The most pronounced changes related to malaria involve the blood and the blood-forming system, the spleen and the liver. Secondary changes can occur in all the other major organs, depending on the type and severity of the infection. The pathological changes are more profound and severe in case of P. falciparum malaria. Severe malaria is a complex multisystem disorder with many similarities to sepsis syndromes.[Claire LM, 2004]
The growing parasite consumes and degrades the intracellular proteins, mainly hemoglobin. The transport properties of the red cell membrane are altered, cryptic surface antigens are exposed and new parasite derived proteins are inserted. The red cell becomes more spherical and less deformable. In P. falciparum infection, membrane protuberances appear on the red cell surface in the second 24-hour of the asexual cycle. Accretions of electron-dense, histidine-rich parasite proteins are found under these ‘knobs’. These knobs extrude a strain specific, adhesive variant protein of high molecular weight that mediates red cell attachment to receptors on venular and capillary endothelium, causing cytoadherence. P. falciparum infected red cells also adhere to uninfected red cells to form rosettes. Cytoadherence and rosetting are central to the pathogenesis of P. falciparum malaria, resulting in the formation of red cell aggregates and intra vascular sequestration of red cells in the vital organs like the brain and the heart. This further interferes with the microcirculation and metabolism and allows parasite development away from the principal host defense, splenic processing and filtration. As a result, in P. falciparum malaria, only younger forms of the parasite are found in the peripheral circulation and the peripheral parasitemia is usually an underestimate of the true parasite load. Mature forms of P. falciparum are rarely seen in the peripheral blood and when found, indicate severe infection. Sequestration does not occur in cases of P. vivax and P. malariae infections and therefore, all stages of the parasite can be seen in the peripheral blood and complications are very rare.
Hypovolaemia is a major feature of severe malaria and, when further exacerbated by anaemia and microvascular obstruction from sequestered parasites, is likely to lead to decreased delivery of oxygen to tissues, anaerobic metabolism and lactic acidosis.[Claire LM, 2004]
Immunopathogenic processes are now recognized as having a central role in severe malaria, with proinflammatory cytokine cascades leading to complex downstream metabolic changes. As in sepsis, cytokine-induced failure of oxygen utilization is likely to play an important role. Proinflammatory cytokines and anti-inflammatory cytokines, such as interleukin-10 (IL-10), have been proposed to have a protective or counter-regulatory role. Tumour necrosis factor (TNF) is raised in those with severe malaria and has been implicated in the pathogenesis of murine cerebral malaria. TNF is also raised in placental malaria and is associated with low birth weight.[Claire LM, 2004]
Nitric oxide (NO) seems to offer protection from severe malaria. NO synthesis requires extracellular arginine, and recent studies found an association between hypoargininaemia and severe malaria and death in children. Immunohistochemistry of cerebral tissue postmortem revealed increased inducible NOS expression and markers of NO production in severe malaria. NO has been implicated in the pathogenesis of severe sepsis, and it has been suggested that NO could alternatively play a role in the pathogenesis of severe disease.[Claire LM, 2004]
Recent studies have provided strong evidence supporting a role for perforin in the pathogenesis of severe murine malaria, through disruption of the blood–brain barrier. Mice deficient in perforin appear to be resistant to cerebral and severe complications of malaria. CD8C T cells have been implicated in the pathogenesis of murine CM and might be a source of perforin, as might NKT cells. Changes in prostaglandin synthesis and expression of chemokines have also been implicated in disease pathogenesis in mice and to a lesser extent in a protective role in humans. It remains to be established how these changes relate to one another in the causal pathway, and to what extent these processes contribute to human severe malaria.[Claire LM, 2004]
The triggers that lead to excess proinflammatory cytokines are not well understood, but glycosylphosphatidylinositol (GPI) of Plasmodium falciparum has been implicated in several studies. GPI can stimulate TNF production by macrophages and increase iNOS expression.[Claire LM, 2004]
Sequestration of parasitized RBCs (pRBCs) within the small vessels of many tissues have been found on post-mortem examinations of people who have died from P. falciparum infection. Although it may contribute to high total body parasitaemia, establishing a direct cause-and-effect relationship between sequestration and cerebral malaria has proven difficult. During pregnancy, pRBCs typically sequester in the placenta. Maternal health also suffers through the development of maternal anaemia and the resultant increased likelihood of maternal death.[Claire LM, 2004]
