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 for Plasmodium falciparum,
Plasmodium vivax, or Plasmodium ovale.
6]

Genetic Iactors, pregnancy, and malnutrition may play a role in the etiology oI 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 aIter malarial inIection.
Although the exact mechanism is uncertain, evidence suggests that exposure to malaria elicits
exaggerated stimulation oI polyclonal B lymphocytes, leading to excessive and partially
uncontrolled production oI immunoglobulin M (IgM) as the initiating event.
|7|
IgM is polyclonal
and is not speciIic Ior any particular malarial species.
DeIective immunoregulatory control oI 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 inIiltration oI the hepatic and splenic
sinusoids accompanies this process. Serum cryoglobulin and autoantibody levels increase, as
does the presence oI high molecular weight immune complexes. The result is anemia, deposition
oI large immune complexes in KupIIer cells in the liver and spleen, reticuloendothelial cell
hyperplasia, and hepatosplenomegaly.
Antimalarial treatment is eIIective in decreasing the size oI the spleen, but premature
discontinuation oI treatment may lead to relapse. EIIective malarial chemoprophylaxis and
eradication measures have been associated with a decrease in the incidence oI HMS.
O The most common presenting symptoms oI hyperreactive malarial syndrome (HMS), or
tropical splenomegaly syndrome, are chronic abdominal swelling (64) and pain
(52).
|3|

O Abdominal swelling may wax and wane.
O Almost all patients (97) report weight loss.
O Many patients do not have any symptoms and are capable oI normal daily activity.
O Rarely, patients have intermittent Iever. Persistent, severe Ievers should raise the
possibility oI an alternative diagnosis.
O Some patients present with acute abdominal pain.
O Patients physiologically adapt well to the chronic evolution oI anemia and are
symptomatic only when anemia is severe.
O eakness and loss oI energy may reIlect the degree oI anemia.
O onspeciIic symptoms include cough, dyspnea, epistaxis, and headache.
O Pressure on the abdominal contents may lead to hernias and leg swelling.
O A history oI chronic splenic enlargement diIIerentiates HMS Irom simple malarial
splenomegaly.
O Bleeding complications are uncommon because thrombocytopenia is usually not severe.
O Susceptibility to inIections, especially skin and respiratory inIections, is slightly
increased.
O Pregnant women are susceptible to episodes oI massive Coombs-negative hemolysis,
which are usually preceded by Iebrile episodes; the basis
O B-cell Lymphoma
O Brucellosis
O elty Syndrome
O Histiocytosis
O InIectious Mononucleosis
O Leishmaniasis
O Malaria
O Salmonella InIection
O Schistosomiasis
O Sickle Cell Anemia
O Splenic Lymphoma
O Thalassemia
O Trypanosomiasis
O Tuberculosis
iagnostic criteria for hyperreactive malarial syndrome
The mere exclusion oI other disease processes causing splenomegaly is insuIIicient to establish a
diagnosis oI hyperreactive malarial syndrome (HMS). akunle was the Iirst to establish
diagnostic criteria Ior the deIinitive diagnosis oI HMS.
|3|
Bates and Bedu-Addo reIined these
major criteria in 1997 to the current accepted list.
|5|
hen these stricter criteria are applied, as
many as one halI oI patients with splenomegaly may not have HMS.
Major criteria include the Iollowing:
O Gross splenomegaly 10 cm or more below the costal margin in adults Ior which no other
cause can be Iound
O Elevated serum IgM level 2 standard deviations or more above the local mean
O Clinical and immunologic responses to antimalarial therapy
O Regression oI splenomegaly by 40 by 6 months aIter start oI therapy
O High antibody levels oI !,824/:2 species (_ 1:800)
Minor criteria include the Iollowing
O Hepatic sinusoidal lymphocytosis
O ormal cellular and humoral responses to antigenic challenge, including a normal
phytohemagglutination response
O Hypersplenism
O Lymphocytic proliIeration
O amilial occurrence
Hematologic manifestations
O ormocytic normochromic anemia is almost always present and is related to the degree
oI splenomegaly. Several Iactors contribute to its etiology, including pooling oI RBCs in
the spleen, hypersplenism, and increased RBC destruction and turnover; however, the
major Iactor is increased plasma volume. The reticulocyte count is increased and reIlects
erythroid hyperplasia. The anemia is Coombs negative. DeIiciency oI vitamin B12, Iolic
acid, or glucose-6-phosphate dehydrogenase has not been demonstrated.
O Leukopenia is common and is sometimes associated with lymphocytosis.
O Thrombocytopenia is generally mild. Both neutropenia and thrombocytopenia are due to
splenic trapping.
O Peripheral smears usually do not reveal the malarial parasite.
ther findings
O IgM levels are increased. An elevation oI 2 standard deviations above the local mean
should be present. Serum IgM levels are correlated with the degree oI splenomegaly.
O Patients with HMS have high titers oI malarial antibodies.
O Titers oI cold agglutinins, rheumatoid Iactor, antinuclear Iactor, cryoproteins, and
thyroglobulins may be high.
|21|

