Clinical profile of malaria at a tertiary care teaching hospital in North India.

INTRODUCTION: Despite recent reductions in the overall malaria case incidence, malaria remains an important public health issue. There has been a change in clinical and epidemiological profile of malaria in our country and vivax malaria known to be benign has been reported to cause severe complications. Therefore, the present study was conducted to delineate the clinical profile of malaria, proportion of severity, spectrum of complications, and presence of comorbidities among adult patients admitted at a tertiary health-care center in North India.
MATERIALS AND METHODS: This was an observational prospective study conducted in all adult patients (>15 years of age) diagnosed to have Plasmodium vivax malaria, Plasmodium falciparum, and mixed malarial infection at a tertiary care teaching hospital on the basis of peripheral smear or rapid diagnostic tests.
RESULTS: The study included 295 patients, the most common species was vivax (62%) followed by falciparum (29%) and mixed plasmodium spp. (9%). The mean age of the patients was 34.23 ± 15.7 years, with 64% male and 36% female. Out of all patients, 23% patients had at least one component of severe malaria. Severe anemia (hemoglobin <5 mg/dl), thrombocytopenia (platelet count <1 lac/cmm), and acute kidney injury were significantly greater in patients with P. vivax. Presence of comorbid conditions was observed in a significant proportion (32%) of patients.
CONCLUSION: P. vivax is the plasmodium species which is responsible for most of the cases. Its potential to cause life-threatening illness is the cause of concern. The role of comorbid conditions in influencing the clinicaloutcome of malaria should be further explored. Copyright:

INTRODUCTION

Malaria is a major global infectious disease caused by parasitic protozoans of the genus Plasmodium. Infections in humans primarily involve five Plasmodium species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi.[1] In the 20th century, malaria was a dreaded disease. With the efforts of public health agencies and availability of artemesinine derivatives, morbidity and mortality associated with malaria have decreased and there is revival of hopes that malaria will be eradicated from our country in the coming decades. Despite recent reductions in the overall malaria case incidence, malaria remains an important cause of morbidity and mortality. Global estimates suggest that the disease accounts for 300–500 million morbidity cases and contributes to approximately 3 million deaths annually.[2]

Malaria due to P. falciparum has been associated with severe complications and mortality. If we compare the clinical and epidemiological profile of malaria in recent times from what it was in the past, it has been considerably different. The World Health Organization (WHO) estimated the global incidence of P. vivax to be 7.5 million cases in 2017, and it is the most prevalent malaria species in Southeast Asia.[23] P. vivax is particularly troublesome in urban settings because of increased constructional and developmental activities; there is a rising population of migrant workers in cities of India. Previously labeled as benign, severe manifestations are being reported increasingly in vivax malaria across the globe.[45]

In the tertiary-level health-care facilities, which function as referral centers, patients come from peripheral urban or rural centers and they are partially treated. These patients also have comorbidities which can affect the clinical course and final outcome of the patients. There are not many studies on adult patients with severe malaria in recent times in this part of the country. Therefore, the present study was conducted to delineate the clinical profile of malaria, proportion of severity, spectrum of complications, and presence of comorbidities among adult patients admitted at a tertiary health-care center in North India.

MATERIALS AND METHODS

An observational prospective study was conducted in the Department of Medicine, Dr Ram Manohar Lohia Institute of Medical Science, Lucknow from January 2018 to December 2019. This study was conducted in all malaria-positive patients presented in outpatient departments admitted in the medical wards, high dependency and intensive care unit. The study was approved by the institutional ethics committee before commencement and written informed consent was obtained from all the study participants.

Inclusion criteria

All adult patients (>15 years of age) admitted with the diagnosis of P. vivax malaria, P. falciparum, and mixed malarial infection. 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 the detection of specific Plasmodium antigen, lactate dehydrogenase. The CareStart™ 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.

National Vector Borne Disease Control Programme (NVBDCP) criteria for the definition of severe malaria were followed and all the patients were treated according to the NVBDCP guidelines which are the same as the WHO criteria.[67]

Clinical features of severe malaria

Cerebral malaria as characterized by impaired consciousness or coma, convulsions, or both

Acute respiratory distress syndrome (ARDS)

Circulatory collapse (systolic blood pressure <80 mmHg)

Jaundice in the setting of other organ dysfunction (serum bilirubin >3 mg/d)

Haemoglobinuria

Abnormal spontaneous bleeding.

Laboratory features of severe malaria

Hypoglycemia (blood glucose <40 mg/dl)

Severe anemia (hemoglobin [Hb] <5 g/dl, packed cell volume <15%)

Metabolic acidosis (plasma bicarbonate <15 mmol/L or pH <7.35)

Hyperlactataemia (lactate >5 mmol/L)

Acute kidney injury (serum creatinine >3 mg/dl).

