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Clinicopathological Case
-
CNS
Aoife a third year medical student from Trinity College decides to spend
some time in Kenya for her medical overseas voluntary elective.
Q
What vaccinations or medications is she going to need prior to
travel?
Vaccinations:
Hepatitis A
Recommended for all travellers
Typhoid
Recommended for all travellers
Yellow fever
Recommended for all travellers greater than nine
months of age
Polio
One-time booster recommended for any adult
traveller who completed the childhood series but
never had polio vaccine as an adult
Hepatitis B
For travellers who may have intimate contact with
local residents, especially if visiting for more than 6
months
Rabies
For travellers who may have direct contact with
animals and may not have access to medical care
Measles, mumps, rubella
(MMR)
Two doses recommended for all travellers born after
1956, if not previously given
Tetanus-diphtheria
Revaccination recommended every 10 years
Malaria:
Prophylaxis with Lariam, Malarone, or doxycycline is recommended for all
areas except Nairobi and the highlands (above 2500 m) of Central, Eastern,
Nyanza, Rift Valley, and Western Provinces.
She receives the appropriate vaccinations and begins taking Mefloquine
(Lariam) once weekly in a dosage of 250 mg, one-to-two weeks before she
travels which she continues through the trip. While in Africa she feels
generally unwell with symptoms of nausea, vomiting and insomnia.
Comment on these symptoms.
She returns home after her elective and stops taking Mefloquine one week
later. While travelling home she had mild flu like symptoms, so she took
paracetamol and they seemed to clear up after a couple of days.
10 days after her return she developed a fever which lasted two days during
which time she took some more paracetamol to bring her temperature down.
Her flatmate arrived home to find her un-rousable. She shook her gently and
Aoife’s eyes opened, but the girl stared blankly ahead, unable to make eye
contact. Her friend called her mother and by the time she arrived Aoife had
suffered a convulsion - her arms and legs jerking uncontrollably for several
minutes before her body went limp. They called an ambulance and she was
immediately transferred to A&E.
The hospital physician noted that Aoife’s fever was over 103° Fahrenheit and
her gaze was blank and roving. Shortly after the initial examination, Aoife
began convulsing again, and the physician administered an anticonvulsant
drug.
Q
What tests should be ordered?
LABORATORY AND MICROSCOPIC EXAMINATION:
Table 1. Laboratory values at admission
Full Blood Count
Cell Type
Value
WBC
* 2.6
RBC
* 3.06
Hgb
* 9.0
Hematocrit (HCT)
* 25.8
MCV
84.2
MCH
29.5
MCHC
35
RDW
* 16.7
Differential
Neutrophils
* 21
Absolute Neutrophils
* 0.55
Lymphocytes
* 61
Absolute Lymphocytes
1.58
Monocytes
* 15
Absolute Monocytes
0.39
Eosinophils
1
Absolute Eosinophils
0.03
Basophils
0
Absolute Basophils
0.00
Bands
2
Absolute Bands
0.05
Platelets
* 98
* = out of reference range
Reference
4.5-13 (x109/L)
4.5-5.3 (x109/L)
13.5-17.5 (g/L)
37.0-49.0 %
78-98 fL
24-30 pg
32-36 g/dL
11.8-15.2 %
31-61 %
1.80-8.00 (x109/L)
28-48 %
1.40-5.90 (x109/L)
3-9 %
0.00-0.80 (x109/L)
0-3 %
0.00-0.60 (x109/L)
0-2 %
2-8 %
156-369 (x109/L)
Q
What is the tentative diagnosis?
A
Cerebral malaria.
Q
What causes morbidity associated with Malaria?
