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Tropical Splenomegaly Syndrome

Author: Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP; Chief Editor: Robert J Arceci,
MD, PhD

Background
Several reports were published over the last century describing patients
from tropical areas with massive splenomegaly. After excluding known
causes of splenomegaly, tropical splenomegaly syndrome was defined as a
separate entity.
[1, 2, 3]
This condition was later defined as hyperreactive
malarial syndrome (HMS) using clear diagnostic criteria.
[4, 5]

Young patient with hepatomegaly and massive
splenomegaly.
Pathophysiology
HMS is prevalent in native residents of regions where malaria is endemic
and visitors to those regions. Patients with HMS have high levels of
antibody forPlasmodium falciparum, Plasmodium vivax, or Plasmodium
ovale.
[6]

Genetic factors, pregnancy, and malnutrition may play a role in the etiology
of HMS. Relative protection against HMS is observed in patients with sickle
cell trait, as it is with malaria. In experimental models, animals developed a
similar syndrome after malarial infection.
Although the exact mechanism is uncertain, evidence suggests that
exposure to malaria elicits exaggerated stimulation of polyclonal B
lymphocytes, leading to excessive and partially uncontrolled production of
immunoglobulin M (IgM) as the initiating event.
[7]
IgM is polyclonal and is
not specific for any particular malarial species.
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Defective immunoregulatory control of B lymphocytes by suppressor or
cytotoxic T lymphocytes causes the increase in B lymphocytes, although
the mechanism by which malarial parasitemia drives these changes is
unclear.
[8]
T-cell infiltration of the hepatic and splenic sinusoids
accompanies this process. Serum cryoglobulin and autoantibody levels
increase, as does the presence of high molecular weight immune
complexes. The result is anemia, deposition of large immune complexes in
Kupffer cells in the liver and spleen, reticuloendothelial cell hyperplasia,
and hepatosplenomegaly.
Antimalarial treatment is effective in decreasing the size of the spleen, but
premature discontinuation of treatment may lead to relapse. Effective
malarial chemoprophylaxis and eradication measures have been
associated with a decrease in the incidence of HMS.

Epidemiology
Frequency
United States
HMS occurs only in people who have resided in or who have visited areas
where malaria is endemic.
[9]

International
HMS is restricted to native residents of and visitors to the malaria belt
which roughly encompasses equatorial regions of South America, Africa,
the Middle East, South Asia, and Southeast Asia.
HMS has been reported in the following countries:
Algiers
Congo
Madagascar
Ivory Coast
Sudan
New Guinea
Nigeria
India
Philippines
Brazil
China
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Uganda
Yemen
Bangladesh
Ethiopia
Hong Kong
Ghana
Somalia
Zambia
Chile

Accurate assessment of the incidence of HMS is difficult because many
conditions that cause splenomegaly are prevalent in areas where malaria is
endemic. These conditions include hemoglobinopathies, lymphoreticular
disorders,schistosomiasis, hepatic cirrhosis, leishmaniasis, typhoid,
and tuberculosis.
The incidence of massive splenomegaly is estimated to be 1-2% in rural
Nigeria,
[1]
and HMS accounts for 11-45% of massive splenomegaly cases in
Africa.
[10, 11]
The incidence of HMS is highest among the people of the Upper
Watut Valley in Papua New Guinea, where the rate is estimated to be
80%.
[12]

Mortality/Morbidity
The natural history of HMS is not well documented. HMS is associated with
a high mortality rate in untreated individuals; overwhelming infections are
the leading cause of death. A 5-year mortality rate of 50% was reported in
Uganda and New Guinea,
[13]
with a mortality of 85% in hospitalized
patients.
[6]
However, other series found a much lower mortality rate.
[14]

HMS is not a premalignant condition, although an overlap with chronic
lymphocytic leukemia has been noted.
[15]
Whether HMS can undergo clonal
evolution to splenic lymphoma with villous lymphocytes (SLVL) is unclear;
these entities appear to evolve independently in response to chronic
antigen stimulation.
HMS has also been documented in patients with HIV infection and
splenomegaly following the exclusion of other disease entities, such
as Epstein-Barr virus,cytomegalovirus, or lymphoproliferative disorders.
[16]

