Clinicohematological and drug prescription details in children affected with malaria: A retrospective study from a tertiary hospital of an endemic region in India

Introduction

Malaria is a parasitic infection caused by Plasmodium species, transmitted by the bite of an infected female Anopheles mosquito. Humans are infected by mainly four Plasmodium species i.e., P. falciparum, P. vivax, P. malariae and P. ovale.1 Malaria is endemic in many parts of the world and reports suggest that 228 million cases were diagnosed worldwide in the year 2018.2 In India, 0.4 million cases were reported in 2018, majority of cases were from states with forest, hilly and tribal areas like Odisha, Chattisgarh, Jharkhand, Madhya Pradesh, Maharashtra in the central part of India and Tripura, Meghalaya and Mizoram in the eastern part of the country.3 The state of Karnataka, reported 8174 cases in 2018, of which 86% (7042) were from the district of Dakshina Kannada alone.4

Clinically, malaria is a preventable and curable disease, but can be life-threatening, if not diagnosed and treated on time. Most of the cases present with malarial paroxysm with typical high grade fever with chills and rigor, anemia and hepatosplenomegaly.2 Complications like black water fever, cerebral malaria are commonly seen with P. falciparum, whereas relapse is common in P. vivax due to activation of hypnozoites in liver cells.5, 6

Malaria is a serious disease in the pediatric age group. It is estimated that at a global level in the year 2018, 405,000 deaths were due to malaria and that 272,000 were in the most vulnerable population the children under the age of five.2 In Sub - Saharan Africa alone, the burden of the P. falciparium infection in children is as high as 24 million according to the World Health Organization report.2 The principal reason is that being intra-erythrocytic parasite, malaria is known to cause major derangement in hematological parameters mainly RBC, WBC and platelets.5 Severe anemia, leukopenia and thrombocytopenia are very well documented in falciparum malaria. 6, 7, 8, 9, 10 Further, all major organs like the brain, liver and renal can be affected by malaria, patients with hepatorenal dysfunction have poor prognosis. 11

A literature study suggests that the clinicohematological and treatment details of malaria caused by the different species have not been reported. Therefore, in this study, an attempt was made to understand the changes in laboratory parameters like haematology, hepato-renal among the paediatric malaria patients at a tertiary centre in Coastal Karnataka, India, which is documented to be an endemic region in India and the world.

Materials and Methods

The study was approved by the institutional ethics committee of Father Muller Charitable Institute (FMMCIEC/CCM/292/18). The inclusion criteria included all paediatric patients (<18 years of age) who were diagnosed with malaria during the study period (January 2015 to December 2018). The exclusion criteria were children infected with other acute infections (like dengue, leptospirosis, typhoid, tuberculosis and other bacterial, protozoal and viral infections), children suffering from cancers and blood disorders. Children having malaria and other co-infection were also not considered. By Diagnosis of malaria was established by staining a peripheral smear geimsa stain or by QBC test according to availability. All the other laboratory parameters were collected from the medical records of these children diagnosed of malaria. In addition to the haematological and biochemical data of age matched children who had come for nonspecific viral fevers, non-infectious dermatological issues were used as control to ascertain the quantitative difference between the controls verses the study group. The data collected were entered in Microsoft Excel and statistical analysis was done. The mean, standard deviation were done for all the parameters and compared with control cases, using ANOVA / Kruskal wallis test. The p value < 0.05 were considered as significant.

Results

A total of 290 children (males 182: females 108, 2:1) were diagnosed with malaria during the study period. Among them, 204 (70.3%) patients had P. vivax, followed by mixed malaria 71 (24.5%) and 15 (5.2%) had P. falciparum and these three categories were compared with control cases. The majority of the patients (179, 61.72%) belonged to the age group of 11-16 years (Table 1). There was no death reported among any children during the study period. Among the 290 children diagnosed with malaria, all had fever. Vomiting (89, 30.7%) was second most common symptom followed by headache (57, 19.7%) and convulsions (39, 13.6%) as shown in Table 1. Jaundice was observed only in 1 patient with mixed malaria.

Among the haematological parameters, the haemoglobin level was least in group with mixed malaria compared to others (Table 2). There was significant lower total leucocyte count in all categories compared to controls. Among the differential leucocyte counts, there was significant lower lymphocyte, eosinophil with higher monocyte counts among the malaria groups. There was significant difference in differential neutrophil count. The Erythrocyte Sedimentation Rate (ESR) was significantly higher in the infected cases. There was significant thrombocytopenia seen mainly in Falciparum group compared to mixed and vivax in decreasing order. The liver function was deranged significantly. The total bilirubin, and conjugated bilirubins were increased, significantly higher in mixed group.(Table 3) The liver enzymes were elevated, but reported to be higher in falciparum group. No significant difference was seen in AST / ALT ratio. The parameters of the renal system like urea were significantly higher in mixed malaria compared to other groups. The derangement in electrolytes seen was mainly hyponatremia, hypokalemia and hypochloremia. There was no significant difference in creatinine value in among the three infected groups.

When compared to controls, the acute phase protein, C reactive protein was significantly high in all the groups with, highest level was seen in falciparum group.(Table 4) In mixed malaria patients among the haematological parameters, it was observed that there was significant anaemia, monocytosis, reduced PCV, MCV, MCH, renal parameters like blood urea were increased and electrolytes were reduced.(Table 5) Among LFT, there was elevated bilirubin levels compared to other sub-group of patients. In Falciparum group, reduced eosinophil and platelets were observed among the haematological parameters and reduction in serum total protein, albumin, globulin and A/G ratio were observed. CRP was elevated significantly in this group. When compared with other groups, vivax malaria patients had significant leucocytosis, neutrophilia, lymphopenia and increased ESR.