Much of the morbidity and mortality associated with malaria is caused by the
rupture of iRBCs (infected red blood cells) during the asexual reproductive
stages of the parasite. Intense fever, occurring in 24-72 hour intervals, is
accompanied by nausea, headaches, and muscular pain among other
symptoms. The characteristic fever spike has been correlated with
incremental rises in serum levels of TNF- associated with the release of
parasite proteins during erythrocytic rupture. Furthermore, a variety of
potentially fatal symptoms, including liver failure, renal failure, and cerebral
disease are associated with untreated P. falciparum. These symptoms are
consequences of the unique ability of the parasite to bind to endothelial
surfaces; this adherence inhibits circulation and causes localized oxygendeprivation and sometimes hemorrhaging. It has been proposed that ICAM-1,
E-selectin, VCAM-1, and chondroitin sulfate A (CSA), and CD36 are some of
the surface molecules responsible for parasite-endothelial adherence.
Why is the patient anaemic?
The growing parasite consumes and degrades the intracellular proteins,
mainly haemoglobin. 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 electrondense, 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.
Anaemia 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 haemoglobin levels. Anaemia 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%. 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.
Immune and non-immune haemolysis of non-infected red cells, increased
splenic clearance of parasitized as well as non-parasitized red cells, reduction
of red cell survival even after disappearance of parasitaemia,
dyserythropoeisis in the bone marrow, drug induced haemolysis etc. can also
contribute to the anaemia. Some of these mechanisms may perpetuate
anaemia even after completion of the treatment.
Anaemia of malaria is usually normocytic hypochromic with increase in the
number of reticulocytes and polychromatophils. Rarely, atypical
manifestations like macrocytic anaemia or pseudoaplastic picture with
pancytopenia may be seen. Anaemia may be associated with
hyperbilirubinemia of the indirect type, due to the haemolytic 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 anaemia and severe malaria are
usually associated with a higher ESR.
Q
What is Malaria?
A
Malaria is an infectious disease caused by the release of protozoan
parasites into the bloodstream by the bite of a parasite-carrying Anopheles
mosquito. After an incubation period of one to four weeks, initial malaria
symptoms begin that usually include fever, headaches, vomiting, chills, and
general malaise, similar to the flu. These symptoms are caused by the release
of the parasites’ products into the bloodstream. Most people, if treated,
recover relatively easily, but the unlucky others, like Halima, will develop the
disease’s more severe form, cerebral malaria, in which the parasite-infected
red blood cells attach in large numbers to the circulatory vessels of the brain.
GENERAL REVIEW OF PLASMODIUM SP. LIFE CYCLE
The Plasmodium parasite undergoes two cycles of replication; sporogony (the
sexual cycle) and schizogony (the asexual cycle). Sporogony occurs in the
intestinal tract of the anopheline mosquito. Sporozoites, the product of
sporogony, migrate to the salivary glands and are injected into the
bloodstream when a mosquito bites a person. The sporozoites circulate briefly
in the peripheral blood then enter hepatocytes. Inside hepatocytes (the
exoerythrocytic stage) multiplication occurs. After approximately ten days,
the merozoites enter the peripheral blood and infect erythrocytes (the
intraerythrocytic stage). Inside the erythrocyte, the merozoite develops into
the trophozoite or "ring form". The trophozoite develops into a schizont made
up of multiple merozoites, a process called schizogony (the asexual
replication cycle). The schizont matures causing rupture of the erythrocyte
and releasing merozoites into the circulation which in turn infect other
erythrocytes. The paroxysms or cyclical fevers classically associated with
malaria occur shortly before or at the time of erythrocyte rupture. Infection
with P. malaria causes paroxysms every 72 hours (quartan malaria). Infection
with P. ovale or P. vivax cause tertian malaria with paroxysms every 48 hours.
P. falciparum tends to produce irregular fever spikes superimposed upon a
continuous fever or the tertian malaria paroxysms every 48 hours.
Merozoites will develop into gametocytes (female macrogametocytes and
male microgametocytes) following several intraerythrocytic cycles. The
gametocytes are infectious to the mosquito when ingested. In the intestine of
the mosquito, the microgametocyte enters the macrogametocyte (sporogony)
and zygotes are produced. The zygotes enter intestinal cells and develop into
sporozoites. These sporozoites then migrate to the salivary glands continuing
the Plasmodium life cycle.
