Most of the complications in malaria have centred round cerebral malaria1 reported as Falciparum malaria. Though there are few reports on extra-cerebral complications of P falciparum,^2-5 comparative study of P falciparum, P vivax and smear negative cases in children are rare.

A retrospective and prospective analysis of 234 hospitalized cases of malaria in children and adolescents over a five year period in a tertiary hospital was carried out to analyze clinical symptoms⁶ laboratory parameters, complications and drug resistance pattern.⁷ Attempts have been made to analyze hepatic and renal dysfunction and complications thereof in different age groups and types of malaria (P falciparum, P vivax and smear negative patients) in order to study diagnostic parameters in smear negative cases.

Material and Methods

Children and adolescents (n=234) admitted at Bombay Hospital and MRC, Mumbai during five year period (1994-1998), diagnosed as malaria were included in this study. Complete history was taken and thorough clinical examination was carried out. Patient’s blood was collected on the day of the admission for complete haematological profile. Blood biochemistry included: serum bilirubin, SGOT, SGPT, creatinine, platelet count, bleeding, clotting and prothrombin time, LDH, alkaline phosphatase and blood urea. Routine urine was done in all cases. In cases of prolonged fever, sera were screened for somatic ‘O’, flagellar ‘H’ antigen of S. Typhi and AH antigen of S paratyphi and blood sample was sent for culture. Analysis of clinical presentation was done with respect to presenting symptoms, clinical examination and smear positivity. The analysis of the hepatomegaly and hepatic and renal dysfunction was done a) in correlation with the type of malaria as well as b) age groups (0-1, 1-5, 6-12, 13-17 years). Response to various antimalarials including complications developed were also analyzed.^6,7

Smear negative cases were included as a third group in addition to Falciparum and vivax as these cases had clinical features and other laboratory parameters like retic count, LDH and hepatic enzymes suggestive of malaria responding to antimalarial therapy after ruling out other causes of fever using appropriate diagnostic parameters.

Results
Out of 234 subjects, Male to Female ratio was 2.6:1. The peripheral smear was positive for P falciparum (41.45%), P vivax (26.49%) and smear negative (32.05%). Mixed infections were seen in 8.11% cases which have been included in Falciparum group as they showed predominant clinical features of Falciparum. Data was analyzed to correlate clinical manifestations, biochemical parameters in various age groups and the type of malaria. Including hepatic and renal parameters.

a) Hepato-splenomegaly and types of malaria
On analysis, it was observed that hepatomegaly was highest (5.33%) in smear negative cases compared to P vivax (4.84%), P falciparum (4.12%). Splenomegaly was maximum in P falciparum (22.68%) followed by P vivax (11.29%) and smear negative (13.33%). Hepatosplenomegaly was found in 40.32% of P vivax and 27.83% P falciparum malaria compared to 29.33% in smear negative cases (Table 1).

b) Hepatosplenomegaly and age
In P falciparum enlargement of spleen (70%) or liver (44%) was maximum in children < 1 year and hepatosplenomegaly (58%) in the 1-5 year age group.

The picture was reverse in P vivax group : spleen or liver enlargement was in the 1-5 year group and hepatosplenomegaly in 0-1 year group. In smear negative group hepatomegaly as well as hepatosplenomegaly was observed only in higher age group (6-12 years) and only splenomegaly in the adolescents (13-17 years) (Figs. 1, 2 and 3).

a) Hepatic dysfunction and types of malaria
Raised SGPT was seen in 20% each of Falciparum and smear negative cases which was nearly two-fold compared to P vivax (11%). Similar trend was seen in SGOT values. Hyperbilirubinaemia was higher in P. vivax (17.1%) compared to P. Falciparum (10.3%) and smear negative cases (9.33%) (Table 2).

Fig. 1 : Hepatomegaly in malaria.	Fig. 2 : Spenomegaly in malaria.
Fig. 3 : Hepatospelnomegaly in malaria.
Table 3 : Correlation between raised SGPT, age and type of malaria	Table 4 : Correlation between SGOT, age and type of malaria
Table 5 : Correlation between serum bilirubin, age and type of malaria

b) Hepatic dysfunction and age
Hepatic enzymes viz. SGPT and SGOT were raised more in the early years of life in all the groups of malaria. Raised bilirubin levels were seen in all ages in both Pf and Pv (7-33%) maximum being in the 0-1 year. Raised bilirubin was also maximum in 6-12 year group of smear negative cases (13.33%) but none in 1-5 year age group. (Tables 3, 4 and 5).

Blood culture and Widal test in malaria
In order to rule out typhoid fever blood culture and Widal test was done in 57 cases of fever more than a week’s duration. While blood culture reports were negative, 17.54% were positive for Widal test : Pf-20%, Pv-30% and smear negative-50% in a low titre of 1:30 to 1:60. (O titre in 40%, H in 30% and both in 30% cases). Repeat Widal test did not show rising titre.