In all the patients, detailed history and demographic profile were recorded and general and systemic examination was done. Hematological and biochemical investigations were carried out which included complete blood count, erythrocyte sedimentation rate, highly sensitive C-reactive protein, blood glucose, liver function test, renal function test, serum electrolytes, urine examination, prothrombin time, procalcitonin, arterial blood gas analysis, blood and urine cultures, chest X-ray, and electrocardiogram. Cerebrospinal fluid analysis was G6PD screening test which was also done as required. Other specific tests, brain and abdominal imaging, were done as per the clinical judgment.

Exclusion criteria comprised positive serology for dengue, leptospirosis, scrub typhus, typhoid, hepatitis B, hepatitis C, and HIV. All pregnant females were also excluded from the study.

Statistical analysis

Data analyses were performed using SPSS for Windows, version 11.5 (SPSS, Chicago, IL, USA). Data were expressed as mean ± standard deviation or number and percentage. The normal data distribution was analyzed with the Kolmogorov–Smirnov test. Baseline clinical parameters were compared between the subgroups by Chi-square or Student's test. P < 0.05 was considered significant.

RESULTS

A total of 295 patients with peripheral smear and/or antigen-based RDT positive for P. vivax, P. falciparum, or mixed were observed in the study. The most common species was vivax (62%), followed by falciparum (29%) and mixed plasmodium spp. (9%).

Demographics and clinical characteristics of all malaria cases of the present study are shown in Table 1. The mean age of the patients was 34.23 ± 15.7 years. The predominant age group affected was between 21 and 40 years. There was no statistically significant difference in the age of cases in the uncomplicated or severe malaria. Males were predominantly affected, constituting 64.4%, while females were 35.6%. Fever (100%) was the most common symptom observed among the study population, followed by chills (73.4%), headache (48%), icterus (46.2%), vomiting (46%), abdominal pain (29%), decreased urine output (20%), and altered sensorium (16%), while pallor (60.9%) and splenomegaly (34.6%) were the common physical findings present in study participants.

Table 1

Demographics and clinical characteristics of malaria(n=295)

	Frequency (%)
Sex
Female	105 (35.6)
Male	190 (64.4)
Clinical features
Fever	295 (100)
Chills	217 (73.4)
Vomiting	134 (45.5)
Diarrhea	29 (9.9)
Abdominal pain	86 (29.2)
Headache	142 (48.1)
Pallor	180 (60.9)
Icterus	136 (46.2)
Convulsion	11 (3.8)
Altered sensorium	90 (30.4)
Shock	19 (6.4)
Decreased urine output	58 (19.6)
Splenomegaly	102 (34.6)

Table 2 depicts the comparison of different laboratory parameters between various types of malaria. In the present study, Hb was significantly lower in falciparum malaria as compared to vivax and mixed malaria and leukocyte count was significantly lower in mixed malaria as compared to vivax and falciparum malaria. However, no statistically significant differences were observed in other hematological and biochemical parameters. Presence of comorbid conditions was observed in a significant proportion (32%) of patients. The most common disease was type 2 diabetes in the study participants (n = 295), as shown in Table 3.

Table 2

Comparison of different laboratory parameters between different types of malaria

Characteristics	Plasmodium falciparum (n=85)	Plasmodium vivax (n=183)	Mixed (n=27)	Total	P
Hb (g/dl)	7.87±0.7	9.06±2.5	8.08±2.2	8.29±2.6	0.002
Total leukocyte count (/mm3)	9476±7490	9038±5182	7514±4380	9157±6553	0.015
Platelet counts (/mm3)	79768±54979	77771±60371	79230±62373	79036±57337	0.962
Blood glucose (mg/dl)	115.9±61.0	114.4±44.2	96.37±30.7	113.6±53.8	0.190
Serum sodium (mEq/l)	135.0±7.8	135.9±6.0	136.8±8.3	135.5±7.3	0.386
Serum potassium (mEq/l)	4.07±0.7	4.15±0.7	3.74±0.7	4.07±0.7	0.06
Serum urea (mg/dl)	84.01±71.7	76.34±54.5	61.77±49.1	79.44±64.6	0.261
Serum creatinine (mg/dl)	2.03±2.1	1.77±1.6	1.62±1.6	1.91±1.97	0.484
Serum bilirubin (mg/dl)	3.73±4.8	3.23±4.4	2.29±2.4	3.43±4.5	0.224
Alanine transaminase (IU/L)	124.07±154.6	108.85±95.8	61.57±40.2	113.06±131.0	0.131
Aspartate transaminase (IU/L)	101.14±157.0	74.57±73.5	61.87±39.4	88.60±127.4	0.264
Glucose (mg/dl)	68.22±17.3	67.88±15.5	77.75±15.3	69.29±16.3	0.33

