Systemic Manifestations of Malaria

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1 ORIGINAL ARTICLE Systemic Manifestations of Malaria Nitya Nand*, Harikrishan Aggarwal**, Manju Sharma***, Manmeet Singh**** Abstract Clinical profile and renal functions were evaluated in sixty adult patients of malaria requiring hospitalisation to a tertiary care hospital. Liver function tests, renal profile, and haematological investigations were done on admission, day 4, and 7. There were fourteen cases of P. vivax, forty one of P. falciparum, two of mixed, and three of unclassifiable species. The mean haemoglobin was 7.4 ± 2.8 gm% (vivax 9.6 ± 1.6 gm% and falciparum 6.7 ± 2.8 gm%, p <.01). Decreased platelet counts were found in six patients. Impaired coagulation profile with deranged prothrombin time index (PTI) and positive fibrin degradation product (FDP) were observed in 36% and 4.8% cases of P. falciparum infection. Moderate hepatomegaly was seen in 20 cases and jaundice was present in 14 of them. Serum bilirubin was raised in thirty one patients (mean 7.6 ± 8.8 mg%). Transaminases were raised in forty one patients (mean AST 120 ± 134, ALT 130 ± 164 IU/L). Altered sensorium was observed in (58.5%) cases of P. falciparum, 17 had cerebral malaria and no patient of P. vivax infection had features of cerebral involvement. Renal dysfunction was more in patients of falciparum malaria with heavy infestation. In 78% of cases transient proteinuria was observed in the absence of overt renal failure. The creatinine clearance was 91.9 ± 25.4 and 53.7 ± 35.0 ml/min in vivax and falciparum subgroups respectively p < 0.001). Acute renal failure was seen 21.6% cases and was associated with hyperparasitaemia, hyperbilirubinaemia, and intravascular haemolysis. Five patients, who had a glomerular filtration rate less than 10 ml/min, required dialysis. Key words Malaria, Kidney, Acute Renal Failure, Hyperparasitaemia. Introduction Malaria is one of the most common parasitic diseases causing morbidity and mortality in the tropics. The manifestations of malaria are protean. The possible pathogenetic mechanisms are hyperparasitaemia with sequestration in internal organs, intravascular haemolysis, DIC, and immune mediated; role of cytokines mediated injury has also been documented 1,2. Recently there is a changing trend not only in the clinical manifestations but also the complications, and more and more patients are presenting with ominous systemic manifestations specially to the tertiary care hospitals. The hepatic and renal manifestations have been frequent and their mode of presentation has undergone a change making * Professor and Head, Unit IV Medicine; ** Reader, Medicine; *** Associate Professor, Biochemistry; **** Lecturer, Medicine, Department of Medicine, and Department of Biochemistry, Pt. B.D. Sharma Post-Graduate Institute of Medical Sciences, Rohtak , Haryana. it difficult for the treating physician to differentiate these from other ailments. The renal involvement in malaria varies widely, from asymptomatic proteinuria to acute renal failure(arf) 3,4. Reversible nephrotic syndrome is specifically associated with P. malariae infection 5. In the last few years there has been a mass resurgence in malaria. This was noticed after the floods in Haryana state, when a large number of patients with malaria were admitted to our institution. It was in this context that we carried out this prospective study to find out the type and extent of renal and hepatic dysfunction in these cases and also the comorbid factors associated with high mortality. Material and methods This study was performed on sixty patients of malaria for evaluation of clinical profile and renal derangements. Diagnosis of severe malaria was as per WHO criteria, i.e., (1) cerebral malaria (unarousable coma), (2) severe normocytic anaemia, (3) renal failure, (4) pulmonary oedema, (5) hypoglycaemia, (6) circulatory collapse, (7) DIC, (8) repeated generalised convulsions, (9)

