The Role of Platelets in Malarial Acute Lung Injury and Acute Respiratory Distress Syndrome: A World of Possibilities.

In recent decades our understanding of platelets’ role in immune response has increased. Traditionally platelets were considered as bleeding-stopping and thrombosis-causing cells. In recent years the platelets’ role in malarial innate and adaptive immune responses is being recognized. Platelets play critical role in pathogenesis of malaria infection leading to variety of outcomes. It is being realized that platelets play dual role in case of malaria (i) by preventing early stage exponential growth of parasitemia (ii) promoting exaggerated immune responses later. Platelets role in pathogenesis of severe and cerebral malaria has been widely studied. However their role in malaria related acute lung injury and respiratory distress has gained less attention. Recently the presence of active megakaryocytes and proplatelets have been explained in human lungs. Simultaneously, the platelets role in pathogenesis of acute lung injury and respiratory distress (ALI/ARDS) was also recognized. This gives a hint that there is a possible association of platelets with malaria related respiratory diseases as well. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. In this review we have attempted to establish the importance of role of platelets in malaria related acute lungs injury and malaria acute respiratory distress syndrome and try to explain the underlying mechanism of this process. In ALI/ARDS, including those caused by malaria, platelets participate sequestration to the vascular bundle facilitating the recruitment of immune cells viz. neutrophils. Additionally, they secrete or induce the secretion of chemokines that result into vascular damage.

Hypohaptoglobinaemia as a biochemical and epidemiological marker of falciparum malaria.

OBJECTIVES: The study was conducted in two parts to find out the usefulness of hypohaptoglobinemia (Hpo) as a biochemical and epidemiological marker of malaria. Part-I study was conducted in a Medical College Hospital to find out Hpo in malaria and the time required for normalization of Hpo. Part-II study was undertaken in two endemic areas of malaria to find out the prevalence of Hpo and haptoglobin index (HI) throughout the year along with other indicators of malaria. METHODS: In Part-I study, 172 patients of malaria constituting 58, 52 and 62 patients of cerebral malaria, uncomplicated falciparum malaria and vivax malaria, respectively were enrolled. Along with routine haematological and biochemical investigations, haptoglobin (Hp) estimation was done by endoplate haptoglobin test kit on admission and at 15 days interval for 3 months. In Part-II study Hp was estimated is 305 subjects in two endemic areas of malaria. HI, parasitic index, slide positivity rate (SPR), slide falciparum rate (SFR) were estimated throughout the year and HI was compared with these epidemiological markers. RESULTS: Hpo was present in 102 (92.7%) cases of falciparum malaria which was significantly more than vivax malaria and non-malarial fever. The normalisation of Hpo took about a month or more. The incidence of Hpo was 32.1% is endemic and 4.7% in nonendemic area of malaria. The HI varied between 12.4 to 25.2% throughout the year and was found to be a better marker than other classical markers of malaria. CONCLUSION: Hypohaptoglobinemia may be considered as a useful indirect indicator of falciparum malaria. HI can be used as an epidemiological maker which is better than classical markers of malaria used at present.

Importance of blood glucose level at the time of admission in severe and complicated malaria.

A prospective study of blood glucose level at the time of admission was done on 532 cases of severe and complicated malaria admitted in classified malaria ward at PBM Hospital, Bikaner. Eleven patients had blood glucose level < 40 mg% (< 2.2 mmol/L) and all were unconscious with diagnosis of cerebral malaria. Four patients became conscious with i.v. infusion of 25% dextrose only without receiving any specific antimalarial treatment. Recognition of these patients of "falciparum malaria with hypoglycaemia" by blood glucose estimation at the time of admission can significantly affect the ultimate outcome. The mortality trend was more in patients having blood glucose level < 40 mg% (< 2.2 mmol/L) in comparison to group of patients having blood glucose level between 41 to 60 mg% (2.2 to 3.3 mmol/L) and was least in those having blood glucose level > 60 mg% (> 3.3 mmol/L).

Serum cortisol levels in patients with uncomplicated and cerebral malaria.