Sequestration occurs principally during the second half of the intra-erythrocytic asexual growth phase of the parasite, following the adherence of mature parasites to endothelial cells through electron-dense knobs on the pRBC surface (cytoadherence). In vitro studies have identified several cell-surface molecules as potential receptors for pRBC binding, including thrombospondin (TSP), CD36, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule, E-selectin, chondroitin sulphate A (CSA), CD31 and hyaluronic acid (HA). In addition to adhering to endothelial cells and syncytiotrophoblasts, mature-stage pRBCs can also adhere to non-infected RBCs, forming rosettes, and to other pRBCs, forming clumps (with platelets) or autoagglutinates.[Claire LM, 2004]
Linking specific cytoadherence phenotypes to clinical syndromes has proved difficult. A plausible case can be made for ICAM-1 as a key host receptor in the brain: it is widely distributed on cerebral vessels, is upregulated by cytokines including TNF-a and was co-localized with pRBCs in brains of patients dying of cerebral malaria.[Claire LM, 2004]
Another major endothelial receptor, CD36, is not detected on human cerebral vasculature, but is ubiquitously expressed in lung, kidney, liver and muscle vasculature. Most parasite isolates causing clinical disease in non-pregnant individuals can bind to CD36. The relationship between CD36 binding and pathogenesis is not clear.[Claire LM, 2004]
Most cytoadherence phenomena appear to be mediated by PfEMP-1, a high-molecular-weight protein of approximately 240 kDa, and inserted into the erythrocyte membrane between 16 and 20 h after invasion. PfEMP-1 has been shown to bind to many host receptors.[Claire LM, 2004]
Placental sequestration is also associated with cytoadherence to HA and it has been shown that pRBC binding to CSA is mediated by PfEMP-1.[Claire L, 2004] It has been demonstrated in vitro that P. vivax isolates adhered to CSA and HA, which are receptors implicated in placental P. falciparum malaria, but not to CD36, ICAM-1 or TSP. This may explain the fact that P. vivax infection during pregnancy may be associated with severe clinical outcomes such as low birth weight, especially in multigravidous women, while the clinical consequences of infection with P. vivax are otherwise iless severe than infection with P. falciparum.[Claire LM, 2004]
Anemia is a fairly common problem encountered in malaria and it poses special problems in pregnancy and in children. It can be due to multiple causes. Repeated hemolysis of infected red cells is the most important cause for a reduction in hemoglobin levels. Anemia depends on the degree of parasitemia, duration of the acute illness and the number of febrile paroxysms. It may occur even after 3-5 febrile paroxysms. P. vivax predominantly invades young red cells and the number of parasites infected rarely exceeds 2%. P. malariae develops mostly in mature red cells and the parasitemia is rarely greater than 1%. The pathogenesis ofmalarial anaemia is complex and undoubtedly involves multiple processes relating to both the destruction of erythrocytes and their reduced production.[Claire LM, 2004] P. falciparumaffects red cells of all ages and the parasitemia can be as high as 20-30% or more. Massive destruction of red cells accounts for rapid development of anemia in P. falciparum malaria. Nonparasitized RBCs are also removed from the circulation by complement-mediated lysis and phagocytosis resulting from immune complex deposition and complement activation.[Claire LM, 2004] Increased splenic clearance of parasitized as well as non-parasitized red cells, reduction of red cell survival even after disappearance of parasitemia, dyserythropoeisis in the bone marrow, drug induced hemolysis etc. also contribute to the anemia. During P. falciparum infections, reticulocyte levels are inappropriately low, reflecting suppression of the normal response of erythropoietin (EPO).[Claire LM, 2004] Some of these mechanisms may perpetuate anemia even after completion of the treatment.
Anemia of malaria is usually normocytic hypochromic with increase in the number of reticulocytes and polychromatophils. Rarely, atypical manifestations like macrocytic anemia or pseudoaplastic picture with pancytopenia may be seen. Anemia may be associated with hyperbilirubinemia of the indirect type, due to the hemolytic process. Splenomegaly may also be seen.
Leukocyte count is usually low to normal in most cases of malaria. Increased leukocyte count indicates either a severe infection or secondary bacterial infection. Reduction in the leukocyte count is attributed to hypersplenism or sequestration in the spleen. Relative lymphocytosis, monocytosis, eosinopenia, presence of stab neutrophils are observed with prolonged duration of the illness.