2 acidosis and (10) malarial haemoglobinuria. Other manifestations of severe malaria as per WHO criteria are impaired consciousness but rousable, prostration, extreme weakness, hyperparasitaemia, jaundice, and hyperpyrexia 6. The diagnosis of malaria was established by a peripheral blood film examination. A detailed clinical history and examination were carried out. Routine investigations included blood sugar, serum electrolytes, electrocardiogram, and chest skiagram. Haematological profile including haemoglobin, total leucocyte count, differential leucocyte count, reticulocyte count, platelet count, glucose-6-phosphatase dehydrogenase deficiency, and fibrin degradation products and liver function tests were done including transaminases, serum bilirubin, and prothrombin time index. Renal profile included complete urine examination including urinary sodium and haemoglobinuria, blood urea, serum creatinine, 24 hours urinary protein, and endogenous creatinine clearance. Kidney biopsy was done if proteinuria was more than 0.4 mg/day or the patient had renal derangement or complicated malaria for which clearance from postgraduate board of studies in medicine and allied sciences was obtained. The data is presented as mean ±1 SD. The statistical analysis between falciparum and vivax group was done by using student s unpaired t test. The correlation between different variables has been calculated using Pearson s correlation coefficient. Results Out of sixty patients studied, mean age was 32.7 ± 14 years and the group consisted of thirty four male and twenty six female patients. Fourteen patients of vivax malaria, forty four of falciparum malaria, and two patients of mixed infection constituted the group. Presenting signs and symptoms included fever (100%), bodyaches (45%), headache (55%), diarrhoea (10%), dark urine (10%), altered sensorium (46.6%), jaundice (46.6%), oliguria (11.6%), pallor (78.3%), splenomegaly (60%), and hepatomegaly (33.3%). On routine investigations, mean blood sugar was 97.3 ± 11.6 mg%. Hypoglycaemia (blood sugar < 40 mg%) was observed in six patients. Twenty seven (58.5%) patients of P. falciparum had altered sensorium of which 17 had cerebral malaria. Five patients had serum bilirubin > 20 mg%. In the remaining patients, unconsciousness was secondary to renal failure or electrolyte imbalance. Haematological profile revealed mean haemoglobin of 7.4 ± 2.8 gm%, mean total leucocytic count of 7,206 ± 2,743/c.mm, and thrombocytopenia in six patients. Mean haemoglobin in vivax and falciparum group was 9.6 ± 1.68 gm% and 6.7 ± 2.8 gm% (p <.01), respectively. Hepatomegaly was seen in 1/3 of cases and 14/20 had clinical jaundice. Serum bilirubin was raised in thirty one patients (mean 7.6 ± 8.8 mg%); (median mg%); (range mg%) and it was more than 20 mg% in five of them. Forty one patients showed increased level of transaminases [mean aspartate 120 ± 134 IU; (median - 72 IU); (range )], [Mean alanine 130 ± 164 IU, (median - 84 IU); (range )]. Prothrombin index was deranged in seventeen patients, positive FDP were found in five patients and glucose-6-phosphatase deficiency (G-6PD) was seen in one patient. All the patients with deep jaundice with or without altered level of consciousness had enlarged liver, rather than a shrunken liver, and the rise in the transaminases was mild to moderate. Raised blood urea was found in nineteen patients. On admission, mean blood urea in vivax and falciparum group was 20 ± 2.5 mg% and ± mg%, (median mg%), (range : mg%), (p <.05) respectively, whereas mean serum creatinine was ± 17 and 2.1 ± 2.09 mg% (p >.05) respectively. Proteinuria more than 200 mg/day was found in forty seven patients (11-vivax, 35 falciparum, 1 mixed), with mean proteinuria being 0.52 ±.89 gm/day. Mean creatinine clearance was 91 ± 35.4 ml/min and ± ml/min in vivax and falciparum group (p <.01). Fractional excretion of sodium showed intrinsic renal 190 Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001

