Blood | Bone marrow | Spleen | Liver | Lungs | Cardiovascular System | Gastrointestinal Tract | Kidneys | Central Nervous System
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]
Red blood cells: Red blood cells
are the principal sites of infection in malaria. All the clinical manifestations are
primarily due to the involvement of red blood cells.
P. falciparum
infected Red Blood Cells (x 10,500)
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. falciparum affects 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
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
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.
Liver
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.
Lungs
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.
Cardiovascular
system
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.
Gastro-intestinal
tract
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.
Kidneys
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
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.
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