Hb: Hemoglobin

Table 3

Prevalence of comorbidities(n=295)

Comorbid condition	Frequency (%)
Diabetes mellitus	26
Hypertension	9
Chronic kidney disease	8
Chronic liver disease	8
Malignancy	6

Out of all patients, 23% of patients had at least one component of severe malaria. Clinical characteristics and laboratory parameters of uncomplicated and severe malaria patients are described in Table 4a and b. Inflammatory markers were significantly higher in patients with severe malaria in addition to the prevalence of comorbidities, acute kidney injury, altered sensorium, anemia, thrombocytopenia, and transaminitis. It was noted that nearly equal proportion of P. vivax and P. falciparum patients had severe malaria. None of the patients with mixed infection had severe malaria. Various manifestations and their prevalence in different species are summarized in Table 5. Severe anemia (Hb <5 mg/dl), thrombocytopenia (platelet count <1 lac/cmm), and acute kidney injury were significantly greater in patients with P. vivax. Superficial hemorrhages in the form of subconjunctival hemorrhage and gum bleeding were present in 2% of patients who required platelet transfusions and 8% were given packed red blood cell transfusions. Renal replacement therapy in the form of hemodialysis was given in 5% of patients.

Table 4a

Clinical features according to the severity of malaria

Characteristics	Uncomplicated malaria (n=227)	Severe malaria (n=68)	P
Age (years)	32.8±12.6	40±8.4	0.01
Gender (male)	64	63.5	0.56
Fever	100	100	0.4
Headache	76	74	0.8
Vomiting	32	30	0.12
Abdominal pain	23	24	0.6
Altered sensorium	0	29	0.001
Decreased urine output	12	26	0.01
Presence of comorbidity	5	27	0.001
Pallor	42	66	0.001
Icterus	27	47	0.002
Hepatomegaly	31	32	0.5
Splenomegaly	33	30	0.4

Table 4b

Laboratory parameters according to the severity of malaria

Characteristics	Uncomplicated malaria (n=227)	Severe malaria (n=68)	P
Hb	12.2±2.8	10.4±4.6	0.02
Total leukocyte count (cells/mm3)	5100±2350	5600±3200	0.01
Platelet count (cells/mm3)	89000±14000	52500±27000	0.001
Hs CRP	24±8	42±14	0.002
ESR	19±12	36±17	0.01
Total bilirubin	1.6±0.8	2.4±1.3	0.03
Alanine transaminase (IU/L)	46±12	58±14	0.04
Aspartate transaminase (IU/L)	42±11	56±12	0.01
Blood urea	27±7	42±11	0.001
Serum creatinine	1.2±0.6	1.8±1.0	0.02

ESR: Erythrocyte sedimentation rate, Hs CRP: High-sensitivity C-reactive protein, Hb: Hemoglobin

As far as mortality was concerned, among all, 1% of patients expired. Two patients who died had multi-organ dysfunction and ventilator-associated pneumonia and one had advanced malignancy in the brain.

DISCUSSION

Malaria is a major public health problem, endemic in over hundred countries across the world.[8] The burden of malaria in India is complex because of the highly variable geographical and epidemiological profiles and transmission factors. Severe malaria is historically caused by P. falciparum, but it has been increasingly observed that vivax malaria and mixed infection malaria can also cause similar complications and death.[9] This is an important notable point that since there are no separate severity criteria exist for P. vivax malaria, criteria of severe malaria which were advocated for falciparum malaria, all parameters exept parasite severity index have been adopted for other plasmodium species as well. The WHO criteria for P. falciparum malaria which has been endorsed by NVBDCP also seems to be applicable for P. vivax.

The aim of our study was to observe the profile of patients with malaria, proportion of severe malaria, and detection of comorbidities which are likely to influence the clinical course of illness.

The present study had a similar proportion of Plasmodium species as reported by other authors from North India. The results are in accordance with the earlier findings in which P. vivax and P. falciparum were reported to be 56.5% and 39.1%, respectively.[10] Others have also observed a higher prevalence of vivax than falciparum in our country.[11] We had noted that maximum patients in the age group 21–40 years with male gender predominantly affected similar to other reports.[12] The possible explanation for both might be the greater outdoor exposure.