3 failure in thirteen patients. Hyponatraemia on admission was present in eight patients and hypernatraemia in five. One patient had hyperkalaemia and fourteen had hypokalaemia on admission (Table I). Five patients who had a glomerular filtration rate less than 10 ml per minute required dialysis. In addition to raised blood urea these patients also had oligoanuria, metabolic acidosis, hyperkalaemia, and hypervolaemia. 18% each. These histopathological changes had no clinicopathological correlation. Hyperparasitaemia (> 5% parasitaemia) was observed in seven patients (Table II). An adverse outcome was recorded in four of them (57%). The degree of hyperparasitaemia varied from 10-42%. Statistical analysis of hyperparasitaemia revealed an excellent correlation extent of hyperparasitaemia with increase in blood urea (r = 0.96, p < 0.001), Table I : Number of patients showing renal derangement in malaria. P.v. P.f. Mixed (n=14) (n=44) (n=2) Blood urea (mg%) > Serum creatinine (mg%) > GFR (ml/min) > Albuminuria (> 200 mg/day) Haemoglobinuria Serum sodium Hypernatraemia (> 150 meq/l) Hyponatraemia (< 120 meq/l) Serum potassium Hyperkalaemia (> 6 meq/l) Hypokalaemia (< 3 meq/l) Fractional excretion of sodium > < P.f. - P. falciparum; P.v. - P. vivax; GFR - Glomerular filtration rate; Mixed - P. falciparum and P. vivax. Renal biopsy was done in 11 patients. Glomerular changes were found in 54% with mesangial prominence in 45% and glomerular hyperlobulation with focal infiltration and hyalinisation in 9%. Tubular epithelial degeneration and hydropic changes were seen in serum bilirubin (r = 0.8, p < 0.01), and serum creatinine (r = 0.93, p < 0.01). A negative correlation of hyperparasitaemia was recorded with endogenous creatinine clearance (r = 0.7, p < 0.01). A significant correlation was not obtained between extent of hyperparasitaemia Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September

4 and proteinuria (r=0.37, p > 0.05). Severe anaemia, altered sensorium, thrombocytopenia, hyperparasitaemia, hepatic or renal dysfunction were associated with poor outcome (Table II). patients varying from 10-42%. The cause of death was multifactorial. Poor prognostic factors were thrombocytopenia, high parasite index, encephalopathy, and acute renal failure. Table II : Correlation of hepatic and renal parameters with hyperparasitaemia. Sr. Age Sensorium Species Serum Parasite Blood Serum GFR Urinary Renal Outcome No. & Sex Bilirubin index urea creatinine (ml/min) protein failure (mg%) (%) (mg%) (mg%) (g/day) index 1. 65M G-III P.f % > 1 Died 2. 68F G-III P.f % < 1 Died 3. 20M Normal P.f % > 1 Recovered 4. 32M G-I P.f % > 1 Died 5. 18M G-I P.f % < 1 Recovered 6. 27M G-I P.f % > 1 Recovered 7. 45M G-III P.f % < 1 Died P.f. - P. Falciparum; G - Grade of unconsciousness; GFR - Glomerular filtration rate; Mixed - P. falciparum and P. vivax. Table III : Clinical and biochemical profile of patients with adverse outcome. Sr. Age Sensorium Hb Platlets Serum Blood Parasite Species Renal GFR No. (g%) bilirubin urea index failure (ml/min) (mg%) (mg%) (%) index G-I 8.2 Decreased P.f. > G-III 3.8 Normal P.f. < G-III 5 Decreased P.f. > G-III 2.5 Decreased P.f. > G-III 5.4 Decreased Mixed > G-IV 8.9 Normal P.f. > 1 10 Hb - Haemoglobin; G - Grade of unconsciousness; GFR - Glomerular filtration rate; P.f. - P. falciparum; Mixed - P. falciparum and P. vivax. Out of sixty patients, six died, of which five cases were of falciparum and one of mixed infection (Table III). Thus an overall mortality rate of 10% was seen and mortality in falciparum and mixed infection was 13.64% (6/44). All were comatosed and had associated severe anaemia in three of them. Thrombocytopenia was observed in six patients out of which four had adverse outcome. Increased serum bilirubin was found in all these six patients ranging from 5-32 mg% (Table III). Deranged blood urea on admission was found in all these patients. Intrinsic renal failure was seen in all except one. Strong positive correlation was seen with raised blood urea and serum creatinine. Hyperparasitaemia was seen in four or these Discussion The natural history of malaria is variable due mainly to host factors immunity being most important of