Thrombocytopenia is also fairly common in malaria. It has been observed that the platelet count shows a moderate decline during the paroxysms of fever. Thrombocytopenia may be related to the sequestration of the platelets in the spleen. Severe thrombocytopenia however indicates severe infection and may herald bleeding syndromes.
Erythrocyte Sedimentation Rate is usually elevated in malaria up to 30-50 mm in one hour. Prolonged malaria, severe anemia and severe malaria are usually associated with a higher ESR.
Bone marrow may show evidence of dyserythropoeisis, iron sequestration and erythrophagocytosis in the acute phase of falciparum malaria. Maturation defects may be present in the marrow for 3 weeks after the clearance of parasitemia. Large, abnormal looking megakaryocytes have been found in the marrow and the circulating platelets may also be enlarged, suggesting dysthrombopoeisis.
Spleen plays an important role in the immune response against malarial infection and splenectomy invariably activates a latent infection. Enlargement of the spleen is one of the early and constant signs of malarial infection. Spleen may become palpable as early as the first paroxysm.
Spleen may be palpable at the early stages of infection in the right lateral position or even in supine position. Its edge is usually round and hard to palpate and it may be tender. As the disease progresses, the spleen becomes harder, less sensitive and readily palpable. In falciparum malaria, spleen may not be palpable if the patient presents very early (due to severity). Otherwise, splenomegaly is common in all types of malaria.
The early enlargement of the spleen is due to engorgement, oedema of the pulp and later due to lymphoid and reticulo-endothelial hyperplasia with an increased hemolytic and phagocytic function of the organ. Frequent relapses and re-infections lead to pulp sclerosis and dilated sinuses.
Following treatment, spleen regresses in size, usually completely, within two weeks. In cases of large, fibrotic spleen due to repeated malaria, regression is slower, but complete involution with treatment is common.
Rapid and considerable enlargement of spleen may sometimes result in splenic rupture, which is a serious complication of malaria. This is more common in primary attack of malaria. Due to fibrosis and perisplenitis, rupture is less likely in case of chronic splenomegaly.
A small proportion of adults in Africa and India and a high proportion of adults from New Guinea have been found to suffer from huge enlargement of the spleen. This condition has been termed as the Tropical Splenomegaly Syndrome. Its nature still remains unclear. It is characterized by marked enlargement of the spleen whose weight may reach 2000-4400 g. The splenic sinuses are dilated and there is marked lymphoid hyperplasia. There is increased phagocytosis of red and white blood cells. The liver is also enlarged and shows lymphoreticular infiltration of the sinusoids. High levels of Ig G and Ig M antibodies against malaria have been demonstrated in these patients. These patients also have anemia, leucopenia, and thrombocytopenia with fairly well maintained general health. Prolonged anti malarial treatment may reduce the size of the spleen in these patients.
Enlargement of the liver also occurs early in malaria. The liver is enlarged after the first paroxysms, it is usually firm and may be tender. It is oedematous, coloured brown, grey or even black as a result of deposition of malaria pigment. Hepatic sinusoids are dilated and contain hypertrophied Kupffer cells and parasitized red cells. Small areas of centrilobular necrosis may be seen in severe cases and these may be due to shock or disseminated intravascular coagulation. Prolonged infection may be associated with stromal induration and diffuse proliferation of fibrous connective tissue. However, changes of cirrhosis are not seen. In falciparum malaria, in addition to the involvement of the mesenchyma, the hepatocytes may also be involved, causing functional changes as well (malarial hepatitis).
Malarial hepatitis is characterized by hyperbilirubinemia with elevation of conjugated bilirubin, increased levels of transaminases and alkaline phosphatase. Being part of the severe falciparum infection, it may be associated with renal failure, anemia or other complications of falciparum malaria. Liver involvement in severe falciparum malaria is due to impairment of local microcirculation associated with hepatocellular damage.
In patients with repeated attacks of malaria, liver also enlarges significantly along with a large and hard spleen. However, there is no functional abnormality of the liver in these patients. Malaria is not a proven cause for cirrhosis of the liver.
Involvement of the lungs occurs in P. falciparum malaria and is secondary to the changes in the red blood cells and the microcirculation. Acute pulmonary oedema is an infrequent but nearly fatal complication of P. falciparum malaria, largely due to capillary endothelial lesions and perivascular oedema. Fluid overload and blood transfusion may also contribute to this problem. Pulmonary capillaries and venules are packed with inflammatory cells and parasitized red cells. The vascular endothelium is oedematous with narrowing of the lumen. Interstitial oedema and hyaline-membrane formation is also seen.