Ten patients with uncomplicated malaria, ten with cerebral malaria and 37 controls (blood donors from blood bank) were included in the study. The serum cortisol levels of the patients were determined daily for 7 days while they were at the hospital. A radio-immunoassay method was used for quantitative measurement of cortisol in human serum. The mean serum cortisol level of patients with uncomplicated malaria was 528.2 +/- 123.9 nmol/l, with cerebral malaria was 516.0 +/- 80.5 nmol/l, and in controls was 393.8 +/- 141.0 nmol/l. There was a significant rise of serum cortisol levels in patients with malaria when compared to controls at the day of admission to hospital. There was no significant difference between uncomplicated malaria patients and those with cerebral malaria. There was also no significant difference between the different days of treatment up till day 7. We found no cortisol insufficiency in cases with falciparum malaria during acute and convalescent stages of illness.

Serum complement C4 levels during acute malarial infection and post-treatment period.

The researches are conducted in adults and children infected with the species P. falciparum and P. vivax. The results indicated that complement C4 level showed a marked fall during the course of acute malaria in both the children and adults infected with both species. A highly significant hypocomplementaemia was recorded (p < 0.01). Children infected with P. falciparum developed acute cerebral malaria, which was associated with marked hypocomplementaemia. A marked rise in C4 level was noticed on 10th day and it was found normal with reference to control, on 20th and 30th day. A considerable reduction in C4 complement was recorded in P. falciparum when compared to P. vivax.

Serum transcobalamin II levels in patients with malaria infection.

Serum transcobalamin II (TCII) levels were determined in 56 patients with P. falciparum malaria infection. They were divided into 3 groups: severe (malarial parasite > 5% or patients with cerebral malaria or renal insufficiency), moderate (1-5% infection without complications) and mild (1% infection). Elevated serum TCII values were found only in patients with severe malaria infection. These values correlated directly with parasitemia, blood urea nitrogen and creatinine, but were not correlated with alkaline phosphatase. As 17 patients with azotemia had elevated serum TCII levels while other 3 patients with normal BUN and creatinine concentrations had serum TCII levels within the normal limits. These findings indicated that malarial patients with renal insufficiency had increased serum TCII. A possible mechanism is the reduced TCII-B12 that filtered through the glomeruli due to the reduced renal blood flow with the decreased its uptake by proximal tubular cells resulting in the decreased degradation of TCII by the tubular lysosomal enzymes. Determination of serum TCII level may be used as an indicator of renal function in malarial patients with renal insufficiency.

Abnormally elevated serum transcobalamin II levels in patients with cerebral malaria.

Transcobalamin II (TCII) levels have been reported to be elevated in patients with many clinical conditions including proliferative reticuloendothelial system. As reactive macrophage hyperplasia frequently occurs in patients with malaria, the objective of the present study was to determine TCII in patients with Plasmodium falciparum with cerebral symptoms. The studies were performed on 14 cerebral malaria patients as well as 60 normal subjects. The mean values of serum vitamin B12 and TCII levels were significantly higher in the patient group and 6 and 7 patients had serum vitamin B12 and TCII levels higher than the normal values. There was direct relationship between serum TCII levels and BUN or creatinine levels. These findings indicated that raised serum TCII level occurred only in patients with renal insufficiency. A decreased glomerular fiLtration rate reduced the amount of vitamin B12 and TCII-B12 that filtered through the glomeruli resulting in the reduced proximal tubular cells uptake and its degradation of TCII. This reduced lysosomal enzyme activity, therefore, prolongs the intravascular TCII survival and increased secretion of TCII into the circulation. Therefore, serum TCII levels were elevated in these cerebral malaria patients.

Overview: pathophysiology and management of cerebral malaria.

Cerebral malaria is still a major cause of death in patients suffering from malaria. Much of the research work in the past two decades has been done to clarify the pathophysiology of cerebral malaria which hopes to improve the management of the disease and concomitantly reduce mortality. However, the pathogenesis of cerebral malaria is still not clear. The pathophysiology of coma is believed to be brain anoxia from ischemia due to sequestration of erythrocytes containing mature parasites in cerebral capillaries and venules. Three possible mechanisms of sequestration (cytoadherence, rosette formation and decreased deformability of the infected erythrocytes) are postulated. The management of cerebral malaria includes early diagnosis and early treatment with potent antimalarial drugs, early detection and treatment of complications, correction of fluid and electrolyte imbalance and proper nursing care. In spite of these efforts, a high mortality rate (ranging 10-40%) is still encountered.