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Race
Certain racial and immunologic factors may be important in the
pathogenesis of HMS, although results of phenotypic studies of human
lymphocyte antigens have not been conclusive.
The incidence of splenic enlargement at autopsy was greater in individuals
who migrated from malaria-free Rwanda to malaria-endemic Uganda, than
in local residents. Rwandan immigrants have also shown evidence of
familial clustering, and many Rwandans with HMS were born and raised in
the Baganda groups in Uganda. In Ghana, patients with HMS were more
likely to have family members with splenomegaly.
[17]

HMS has been reported in whites who resided in or moved to areas where
malaria was endemic. It has also been described among visitors who
received inadequate prophylaxis against malaria.
[18]

Sex
Overall, HMS is more common in female individuals, especially lactating
mothers, than in male individuals, with a female-to-male ratio of 2:1. Only
one study in Eastern Sudan showed men to have a higher incidence.
[19]

Age
HMS is most common in young and middle-aged adults, although the
process probably commences during childhood. HMS is rare in children
younger than 8 years but was reported in a 3-year-old patient.
[20]
These
observations support the theory that chronic antigenic stimulation is an
important factor in the development of HMS.

History
The most common presenting symptoms of hyperreactive malarial
syndrome (HMS), or tropical splenomegaly syndrome, are chronic
abdominal swelling (64%) and pain (52%).
[3]
Abdominal swelling may wax
and wane. Some patients present with acute abdominal pain. Pressure on
the abdominal contents may also lead to hernias and leg swelling.
A history of chronic splenic enlargement differentiates HMS from simple
malarial splenomegaly.
Almost all patients (97%) report weight loss.
Patients physiologically adapt well to the chronic evolution of anemia and
are symptomatic only when anemia is severe. Many patients do not have
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any symptoms and are capable of normal daily activity. Weakness, loss of
energy, and severe headache may signify severe anemia.
Rarely, patients have intermittent fever. Persistent, severe fevers should
raise the possibility of an alternative diagnosis.
[20]

Bleeding complications such as epistaxis are uncommon because
thrombocytopenia is usually not severe.
Susceptibility to infections, especially skin and respiratory infections, is
slightly increased.
Pregnant women are susceptible to episodes of massive Coombs-negative
hemolysis, which are usually preceded by febrile episodes. Coombs-
positive hemolysis is associated rarely with acute attacks of plasmodium
vivax malaria.
[21]



Physical
Patients are usually afebrile at presentation. Pallor is common, and the
patient may be malnourished and jaundiced.
In general, tachycardia is absent. If tachycardia is present, it indicates a
concurrent complication.
The hallmark of HMS is splenomegaly, which is usually moderate to
massive. Most spleens (63%) are not tender, and almost all have a smooth
surface, soft consistency, and sharp border.
[19]
The enlarged spleen may be
seen to protrude against the abdominal wall, and a splenic bruit may be
audible. Despite the size of the spleen, splenic rupture is rare.
Hepatomegaly is common; in a study of 69 Nigerian patients, 93% had
accompanying hepatomegaly.
[3]
Ascites is uncommon.
Dilatation of the veins, cardiomegaly, low blood pressure, and flow
murmurs reflect hypervolemia.
Lymphadenopathy is absent, but bilateral parotid swelling has been
described.





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Causes
The most important predisposing factor for HMS is residence in or visitation
to an area where malaria is endemic.
Other risk factors include malnutrition and an as-yet-undefined genetic
predisposition.

Differential Diagnoses
B-cell Lymphoma
Brucellosis
Felty Syndrome
Histiocytosis
Infectious Mononucleosis
Leishmaniasis
Malaria
Salmonella Infection
Schistosomiasis
Sickle Cell Anemia
Splenic Lymphoma
Thalassemia
Trypanosomiasis
Tuberculosis