CLINICAL MANIFESTATIONS
Fever develops 7-10 days following infection, during the exoerythrocytic cycle
of merozoite development in hepatocytes. It is during the intraerythrocytic
cycle that the spiking fevers associated with erythrocyte lysis occur. Other
symptoms include malaise, fatigue, anemia, headache and myalgias.
Complications associated with P. falciparum infection include acute renal
failure, pulmonary edema, and cerebral malaria (with seizures and coma).
Hepatomegaly and splenomegaly have been documented with splenic
rupture most commonly associated with P. vivax infection. P. malariae has
been associated with an immune complex glomerulonephritis. Abnormal
laboratory findings include decreased hemoglobin, hematocrit, platelet count
and haptoglobin. Lactic dehydrogenase and reticulocyte count are generally
increased. Increased bilirubin and increased serum enzymes may be noted
and are not specifically associated with the exoerythrocytic stage.
DIAGNOSIS
Diagnosis is best made utilizing thick smears of peripheral blood but thin
smears can also be used. In P. falciparum infection the parasite is identified as
a tiny ring form within normal sized erythrocytes. These ring forms often
show double nuclei and "applique" morphology against the cytoplasmic
membrane. Multiple ring forms are commonly seen in P. falciparum.
Merozoites when seen are usually >24 per cell. The gametocytes show a
classic boomerang or banana shape. In P. vivax infection the parasite is
identified as large ring forms (approximately 1/3 of cell width) in an enlarged
erythrocyte. Shuffner's dots (pink granules) are commonly seen. Merozoites
usually number between 12-24 per erythrocyte. Gametocytes are large and
circular or ameoboid. P. malariae may demonstrate band like trophozoites. In
P. malariae, the ring forms are rarely multiple and when multiple the
possibility of a double infection with another Plasmodium species should be
considered. Usually less than 12 merozoites per cell are seen. Indirect
immunofluorescence may be used for serodiagnosis of malaria and a titer
greater than 1:64 is considered diagnostic.
TREATMENT
Decisions regarding treatment of malaria must take into account where the
patient will be living while on therapy, the parasite load, the need for natural
acquired immunity, patient symptoms, complications, and the problem of
drug resistance. Pharmacologic treatment of malaria has become complicated
by the emergence of drug resistant forms of parasites. Resistant forms of P.
falciparum have been well documented for almost all antimalarial drugs,
including chloroquine, other 4-aminoquinolines, and Fansidar. Cross
resistance has quickly developed due to molecular similarities of drugs and
limited modes of action on the parasite.
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Cerebral malaria is a life-threatening complication of P. falciparum
infestation that occurs in approximately 2% of the cases.
In endemic areas it affects mainly children. Occurrence in adults is far
less frequent, yet it is seen among persons who have lived away from
endemic areas for a sufficient time to have lost their immunity.
Progressive clinical changes occur along with high fever and chills.
The neurologic manifestations are nonspecific because of diffuse
involvement of the brain.
Transient extrapyramidal and neuropsychiatric manifestations as well
as isolated cerebellar ataxia may occur, but localizing signs are rare.
Coma may ensue, and approximately one third of patients die.
•
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These red blood cells, shown in a
coloured electron micrograph, are
infected with malarial parasites.
The parasites swell the cells and
eventually break out and spread,
infecting additional cells.
The more blood cells infected, the more
severe the disease.
Q
What is the treatment?
A
Quinine and intravenous fluids.
Q
How does malaria produce such profound symptoms?
Several reasons could be responsible for the more complicated forms of
malaria and their neurological symptoms, for example a lack of blood flow to
the brain or slower blood flow resulting in brain damage, swelling, and
inflammation of clogged blood vessels, or perhaps damage stemming from
seizures.
It is likely that the reason that some people contract cerebral malaria while
others develop only an uncomplicated form of infection pertains more to
individual differences in how the immune system responds to the parasite
than to the parasite itself.
Q
Could the body itself be causing damage in its attempts to keep the
parasite at bay?
