54.7%) were between 21 and 40 years of age, and the mean age of presentation was 35.61 years. This correlates with studies conducted at Aligarh[13] and Mumbai.[10]

Fever was universally present in all the cases. Jaundice, vomiting, abdominal pain, and headache were the other most common symptoms observed. Hepatomegaly and splenomegaly were noted in around half of the cases. The symptoms of vomiting, abdominal pain, headache, altered consciousness, cough with breathlessness, as well as signs of icterus and hepatosplenomegaly were more frequent in cases of severe malaria. Therefore, these symptoms and signs could serve as potential risk factors, indicating a poor prognosis in cases of malaria. In a study at Columbia,[16] persistent vomiting, tachypnea, consciousness alteration, and convulsions were identified as warning signs, suggesting the development of severe malaria.

Thrombocytopenia (<1.5 lakh/mm3) was seen in a large proportion of 86.7% of patients, which correlated with the results of the studies done at Delhi and Manipal.[69] Severe thrombocytopenia (<50,000) was found exclusively in cases of severe malaria; however, spontaneous bleeding occurred in just 9 cases. Severe anemia was seen in 4 (2.6%) cases. In the study done at Mangalore, severe anemia was seen in 0.47% cases.[9] Hemoglobin levels were not significantly different among uncomplicated or severe cases. Uncomplicated cases had significantly higher platelet counts and lower ESR, total bilirubin, and prothrombin time. In contrast, severe thrombocytopenia, leucopenia, raised total bilirubin, elevated serum creatinine, and prolonged prothrombin time were more significantly associated with severe malaria. Therefore, these parameters could be useful predictors of the severity of malaria.

Severe malaria defined by WHO criteria was found in 42% (63/150) of cases in our study. Severe disease was reported in 22.2% of cases in a tertiary care in Kolkata.[12] Kochar et al. observed severe malaria in 45.3% of P. vivax cases, with similar features to that of P. falciparum monoinfection.[14] Jaundice was the most common complication present in 54 (85.7%) cases. Other frequent manifestations were ARDS reported in 20.6%, significant bleeding in 14.2%, metabolic acidosis in 12.6%, and acute kidney injury and cerebral malaria in 7.9% each of severe malaria cases. Jaundice (66%), cerebral malaria (34%), renal failure (7.4%), and pulmonary involvement (3.7%) were reported among 200 severe malaria cases in Kolkata.[12] The study by Sharma and Khanduri reported hepatic dysfunction, renal failure, ARDS, and hemolysis as common complications in severe vivax malaria.[6]

Neurological manifestations were observed in 3.3% of our study population. In the study done at Mumbai, cerebral malaria was seen in 3.5% of vivax cases as compared to 13.19% in falciparum cases.[10]

In our study, 46 of 63 severe malaria cases had a single complication, while 17 (26.98%) cases developed multiple complications. In a study at Bikaner, multiorgan dysfunction was reported in 33.48% cases of severe vivax malaria, with similar relative risk to that of P. falciparum monoinfection.[14]

The mortality rate was 1.33% (2/150) in our study, which correlated to the study done at Delhi.[6] The incidence of mortality was 3.17% (2/63) in severe malaria cases. Severe anemia and jaundice were associated with better survival. However, shock, renal impairment, metabolic acidosis, cerebral malaria, and ARDS were associated with higher case fatality. Furthermore, there was no mortality among cases with a single complication, while mortality of 40% was observed in cases with evidence of multiorgan dysfunction (more than three complications). Similar findings were reported by Sarkar et al. where mortality was 34.8% among patients with multiple complications and 7.4% in those with single complication.[12] A mortality of 4.52% in severe vivax malaria was found by Kochar et al., and all these cases had multiorgan dysfunction.[14]

Limitations

The study was conducted in a tertiary care hospital including only admitted patients; thus, the proportion of severe malaria cases was high. Estimation of the true incidence of severe vivax malaria and its complications would require large scale, population-based studies.

CONCLUSION

This study highlights that certain clinical features such as vomiting, abdominal pain, headache, altered consciousness, cough with breathlessness, hepatosplenomegaly, as well as laboratory parameters such as severe thrombocytopenia, leucopenia, raised total bilirubin, elevated serum creatinine, and prolonged prothrombin time may serve as indicators heralding the onset of severe malaria. Cases demonstrating the above warning signs should be closely monitored to prevent adverse outcome. Once severe malaria develops, outcome depends on the type and number of complications present.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.