Focal or lobar pneumonia and bronchopneumonia can also complicate malaria.
Malaria is commonly associated with cardiovascular function abnormalities. The most frequent changes during a paroxysm include decrease in blood pressure, tachycardia, muffled heart sounds, transient systolic murmur at the apex and occasional cardiac dilation. Also there is peripheral vasodilation, leading to postural hypotension.
In P. falciparum malaria, there could be microcirculatory changes in the coronary vessels. The myocardial capillaries are congested with parasitized red cells, pigment laden macrophages, lymphocytes and plasma cells.
Malaria may aggravate a pre-existing cardiac dysfunction and may prove fatal to patients already suffering from significant cardiac failure or valvular obstruction.
Malaria is often accompanied by nausea and vomiting, mainly central in origin. In the acute phase, patient may have anorexia, abdominal distention, and pain in the epigastrium. Some times the abdominal colics may be so severe as to mimic acute abdomen or appendicitis. Some patients may have watery diarrhoea and the condition may mimic gastro-enteritis or cholera.
Acute colitis may be associated with malaria. Bacillary dysentery, amoebiasis, etc. may complicate malaria.
In falciparum malaria, involvement of splanchnic microcirculation can lead to ischaemia of the gut, mucosal oedema, necrosis and ulceration. This may hamper absorption. Further these changes in the gut may also lead absorption of toxins, precipitating septic shock.
Malaria can cause varied problems in the kidneys. During the acute attack, albuminuria may be seen commonly. Acute diffuse malarial nephritis with hypertension, albuminuria and oedema may also be seen rarely.
In P. malariae infection, nephrotic syndrome may be seen (Quartan malaria nephropathy). This immune complex mediated nephropathy develops weeks after the malarial illness and is characterized by albuminuria, oedema and hypertension. It may be progressive and may require treatment with steroids or immunesuppressants.
In severe P. falciparum malaria, acute renal failure may develop in 0.1-0.6% of the patients. Microcirculation disorders, anoxia and subsequent necrosis of the glomeruli and renal tubules are responsible for this serious complication. Disseminated intravascular coagulation also may cause or aggravate this problem.
Central nervous system manifestations in malaria could be due to pathological involvement of the brain, paroxysms of fever or due to the side effects of antimalarial drugs.
The febrile paroxysms are usually accompanied by head aches, vomiting, delirium, anxiety and restlessness. These are as a rule transient and disappear with normalization of the temperature.
Antimalarial drugs like chloroquine, quinine, mefloquine and halofantrine can cause various symptoms like dizziness, vertigo, tinnitus, restlessness, hallucinations, confusion, delirium or even frank psychosis, convulsions etc. Quinine can induce hypoglycemic coma. Artemisinin derivatives are known to cause brain stem dysfunction in animal studies. These factors should always be kept in mind while managing cases of malaria.
Nervous system gets involved predominantly in P. falciparum malaria and only very rarely in the other forms. Decreased deformability, increased cytoadherence and rosetting of red cells, occlusion of the microcirculation by the red cell rosettes and their thrombosis- all these result in cerebral anoxia, development of malaria granulomas and punctate haemorrhages leading to malarial encephalitis and meningoencephalitis. At autopsy, the brain is found to be oedematous; small blood vessels are congested with parasitized red cells; the surface of the brain appears leaden or plum coloured while the cut surface has a slatey-grey hue. Up to 70% of the red cells in the brain may be found to be parasitised, and many mature forms of the parasite including schizonts could be seen. In larger vessels, the parasites form a layer along the endothelium, called as ‘margination’. The vascular endothelium shows pseudopodial projections, which may be in close apposition to the ‘knobs’ on the surface of the parasitized red cells. Numerous petechial haemorrhages are found in the white matter, proximal to the occlusive plugs in the end arterioles. Dürck’s granulomata, small collections of microglial cells surrounding an area of demyelination may be seen at the site of these haemorrhages.
- Claire L. Mackintosh, James G. Beeson, Kevin Marsh. Clinical features and pathogenesis of severe malaria. TRENDS in Parasitology December 2004;20(12)
- Rowe JA, Claessens A, Corrigan RA, Arman M. Adhesion of Plasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications. Expert reviews in molecular medicine doi:10.1017/S1462399409001082; Vol. 11; e16; May 2009. Abstract
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