eMedicine Specialties > Pediatrics: General Medicine > Hematology

Tropical Splenomegaly Syndrome

Author: Mundeep K Kainth, DO, Resident Physician, Department of Pediatrics, The Children's Hospital at Albany Medical Center
Coauthor(s): Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP, Associate Professor of Pediatric Hematology and Oncology, Department of Pediatrics, Albany Medical Center; Faculty, Alden March Bioethics Institute
Contributor Information and Disclosures

Updated: Mar 19, 2009

Introduction

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

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 for Plasmodium 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.

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.

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
• 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

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.

Clinical

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.
• Almost all patients (97%) report weight loss.
• Many patients do not have any symptoms and are capable of normal daily activity.
• Rarely, patients have intermittent fever. Persistent, severe fevers should raise the possibility of an alternative diagnosis.
• Some patients present with acute abdominal pain.
• Patients physiologically adapt well to the chronic evolution of anemia and are symptomatic only when anemia is severe.
• Weakness and loss of energy may reflect the degree of anemia.
• Nonspecific symptoms include cough, dyspnea, epistaxis, and headache.
• Pressure on the abdominal contents may lead to hernias and leg swelling.
• A history of chronic splenic enlargement differentiates HMS from simple malarial splenomegaly.
• Bleeding complications 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; the basis for hemolysis remains uncertain.

Physical

• The hallmark of HMS is splenomegaly, which is usually moderate to massive.
• Most spleens are not tender (63%). 
• The spleen has a smooth surface (99%), soft consistency (91%), and sharp border (93%).¹⁹  The enlarged spleen may be seen to protrude against the abdominal wall.
• 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
• Pallor is common.
• Patients are usually afebrile at presentation.
• In general, tachycardia is absent. If tachycardia is present, it indicates a concurrent complication.
• Dilatation of the veins, cardiomegaly, low blood pressure, and flow murmurs reflect hypervolemia.
• Lymphadenopathy is absent, but bilateral parotid swelling has been described.
• The patient may be malnourished and jaundiced.
• Ascites is uncommon.

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.

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