Common clinical features such as fever, chills, headache, and abdominal complaints observed in the present study were the same as found in the other studies.[13] Splenomegaly was noted in 34% of all cases. Spleen enlargement occurs due to phagocytosis of parasitized red blood cells and their accumulation in the spleen for clearance. There was no statistically significant difference in splenomegaly in severe malaria and uncomplicated malaria.

We observed that the patients with uncomplicated malaria and with severe malaria were present in equal proportions. This indicates that P. vivax is the most widespread infection in India which results in a profound morbidity.[111415] In recent times, it has been reported that P. vivax has immense potential to cause life-threatening complications.[16] Exact pathogenesis and organ-specific morbidity caused by P. vivax infection remain unrecognized and poorly defined because of a paucity of research in this area.

Out of different manifestations of severe malaria, cerebral malria was observed in 26% and 29% of vivax and falciparum malaria. Hyperbilirubinemia and multi-organ dysfunction were also not significantly different among the two species. These complications have been observed by other researchers.[517] Hyperbilirubinemia and cerebral malaria are believed to be due to sequestration of infected red blood cells in microvasculature of visceral organs.

Anemia was a major clinical finding present in our study. Severe anemia was noted in43% vivax malaria in comparison to 17% in falciparum malaria. In contrast, much lower counts for anemia of around 13% and 3% for P. falciparum and P. vivax, respectively, were reported by Limaye et al.[18] which might be due to the severity of infection and the level of immunity against the parasite in patients of falciparum and vivax malaria and difference in endemicity. Poor nutrition and coexisting helminthiasis can aggravate anemia in our patients, as reported by others.[19] Plasmodium species invade red blood cells and make them rigid and less pliable which get hemolysed. Thrombocytopenia is another hematological parameter which was present in 67% and 48% of severe malaria patients, same as reported by others.[202122] Thrombocytopenia is considered a sensitive marker of malaria. Mechanisms causing thrombocytopenia have been proposed as peripheral destruction, bone marrow alteration, and excessive removal of platelets by splenic pooling and antibody-mediated platelet destruction.

Acute renal failure is a common cause of morbidity and mortality in severe malaria. Acute kidney injury was significantly higher in patients with vivax malaria (34.5%) than falciparum malaria (12%) cases. Similar results were recorded from the patients of other parts of the country.[2324] High levels of parasitemia, immune-mediated and hypoxic glomerular injury by the circulating parasites which causes inflammation and alters renal microcirculation are the probable mechanisms of acute kidney injury which is escalated by coexisting dehydration and hypotension in these patients.[25]

ARDS was observed in 8% P. vivax cases and 16% of P. falciparum cases. In other reports of India, it was 10% and 3%.[26] ARDS occurs due to sequestration of parasites in lung microvasculature. In vivax malaria, it has been postulated to be due to sequestration, cytokine-mediated injury, or nitric oxide production.[27]

In the present study, it was noted that a significantly higher number of patients with comorbidites had severe malaria as compared to those who had uncomplicated malaria. This might be an indicator of the overall host immune status. There has been some evidence in literature which suggests that comorbidities, specifically obesity and diabetes, are risk factors for severe malaria in adults.[28] More evidence is needed to confirm this finding. Two patients in the present study died who had vivax malaria. They had Type 2 diabetes, multi-organ failure and secondary sepsis due to ventilator-associated pneumonia. One patient with falciparum malaria died as he had glioblastoma multiforme.

Prospective design and inclusion of all the positive cases, severe and uncomplicated at a referral health-care facility, were the strengths of the present study. However, single center and small sample size were the limitations of the study. Further large-scale multicentric clinicoepidemiologic studies with the dimensions on pathogenesis and drug resistance involving large populations are required to reduce the burden of malaria in our country.

CONCLUSION

Malaria is still an important public health issue despite a consistent decline in its incidence. P. vivax is the plasmodium species which is responsible for most of the cases. Its potential to cause life-threatening illness is the cause of concern. The role of comorbid conditions in influencing the clinical outcome of malaria should be further explored.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 5

Manifestations of severe malaria according to the Plasmodium species

Characteristics	Plasmodium vivax (n=47), n (%)	Plasmodium falciparum (n=21), n (%)	P
Coma	26	29	0.17
Shock	10	21	0.042
Respiratory distress/ARDS	8	16	0.01
Hb (<5 g/dl)	43.30	17	0.001
Thrombocytopenia (<100,000/mm3)	67.0	48	0. 01
Hypoglycemia (<50 mg/dl)	2.70	1.8	0.56
Serum creatinine (>3 mg/dl)	34.50	12.30	0.01
Serum bilirubin (>3 mg/dl)	32.45	33.30	0.22
Multiorgan dysfunction	15	13.30	0.13

ARDS: Acute respiratory distress syndrome, Hb: Hemoglobin