Laboratory Studies
Diagnostic criteria for hyperreactive malarial syndrome
The mere exclusion of other disease processes causing splenomegaly is
insufficient to establish a diagnosis of hyperreactive malarial syndrome
(HMS). Fakunle was the first to establish diagnostic criteria for the definitive
diagnosis of HMS.
[3]
Bates and Bedu-Addo refined these major criteria in
1997 to the current accepted list.
[5]
When these stricter criteria are applied,
as many as one half of patients with splenomegaly may not have HMS.
Major criteria include the following:
Gross splenomegaly 10 cm or more below the costal margin in adults for
which no other cause can be found
Elevated serum IgM level 2 standard deviations or more above the local
mean
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Clinical and immunologic responses to antimalarial therapy
Regression of splenomegaly by 40% by 6 months after start of therapy
High antibody levels of Plasmodium species ( 1:800)
Minor criteria include the following
Hepatic sinusoidal lymphocytosis
Normal cellular and humoral responses to antigenic challenge, including a
normal phytohemagglutination response
Hypersplenism
Lymphocytic proliferation
Familial occurrence


Hematologic manifestations
Normocytic normochromic anemia is almost always present and is related
to the degree of splenomegaly. Several factors contribute to its etiology,
including pooling of RBCs in the spleen, hypersplenism, and increased
RBC destruction and turnover; however, the major factor is increased
plasma volume. The reticulocyte count is increased and reflects erythroid
hyperplasia. The anemia is Coombs negative. Deficiency of vitamin B12,
folic acid, or glucose-6-phosphate dehydrogenase has not been
demonstrated.
Leukopenia is common and is sometimes associated with lymphocytosis.
Thrombocytopenia is generally mild. Both neutropenia and
thrombocytopenia are due to splenic trapping.
Peripheral smears usually do not reveal the malarial parasite.


Other findings
IgM levels are increased. An elevation of 2 standard deviations above the
local mean should be present. Serum IgM levels are correlated with the
degree of splenomegaly.
Patients with HMS have high titers of malarial antibodies.
Titers of cold agglutinins, rheumatoid factor, antinuclear factor,
cryoproteins, and thyroglobulins may be high.
[22]

Serologies for cytomegalovirus (CMV), toxoplasmosis, Epstein-Barr virus
(EBV), human herpesvirus 6 (HH6), parvovirus B19, and schistosomiasis
may be false-positive.
[23]

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Imaging Studies
Imaging tests are of limited value.
Ultrasonography of the abdomen may help to document and monitor
hepatosplenomegaly.

Other Tests
Polymerase chain reaction (PCR) has been used to detect low-level
parasitemia in patients with HMS, and multiplex PCR can identify the
species of Plasmodiuminvolved. Because of its cost and complexity, this
technique is not in widespread use. Unfortunately, simple rapid malaria
tests, such as the ICT Malaria Test, often fail to detect the low level of
antigenemia in HMS.
[23]

A phytohemagglutination stimulation test may be helpful for differentiating
HMS from lymphomas and chronic lymphocytic leukemia, for which the
result is abnormal.

Histologic Findings
Liver biopsy is rarely indicated.
Hepatic sinusoidal lymphocytosis is present in HMS.
Unlike with malaria, malarial pigmentation is absent in the macrophages in
patients with HMS. This picture may also be present in infectious
mononucleosis, hairy cell leukemia, malignant histiocytosis, and Felty
syndrome.
Kupffer cell hypertrophy and hyperplasia are also present.

Medical Care
The mainstays of therapy are antimalarial drugs.
Surgical Care
Splenectomy plays no role in the treatment of hyperreactive malarial
syndrome (HMS). The mortality rate after splenectomy is high because of
fulminant and overwhelming infections.
Consultations
Appropriate consultation with oncologists and metabolic and infectious
disease specialists may be sought to rule out diseases that mimic HMS.
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Activity
Activity is permitted, as tolerated by the patient. A patient's activity may be
limited because of severe anemia or the pressure effects of massive
splenomegaly.