Among the 204 Vivax group of patients, Chloroquine (187, 91.67%) was the most frequently administered drug, whereas Chloroquine artemether combination was prescribed in very few (13, 6.37%) patients (Table 6). Both Falciparum and mixed group were treated with Artemether. Anti-hypnozoites drug, ie Primaquine were administrated to all vivax and mixed malarial patients as per guidelines for 14 days.

Discussion

Malaria is a multisystem disorder, warranting hospitalization, appropriate antimalarial therapy and prevention of its complications. 12, 13, 14, 15 Plasmodium vivax was the most common causative agent followed by mixed malaria. Isolated Plasmodium falciparum infection was the least common protozoa among cases. Similar, epidemiological trend was noted over a decade where Plasmodium falciparum accounted for 6.8 to 30.9% of all cases. 16 Similar observations were made in a large cross-sectional surveillance of 900 febrile patients at a city same as present study P. vivax and P. falciparum mixed infections were seen in 367 (81.7%), 67 (14.9%) and 15, respectively. 17 We have observed male preponderance with male: female ratio (2:1), similar findings have been reported in earlier reports. 11

Fever was the most common symptom among all subtypes of malaria followed by vomiting (30.7%) and headache (20%). Fever was the single most important feature seen across all subtypes of malaria, which depends on the periodicity of rupture of schizonts. 17, 18, 19 Convulsions were reported in around 15% of our cases, which are in concordance (8-13%) with other studies. 18, 19 Convulsions are common in children compared to adults. Usually, they herald the onset of cerebral malaria. 20 Convulsions occur due to febrile seizure, cerebral oedema, and hypoglycaemia or as a part of cerebral malaria. 20, 21 Similarly, headache was seen in all forms of malaria ranging from 20-26% in present study. It is a common presenting complaint in malaria ranging from 18-66% of cases in different studies. 17, 19, 22 Cytokines, few anti-malarial drugs and post malaria neurologic syndrome are possible reasons for headache in malaria. 23 Though jaundice is one of the common findings in malaria, present study had only one case with clinical jaundice. This can be attributed to the fact that the district has one of the highest literacy rates and is a medical hub in the region. The people are very well aware of malaria and early referral and diagnosis is a possible explanation for the observation.

In pediatric falciparum malaria, the major complications include anemia, cerebral malaria and respiratory distress. 24 The complications in humans are attributed to its intra-erythrocytic phase of life cycle, leading to hematological changes like severe anemia, variations in leukocyte count function and coagulopathy. 6 The most common hematological changes seen in malaria infected individuals are significantly low platelets, leucocytes, erythrocytes and hemoglobin levels. 6, 25, 26, 27, 28 Similarly, in our study population we have observed that the falciparum group showed significant low platelets, low haemoglobin in mixed malaria group (Table 2). In mixed malaria, we have seen with decreased levels of RBC, haemoglobin count, reduced packed cell volume, mean corpuscular volume and mean corpuscular haemoglobin. Our patients had leucocytosis in vivax malaria group which has been reported in other study, 25 in contrary to some studies demonstrating to leukopenia. 29 Other leucocyte changes observed were increased neutrophil and monocyte counts in vivax and mixed malaria group, respectively as explained in various studies. 25, 26, 27, 28, 30

From a mechanistic view point, these derangements in the leucocytes are due to activation of bone marrow to produce and release more leucocytes and reduced lysis at the periphery. 25 Thrombocytopenia was noted among all the groups and it was significantly low compared to controls. Severe thrombocytopenia is the common complication especially in paediatric malaria cases 31. Various studies across Indian subcontinent have documented this complication but need for platelet transfusion was extremely rare. 19, 31, 32 Though exact aetiology for this is not known it is attributed to both immunological and non-immunological destruction of platelets. 33 Demonstrations of Plasmodium vivax within platelets by electron microscopy have been postulated as direct lytic effect of the parasite on the platelets. 34 Oxidative stress induced thrombocyte destruction is also postulated aetiology. 35

At molecular level, the production of cytokines like tumor necrosis factor (TNF) and interleukins is responsible for the derangement in the haematological parameters. These molecules in turn cause increased synthesis of C reactive protein (CRP), an acute phase inflammatory protein from liver, this explains the increased CRP in our study population. 36 However, CRP had a better correlation with infective state than ESR as it was significantly elevated in all groups. Though studies have noted strong linear trends regarding increasing CRP and severity of malaria no such conclusion could be drawn in present study. 37, 38

In malaria, the liver function is deranged with hyperbilirubinemia and increased aminotransferase enzymes. 11, 39, 40 The bilirubin levels were significantly increased in mixed malaria and increased liver enzymes in falciparum malaria. The suggested pathophysiological is the increased hemolysis of infected of RBC with cholestasis and hepatitis. Similarly, acute renal failure in malaria has been reported to be in as many of 60% cases. 41 Acute renal failure is may be seen in 80.9% and 11.7% in patients with P. falciparum and P.vivax, respectively. 42 On contrary, we have observed acute renal failure in mixed malaria group accompanied with hyponatremia, hypokalemia. No mortality was documented in present study, which can be attributed to early diagnosis & referral with less prevalence of HIV and malnourishment among children in our study population which are important contributing factors of mortality in malaria.

Conclusion

In conclusion, the change in clinico-laboratory parameters in various group of malaria infected paediatric population was studied. The most common derangement was seen in haemoglobin, platelets, PCV, MCH, blood urea, electrolytes and liver function parameters. These parameters can be used along with clinical features to consider malaria as differential diagnosis when a paediatric patients present with pyrexia of unknown origin, especially in malaria endemic area presents. The limitations of the study is that it’s a retrospective study with no details of the general health status of the children, previous episodes of malaria infection which has effect on the various parameters studied.

Source of Funding

None.

Conflict of Interest

None.