O Serologies Ior cytomegalovirus (CMV), toxoplasmosis, Epstein-Barr virus (EBV), human
herpesvirus 6 (HH6), parvovirus B19, and schistosomiasis may be Ialse-positive.
|22|

O Polymerase chain reaction (PCR) has been used to detect low-level parasitemia in
patients with HMS, and multiplex PCR can identiIy the species oI !,824/:2 involved.
Because oI its cost and complexity, this technique is not in widespread use.
UnIortunately, simple rapid malaria tests, such as the ICT Malaria Test, oIten Iail to
detect the low level oI antigenemia in HMS.
|22|

O A phytohemagglutination stimulation test may be helpIul Ior diIIerentiating HMS Irom
lymphomas and chronic lymphocytic leukemia, Ior which the result is abnormal.
O Liver biopsy is rarely indicated.
O Hepatic sinusoidal lymphocytosis is present in HMS.
O Unlike with malaria, malarial pigmentation is absent in the macrophages in patients with
HMS. This picture may also be present in inIectious mononucleosis, hairy cell leukemia,
malignant histiocytosis, and elty syndrome.
O KupIIer cell hypertrophy and hyperplasia are also present.
The mainstays oI therapy are antimalarial drugs.
Surgical Care
Splenectomy plays no role in the treatment oI hyperreactive malarial syndrome (HMS). The
mortality rate aIter splenectomy is high because oI Iulminant and overwhelming inIections.
Background
The causes and diagnosis oI massive tropical splenomegaly are not well studied, especially with
modern investigative methods. e aimed to identiIy Ieatures that would help local clinicians
diIIerentiate between the underlying conditions.


Methods
e collected prospective clinical and laboratory data on 221 Ghanaian patients with spleen size
oI at least 10 cm. e identiIied conditions associated with massive splenomegaly with molecular
and immunological investigations as well as routine tests. Patients were assigned to diagnostic
categories on the basis oI these test results and predetermined criteria.
Findings
Hyper-reactive malarial splenomegaly (HMS; 91 patients |41|) and B-lymphoproliIerative
disorders (48 |22|) were the most common disorders associated with massive splenomegaly.
OI the remaining patients, 32 (14) had haematological disorders, and in 50 (23) we could not
identiIy the cause oI splenomegaly. Male sex predominated in all diagnostic groups except HMS
and tropical splenic lymphoma. Age less than 40 years and absolute lymphocyte count (less than
10109/L) were the only useIul and widely available discriminators Ior distinguishing patients
with HMS Irom those with lymphoproliIerative disorders.
Interpretation
B-lymphoproliIerative disorders are a previously unrecognised cause oI massive tropical
splenomegaly. This Iinding has major implications Ior management oI massive splenomegaly.
Diagnosis oI the less common causes oI this disorder is usually straightIorward, but
diIIerentiating between B-lymphoproliIerative disorders and HMS can be diIIicult. HMS is
associated with younger age, a higher proportion oI women, and lower absolute lymphocyte
counts than lymphoproliIerative disorders
Tropical splenomegaly