Medication Summary
Antimalarial drugs are effective in treating hyperreactive malarial syndrome
(HMS). The specific drug of choice is based on the pattern and prevalence
of drug resistance in the patient's geographic area. In endemic areas,
treatment should be prolonged and continued regularly. Months may pass
before a response is observed, and relapses may occur when therapy is
discontinued.
In expatriates returning with HMS, brief courses of treatment may be
adequate.
[18]
To the authors' knowledge, no studies have addressed the
duration of adequate treatment, and no researchers have compared
antimalarial medications.
Chloroquine and proguanil appear to be equally effective. This observation
suggests that eradication of parasitemia is the common pathway for
therapeutic responses. Pyrimethamine may be an alternative.
[24]
Data
regarding the usefulness of other antimalarial drugs in HMS are limited.
Short-term antimalarial treatment may be sufficient to treat patients who
reside outside of an endemic region. The role of lifelong prophylaxis for
individuals residing in endemic areas is unclear. Treatment may last more
than one year or even longer.
The response to therapy is guided by the size of spleen, a decrease in
serum IgM levels, improvement of anemia, and general improvement in the
patient's well-being.
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Antimalarial Agents
Class Summary
Because epidemiologic and other data suggest that HMS is related to
malarial infection, antimalarial drugs have been used and have been
effective.
View full drug information
Chloroquine phosphate (Aralen Phosphate)

4-aminoquinolone widely used to treat malaria until recently, when resistant
strains became major problems. Chloroquine and related drugs
gametocidal (for species except for P falciparum) and schizonticidal (for
parasites in blood but not tissue).
Well absorbed PO. Best taken with food to decrease GI distress.
View full drug information
Proguanil (Paludrine)

Not available as single component in United States. Not prompt in relieving
symptoms of acute malaria, but proguanil and related drugs (eg,
pyrimethamine) effective against erythrocytic stages of malaria; they inhibit
tetrahydrofolate dehydrogenase. Resistance to this group of drugs
develops quickly.
View full drug information
Pyrimethamine and sulfadoxine (Fansidar)
Combination product containing sulfadoxine 500 mg and 25 mg
pyrimethamine. Mechanism of action for pyrimethamine same as that of
proguanil (ie, inhibits dihydrofolate reductase). Pyrimethamine therapy,
perhaps shortened, may rapidly decrease size of spleen.
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Sulfonamides act in synergy with pyrimethamine; used together. Administer
with folinic acid to decrease adverse effects.

Further Inpatient Care
Because of the extended length of treatment often needed, monitoring for
adverse effects is crucial.
Splenectomy is contraindicated, because of increased infection-associated
mortality. However, if the patient's spleen was previously removed,
guidelines for the care of asplenic patients should be followed
(see Asplenia). Guidelines include the following:
Antibiotic prophylaxis
Education
Aggressive management of suspected episodes of fever
Appropriate immunizations

Further Outpatient Care
Regular visits are essential to monitor the patient's clinical improvement
and to document decreases in splenomegaly.
If chloroquine is used, monitor the patient for ophthalmologic effects with
slit lamp, funduscopic, and visual field examinations.
At regular intervals, perform cardiovascular monitoring with ECG and
echocardiography, along with other tests as indicated.
Further workup may be indicated to look for myopathy and peripheral
neuritis.
Liver function tests may be performed regularly if the patient is receiving
proguanil.
Resolution of splenomegaly is accompanied by an improvement of
pancytopenia.

Inpatient & Outpatient Medications
Antimalarials are the mainstays of treatment (see Medication). These drugs
often need to be continued long-term (months to years). However, the
exact length of treatment has not been ascertained.
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Transfer
Depending on the facilities available at the hospital, indications for transfer
may be few. Medication can easily be started after the diagnosis is
established.
Supportive care, including blood transfusions and antibiotic therapy if
indicated, is now commonplace in most hospitals.

Deterrence/Prevention
For travelers to endemic areas, antimalarial prophylaxis is essential to
minimize the risk of hyperreactive malarial syndrome (HMS).
Prophylaxis for residents of endemic areas is controversial and has not
been shown to prevent HMS.
A study in Africa determined that the RTS,S/AS02D malaria vaccine was
safe, well tolerated, and immunogenic in young infants.
[25]


Complications
Complications include infections that may be serious and that may result in
death.
Trapping of hematopoietic elements in the enlarged spleen may cause
thrombocytopenia, anemia, and neutropenia, with resultant problems.
A predisposition to develop malignancy remains unproven.

Prognosis
HMS is a chronic disease that can be fatal because of infections and
bleeding complications.
Appropriate treatment with antimalarial medications can result in a good
outcome.
Splenectomy should be avoided because it increases the risk of fulminant
infections.
The risk of malignancy is ill defined.