CM is the result of an over-vigorous immune response originally evolved for
the protection of the host. Evidence in support of this second hypothesis
comes from studies in murine malaria models in which T cells, monocytes,
adhesion molecules and cytokines, have been implicated in the development
of the cerebral complications.
Recent studies of human CM also indicate a role for the immune system in the
neurological complications. However, it is likely that multiple mechanisms
are involved in the induction of cerebral complications and both the presence
of parasitized erythrocytes in the central nervous system (CNS) and
immunopathological processes contribute to the pathogenesis of CM.
Most studies examining immunopathological responses in CM have focused
on reactions occurring primarily in the systemic circulation. However, these
also do not fully account for the development of cerebral complications in
CM.
Many host and parasite factors have been proposed to play a role in the
induction of cerebral complications during P. falciparum infection (reviewed in
Newton and Warrell).
The more prominent theories include: mechanical or sequestration, toxin,
cytokine, nitric oxide (NO), reactive oxygen species (ROS), permeability,
immunological hypotheses.
One of the dominant hypotheses, the 'sequestration' hypothesis (reviewed in
Berendt et al.), suggests that sequestration causes multifocal abnormalities in
cerebral blood flow (including both vascular obstruction and dilatation)
leading to microheterogeneous hypoxaemia, acidosis, hypoglycaemia and
other metabolic derangements affecting brain function, resulting in coma.
However, this mechanism seems insufficient to explain all the known features
of human CM. For example, blockage of blood flow would be expected to
result in stroke-like pathology involving anoxic neuronal injury and severe
residual impairment.
This contrasts with the findings in the majority of human CM cases, in which
prolonged coma proceeds to apparent functional recovery.
Q
What are the Histologic findings in Cerebral malaria?
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The histologic findings in cerebral malaria include:
– sequestration of infected erythrocytes in brain vessels, mainly
cortical and perforating arteries, with peri-vascular ring
haemorrhages and white matter necrosis.
Presence of oedema is more difficult to document pathologically
because, in postmortem studies, brain oedema may not be appreciated
Pathological features in patients who died of clinically defined cerebral
malaria.
(a) Example of sequestration. Fresh coronal section of brain is swollen and
slightly grey in colour, and has no visible haemorrhages. Bottom left, highpower (x100) view of cortex showing many parasitized vessels. Bottom right,
single cortical vessel (under oil immersion (x1,000) containing unpigmented
parasites.
(b) Pattern of sequestration and microvascular pathology. Fixed coronal
section of brain is swollen and has multiple petechial haemorrhages in the
cortical white matter. Bottom left, high-power (x400) view of cortex showing
haemorrhage surrounding a parasitized vessel. Bottom right, higher-power
(x400) view of cortex showing ring haemorrhage around vessel containing
parasites and a thrombus.
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White matter changes. The first examination, 2 days after the onset of
cerebral malaria, shows hyperintensity in the semiovale centrum along
with abnormal signal in the splenium of the corpus callosum (arrow) on
fast spin-echo T2-weighted MR images (4700/102 (A and B) and on fast
FLAIR images (10,000/ 145; TI 5 2200) (C and D).
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On contrast-enhanced T1-weighted images (620/10) (E and F), only the
unenhanced hypointense lesion of the corpus callosum is visible.
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At follow-up examination, 1 week after the onset of illness, T2weighted (G and H) and FLAIR (I and J) images show resolution of
hyperintensities, except for the lesion of the splenium of the corpus
callosum.
In comparison with the first examination, there is a widening of the
sulci and volume enhancement of the ventricles.
These changes may have been caused by initial brain swelling or by
subsequent atrophy, the former being the most likely, because of the
short time between examinations.
The immune response to malaria
T cells appear to be central to both malaria immunity and to the
manifestations of CM. Using murine models it has been shown that the
primary immune response to asexual blood stage parasites is mediated by
CD4+ T cells, which are required for cell mediated immunity, but not for help
in antibody production.