Discussion
Clinically, overall hepatomegaly / splenomegaly / hepatosplenomegaly were observed in 27-40%. Raised hepatic enzymes were found in 20% each of Falciparum and vivax as well as 11% in smear negative cases. However, Nadgir et al⁸ reported higher incidence of hepatomegaly (48.5%) in vivax and 42.1% in Falciparum in adults. In children however, splenomegaly was higher both in Falciparum (78.9%) and vivax (74.1%). In cases of fever with Hepatosplenomegaly, with or without dysfunction, malaria remains an important diagnosis to be excluded. Nityanand⁹ also showed higher incidence of hepatomegaly in 75% cases of malaria.

Maximum incidence was seen in cases of Falciparum in the 0-1 year age group with splenomegaly - 70%, hepatomegaly - 44%, hepatosplenomegaly - 15% compared to 1-5 year age group which had splenomegaly - 20%, hepatomegaly - 0%, hepatosplenomegaly - 58%. In P vivax malaria, also maximum incidence was in 0-1 year, 68% showing hepatosplenomegaly but none showed isolated organomegaly followed by 1-5 years (splenomegaly - 20%, hepatomegaly - 70%, hepatosplenomegaly - 48%). In smear negative cases, incidence of splenomegaly was 20-30% in all the groups reflecting the maturity of the reticuloendothelial system.

Hepatic and renal dysfunction has been well documented in cases of Falciparum malaria. Majority of these pathological events are due to sequestration of erythrocytes containing highly metabolically active parasites in vascular bed of internal organs leading to capillary blockade and ischaemia. Hyperbilirubinaemia in malaria is due to a number of cases like intravascular haemolysis of parasitized RBCs, microangiopathic haemolysis associated with DIC etc. Unconjugated hyperbilirubinaemia is due to haemolysis whereas conjugated hyperbilirubinaemia is due to hepatocyte dysfunction. This is associated with raised transaminases and increase in prothrombin time.¹⁰ Most of our cases showed unconjugated hyperbilirubinaemia.

Our values are 2.5 times higher than those reported by Bag et al⁴ in a small series of 16 cases of Falciparum. His series showed 8% incidence in children and adolescents with lower values of SGOT (80 ± 2 IU/ml) and SGPT (102 ± 5.2 IU/ml). Our figures (16%) are comparable with the adult series of Gupta et al¹¹ in Falciparum malaria (200 malaria cases) and 15.4% of adult series of Ramchandran et al.¹²

Nityanand et al⁹ reported jaundice in all cases (adult series) of Pf. However, in our series Hyperbilirubinaemia was maximum in P vivax group (17.74%) compared to Falciparum (10.30%) and smear negative cases (9.33%). High bilirubin levels are expected in P falciparum as compared to P vivax. The higher levels of bilirubin in vivax in our series could be due to a mixed infection with P falciparum. It is well known that P falciparum is more difficult to detect than P vivax and can be missed in a mixed infection. Rise in serum bilirubin in Falciparum malaria is considered to be due to haemolysis of peripheral parasitized red blood cell and impairment in bilirubin transport because of reticuloendothelial blockade and disturbances of hepatocyte microvilli.² Dual infection with malaria and typhoid can occur hence it becomes necessary to identify both conditions in certain dual settings. A false positive Widal test has been reported in cases of malaria^13,14 showing negative blood culture, low titres and not responding to antimalarials. In our series 17.54% were positive for Widal test : Pf-20%, Pv-30% and smear negative - 50% in a low titre of 1:30 to 1:60. (O titre in 40%, H in 30% and both in 30% cases). Repeat Widal test did not show rising titre. Study from Hubli⁸ showed 14.1% widal positive in malaria cases. (21% Pf and 9.6% Pv). Significant high O titre was more in falciparum (21%) than vivax (9.6%). H titre was also higher in Falciparum (21%) than vivax (6.4%).

Renal complications include acute renal failure (ARF), glomerulonephritis and nephrotic syndrome. Glomerulonephritis is usually mild and could be due to antimalarial therapy. ARF is due to renal ischaemia and tubular injury. Presence of jaundice indirectly increases renal injury by various factors like increasing plasma renin activity and vascular response of catecholamines etc.¹⁵ Nityanand⁹ reported oliguria in 50% cases while Bag et al⁴ observed renal failure in 6% cases of P falciparum. Sharma et al¹⁶ reported acute renal failure due to P falciparum in a series consisting of 36 adults. Associated risk factor was jaundice (22.2%). Kidney biopsy showed acute tubular necrosis. Only one patient (1.3%) in our series with P falciparum had renal failure. Routine urine examination was done in 187 cases. WBC 75 phpf were seen in 10.69%, granular casts in 2.67% and RBC in 6.4%.

Literature review shows 10-40% mortality in children with cerebral malaria in cases.¹⁷ Bag et al⁴ reported 4% mortality in children with cerebral malaria while in adults it ranges from 9.5%,¹⁶ 12.4%,¹¹ 37.5%⁹ and 41.17%.¹⁸ In the present study, only one patient died of Falciparum. He had cerebral malaria with underlying malignancy and DIC during hospitalization.

Low incidence of renal failure and lower mortality in our series of cerebral malaria, could be due to prompt detection, early intervention and better care.

References

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