Enlargement oI the spleens oI those who live in the tropics can be due to many causes,
particularly malaria and leishmaniasis. In many patients the exact cause remains unknown. There
are no characteristic imaging Iindings either radiographically or with ultrasound, apart Irom the
large homogeneous spleen. Since the spleen is very large and Iirm, distorsion oI the leIt kidney
can occur, with Ilattening oI the upper pole in particular. The enlarged spleen emergas Irom the
protective abdominal rib-cage, becoming easily ruptured with minor abdominal trauma.
A chronic disease, occurring in India, Assam, China, the area Iormerly known as the
Mediterranean littoral areas, the Middle East, India, Pakistan, China, South and Central America,
Asia, AIrica caused by Leishmania donovani and transmitted by the bite oI an appropriate
species oI sandIly oI the genus Phlebotomus or Lutzomyia; the organisms grow and multiply in
macrophages, eventually causing them to burst and liberate amastigote parasites which then
invade other macrophages; proliIeration oI macrophages in the bone marrow causes crowding
out oI erythroid and myeloid elements, resulting in leukopenia, and anaemia, splenomegaly, and
hepatomegaly which are characteristic, along with enlargement oI lymph nodes; Iever, Iatigue,
malaise, and secondary inIections also occur; diIIerent strains oI leishmaniasis donovani occur;
leishmaniasis inIantum in Eurasia, leishmaniasis chagasi in Latin America. Synonym: Assam
Iever, black sickness, Burdwan Iever, cachectic Iever, Dumdum Iever, kala azar, tropical
splenomegaly. (05 Mar 2000)
O Because oI the extended length oI treatment oIten needed, monitoring Ior adverse eIIects
is crucial.
O Splenectomy is contraindicated, because oI increased inIection-associated mortality.
However, iI the patient's spleen was previously removed, guidelines Ior the care oI
asplenic patients should be Iollowed (see Asplenia). Guidelines include the Iollowing:
4 Antibiotic prophylaxis
4 Education
4 Aggressive management oI suspected episodes oI Iever
4 Appropriate immunizations
ropical Splenomegaly Syndrome or Big Spleen Disease is massive enlargement oI the spleen
resulting Irom abnormal immune response to repeated attacks oI malaria. It is seen among
residents oI endemic areas oI malaria and it is not species speciIic. It occurs mainly in tropical
AIrica, but also in parts oI Vietnam, ew Guinea, India, Sri Lanka, Thailand, Indonesia, South
America and the Middle East. It must be diIIerentiated Irom splenomegaly associated with
acquisition oI immunity in endemic and hyperendemic areas.
Tropical Splenomegaly Syndrome is characterised by massive splenomegaly, hepatomegaly,
marked elevations in levels oI serum Ig M and malaria antibody. Hepatic sinusoidal
lymphocytosis is also seen. In about 10 oI AIrican patients, it may be associated with
peripheral lymphocytosis (B cells).
The interaction oI repeated malarial inIection and unknown host Iactors results in the production
oI cytotoxic Ig M antisuppressor lymphocyte (CD8) antibodies. This causes inhibition oI
suppressor T cells, which normally regulate IgM production. This leads to uninhibited B cell
production oI IgM and the Iormation oI cryoglobulins (IgM aggregates and immune complexes).
The need to clear these macromolecular aggregates stimulates the reticuloendothelial system,
resulting in hyperplasia. This causes the progressive and massive enlargement oI the spleen and
hepatomegaly.
The spleen is massively enlarged. It shows dilated sinusoids lined with reticulum cells showing
marked erythrophagocytosis and lymphocytic inIiltration oI the pulp. Liver exhibits sinusoidal
dilatation, inIiltration with lymphocytes and hyperplasia oI the KupIIer's cells with phagocytosis
oI cellular debris and red cells.
Most patients present during adult liIe. Patients present with dragging pain in the upper
abdomen, or sometimes may even complain oI a palpable mass. Some may experience recurrent
sharp pains in the upper abdomen, probably due to perisplenitis or splenic inIarcts. Some patients
may have weight loss and cachexia. On examination, there is massive splenomegaly and
hepatomegaly.
The peripheral smear shows normocytic normochromic anemia with increased reticulocyte
count. Leukopenia and thrombocytopenia may also be seen due to hypersplenism. Malarial
parasites are not Iound in the peripheral blood. There is increase in the serum levels oI
polyclonal IgM with cryoglobulinemia, reduced C3 and the rheumatoid Iactor may be positive.
The condition should be diIIerentiated Irom other causes oI splenomegaly in the tropics- Kala-
Azar, Schistosomiasis, post-necrotic cirrhosis, thalassemia, leukemia, lymphoma, myeloIibrosis,
non-tropical idiopathic splenomegaly, elty's syndrome etc. In patients with splenic lymphoma,
more than 30 oI circulating lymphocytes are villous and they can be diIIerentiated Irom hairy-
cell leukemia by their lack oI CD
25
, CD11
C
and tartrate-resistant acid phosphate markers.
Increased levels oI IgM and antimalarial antibody, hepatic sinusoidal lymphocytosis on liver
biopsy and response to antimalarial therapy (improvement in clinical condition as well as
reduction in IgM and malarial antibody titre within three months oI continuous antimalarial
treatment) Iavour a diagnosis oI tropical splenomegaly syndrome.
The disease generally runs a benign course. However, sometimes it may be associated with
severe anemia, leading to congestive cardiac Iailure. These patients are also more prone Ior
secondary bacterial inIections oI the skin and respiratory tract and have an increased mortality.
Portal hypertension does not develop and the condition is reversible with antimalarial treatment.
Some patients in Ghana were Iound to develop splenic lymphoma with hairy lymphocytes.
The treatment oI tropical splenomegaly syndrome involves administration oI antimalarial
prophylaxis Ior prolonged periods oI time. This removes the antigenic stimulus provided by
repeated malarial inIection and allows the immune system to return to normal. The choice oI
antimalarial depends on the local sensitivity pattern. Chloroquine weekly or proguanil daily have
been Iound to be useIul. These drugs may have to be continued Ior long periods, possibly Ior liIe.
Severe anemia may require blood transIusion. Splenectomy may do more harm than good and it
may be beneIicial in only patients with splenic lymphoma. Splenic irradiation or antimitotic
therapy are not beneIicial and may be even dangerous.