There is evidence of marked T-cell activation in human CM.Riley and
colleagues examined, in a malaria-endemic population with differing levels of
clinical immunity to malaria, the relationship between:
(i) soluble IL-2 receptors and lymphoproliferative responses to malaria
antigens; and
(ii) plasma IL-2 receptor levels, age, malaria parasitaemia and clinical
symptoms.
They found high levels of soluble IL-2 receptor in the plasma of malariainfected individuals and this was independently associated both with age and
parasitaemia. As the plasma concentration of soluble IL-2 receptor is an
indication of T-cell activation in vivo, this group concluded that a vigorous
cellular immune response to malaria antigen occurs in vivo.
Monocyte and macrophage involvement in immunity to murine and human
malaria
Hepatomegaly and splenomegaly are characteristic features of murine and
human malaria infection and have been attributed not only to
erythrophagocytosis, but also to increased numbers of macrophages recruited
from the circulation The role of spleen macrophages and liver Kupffer cells in
the host response to malaria is well established experimentally. Macrophages
in the spleen and liver have been shown to eliminate parasites from mice
infected with plasmodia. It is believed that circulating pRBC become coated
with antibody against parasite-derived proteins, facilitating phagocytosis.
Some events proposed to be of importance in the pathogenesis of murine
cerebral malaria.
Astrocytes regulate CNS Function
An important role of astrocytes in the normal CNS is to induce and maintain
BBB properties in the vascular endothelium. The endothelial cells themselves
have complete belts of tight junctions between each cell that are
uninterrupted by gap junctions. These features of the endothelium restrain
the rate of exchange of solutes between the blood and nervous tissue by
reducing the effects of fluctuations in the blood plasma metabolites and other
constituents, helping to maintain the unique CNS milieu conducive to
neuronal functioning.
Astrocytes also make close contact with neuronal synapses and are thought to
be intimately involved in maintaining acid-base, electrolyte and
neurotransmitter balance. In addition, astrocytes regulate the concentration of
neurotransmitters, such as glutamate, in the extracellular fluid. Any alteration
in these astrocyte functions has profound effects on normal neuronal function.
Microglia are the central nervous system counterpart of the mononuclear
phagocyte system
Microglial cells comprise 5–20% of the total glial population in the brain and
are pluripotent members of the monocyte/ macrophage lineage. Just like
other tissue macrophages, microglia, when stimulated by substances such as
LPS and IFN- , can secrete IL-1, IL-6 and TNF- .IL-1 released by microglia
has been shown to be an astrocyte mitogen. TNF- has been shown in some
studies to have a cytotoxic effect on oligodendrocytes and to destroy myelin
structure, and is induced on microglia in demyelinating lesions. In addition,
both IL-1 and TNF- have been found on activated microglia surrounding
senile plaques in Alzheimer's disease.
REFERENCES:
Review Article
Immunology and Cell Biology (2001) 79, 101–120; doi:10.1046/j.14401711.2001.00995.x
Central nervous system in cerebral malaria: 'Innocent bystander' or
active participant in the induction of immunopathology?
Isabelle M Medana, Geeta Chaudhri, Tailoi Chan-Ling and Nicholas
H Hunt
Newton CR, Warrell DA. Neurological manifestations of falciparum
malaria. Ann. Neurol. 1998; 43: 695–702.
Berendt AR, Turner GDH, Newbold CI. Cerebral malaria: the
sequestration hypothesis. Parasit. Today 1994; 10: 412–4.
Clark IA, Rockett KA. The cytokine theory of human cerebral malaria.
Parasit. Today 1994; 10: 410–2
Riley EM, Rowe P, Allen SJ, Greenwood BM. Soluble plasma IL-2
receptors and malaria. Clin. Exp. Immunol. 1993; 91: 495–9.
Zaman V, Keong LA. Handbook of Medical Parasitology. New York:
ADIS Health Science Press, 1982.
What is the prognosis for a child whose malarial infection has localized in
the blood vessels of the brain?
If not immediately treated, cerebral malaria is likely to be fatal.
What other pathological processes may be seen?
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.