them. In the immune adult belonging to an endemic zone, parasitaemia may not be accompanied by fever or illness even in the face of heavy parasitaemia. In contrast, in non-immune adult primary attack can be rapidly fatal 1. The major derangements observed in this study were hepatic, cerebral, haematological, and renal. Jaundice in malaria is multifactorial. It is believed to occur as a result of intravascular haemolysis of parasitised erythrocytes, hepatic dysfunction, and possibly due to microangiopathic haemolysis associated with disseminated intravascular 192 Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001

5 coagulation. While most patients have unconjugated bilirubinaemia due to haemolysis, conjugated bilirubin may predominate due to hepatocyte dysfunction 7. The incidence of jaundice in malaria has been reported to range from % and it was predominantly haemolytic rather than hepatic 8,9. However, in the present study thirty one (57%) patients had raised serum bilirubin and it was predominantly hepatic in twenty and both hepatic and haemolytic in eleven patients; and fourteen of these patients had hepatomegaly indicating that hepatic dysfunction/involvement is on the rise. Further there was a positive correlation between the bilirubin and parasitic index; and out of eleven patients with a bilirubin level of more than 5 mg%, nine had renal derangement and five had altered level of consciousness. It is important to known that concomitant viral hepatitis may be present at times. In India, the incidence of cerebral malaria has increased from 21% to 41% in the last two decades. The most vulnerable group comprises of children, pregnant women, and elderly individuals 10. Global case fatality rate due to malaria is 1% of which 80% are due to cerebral malaria. The diagnosis of cerebral malaria is restricted to an unarousable patient (< 30 minutes) with GCS < 7/15 and evidence of acute falciparum infection 11. The pathogenesis of sequestration of parasitised RBCs in microvascular system of brain is due to cytoadherence, rosette formation, and decreased deformability of infected erythrocytes 12,13. Recent observations suggest that TNF-β found in the plasma upregulate the nitric oxide synthetase activity which interferes with the calcium influx mechanisms, producing coma 2. Anaemia is a common feature of acute malarial infection. It may develop rapidly, taking a serious turn in falciparum infection due to heavy parasitaemia. Both immuno-haemolytic and destruction of parasitised RBCs may be responsible. In this study, anaemia was observed in 85.3% in group B and 57.1% in group A patients. However, anaemia observed in endemic areas due to chronic malarial infection is largely due to immuno-haemolytic mechanisms and hypersplenism 14. Deranged renal functions, like rise in blood urea and creatinine in malaria have been attributed to various factors like dehydration, increased catabolism, and impaired renal function 15. Pathophysiology of ARF in malaria is complex and may be due to interplay of a number of factors. Three types of renal lesions are known in human malaria. They are ARF, glomerulonephritis (GN), and nephrotic syndrome. Two mechanisms are known in the pathogenesis of renal failure in P. falciparum malaria: specific effects of parasitised erythrocytes with haemorrheologic changes 16 and nonspecific inflammatory and associated factors like hypovolaemia, intravascular haemolysis, intravascular coagulation, catecholamine effect, endotoxaemia, and jaundice 17. Chronic or repeated infections with P. malariae cause soluble immune-complex injury to renal glomeruli, resulting in nephrotic syndrome. Other unknown factors may contribute because only a small proportion of infected persons develop renal disease. Renal dysfunction in the form of albuminuria is seen in 20-90% of patients in P. falciparum malaria 18,19. The incidence of acute renal failure in these patients may vary from 2.3% to 17.2% 19,20. In the present study, forty seven patients had renal dysfunction in the form of transient albuminuria. GFR was decreased in forty five patients (73%) and thirteen had acute renal failure which was multifactorial in most of the cases. Ten had intrinsic renal failure and three had prerenal ARF. Since no specific glomerular damage was seen and albuminuria decreased significantly, it appears that glomerulopathy was transient or proteinuria was tubular in origin. The higher incidence of glomerular changes was probably due to selection bias. In our patients, hyperbilirubianaemia (serum bilirubin > 5 mg%) was present in nine patients and intravascular haemolysis contributed to ARF in six patients, whereas hypovolaemia and dehydration were present in five patients. The slightly higher incidence of decreased clearance Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September

6 observed in our study may be due to advanced stage of infection in the cases evaluated. In this study, a high incidence of hepatic and renal derangements were found. The factors contributing to acute renal failure in this study were hyperparasitaemia, hypovolaemia, and multiorgan involvement. The jaundice in these cases was also multifactorial and in no case of deep jaundice/coma the liver was shrunken. The morbidity was higher in cases with multiple complications specially thrombocytopenia and hyperparasitaemia. References 1. Bhattacharya PC, Manesh PB. Unusual manifestations of pernicious malaria and newer diagnostic avenue. In: Medicine Update. APICON 1998; 8: Garg RK. Cerebral malaria (review article). JAPI 2000; 45: Boonpucknavig V, Sitprija V. Renal disease in acute P. falciparum infection in man. Kidney Int 1979; 16: Nand N, Aggarwal HK, Kumar P et al. Hepatic and renal dysfunction in falciparum malaria. J Assoc Phys India 1997; 45: Editorial: Renal lesions in human malaria. Brit Med J 1976; 2: Warrell DA, Molyneux ME, Beales PF. Severe and complicated malaria. Trans Royal Society Trop Med Hygiene 1990; 84 (2): Warrel DA, Francis N. Malaria. In Mclntyre N, Benhamou UP, Bircher J, Rizzetto M, Robes J eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford University Press Mishra SK, Mohanty S, Das BS et al. Hepatic changes in falciparum malaria. Ind J Malariol 1992; 29 (3): Wilairatana P, Looareesuman S, Choroenlarp T. Liver profile changes and complications in jaundiced patients with falciparum malaria. Trop Med Parasitol 1994; 45 (4): Patnaik S, Sharma VP, Kalra NK et al. Malaria paradigms in India and control strategies. India J Malarial 1994; 31: Newton CR, Warrell DA. Neurological manifestations of falciparum malaria. Ann Neurol 1948; 43: Patnaik JK, Das BS, Misra SK et al. Vascular clogging, mononuclear cell migration and enhanced vascular permeability in the pathogenesis of human cerebral malaria. Am J Trop Med Hyg 1994; 51: Rowe A, Obeiro J, Newbald CI et al. P. falciparum rosetting is associated with malaria severity in Kenya. Infect Immune 1995; 63: Weatherall DJ, Abdulla S. The anaemia of P. falciparum malaria. Br Med Bull 1982; 38: Sitpriya V, Indrapraset S, Poochanugul C et al. Renal failure in malaria. Lancet 1967; 1: Meyer LH. The ultrastructure of red cells infected with P. falciparum in man. Trans R Soc Trop Med Hyg 1972; 66: Sitprija V, Vongsthogsri M, Poshyachinda Y et al. Renal failure in malaria: A pathophysiological study. Nephron 1977; 18: Ehrich JHH, Horstmann RD. Origin of proteinuria in human malaria. Trop Med Parasitol 1985; 36: Rath RN, Patel DK, Das PK et al. Immunopathological changes in kidney in P. falciparum malaria. Ind J Med Res 1990; 91: Mahakur AC, Pattanayak BC, Panda SK. Acute renal failure following P. falciparum malaria in Orissa: Abstract (IPP-121): 5th Asian Pacific Congress of Nephrology, Dec 9-3, New Delhi. Ind J Nephrol 1992; 2: Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001

Study on admitted cases of complicated malaria in Government General Hospital, Guntur

Original article: Study on admitted cases of complicated malaria in Government General Hospital, Guntur 1Dr. T. V. Adi Seshu Babu, 2 Dr.Uday Shankar Sanakayala 1Associate professor, Department of General