Practice Essentials
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] In nonendemic areas, the diagnosis of HMS can be a challenge; extensive testing may be needed to exclude conditions that cause massive splenomegaly and are more prevalent.
See the image below.
Young patient with hepatomegaly and massive splenomegaly.
Signs and symptoms of hyperreactive malarial syndrome
The most common presenting symptoms of hyperreactive malarial syndrome (HMS) are chronic abdominal swelling (64%) and pain (52%). [3] Abdominal swelling may wax and wane, and pressure on the abdominal contents may lead to hernias and leg swelling; abdominal pain may be acute. Many patients do not have any symptoms and are capable of normal daily activity.
Workup in hyperreactive malarial syndrome
Major criteria in the diagnosis of hyperreactive malarial syndrome (HMS) include the following:
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Gross splenomegaly 10 cm or more below the costal margin in adults for which no other cause can be found
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Elevated serum immunoglobulin M (IgM) level two standard deviations or more above the local mean
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Clinical and immunologic responses to antimalarial therapy
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Regression of splenomegaly by 40% by 6 months after start of therapy
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High antibody levels of Plasmodium species (≥1:800)
Management of hyperreactive malarial syndrome
Therapy is based on the use of antimalarial drugs. Splenectomy plays no role in the treatment of hyperreactive malarial syndrome (HMS) and should be avoided, as it can result in fulminant and overwhelming infections with high mortality.
Pathophysiology
Hyperreactive malarial syndrome (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] Chronic antigenic stimulation may be an important factor in the development of HMS.
Although the exact mechanism is uncertain, evidence suggests that repeated or chronic 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.
Genetic factors, pregnancy, and malnutrition may also 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. Conversely, patients with sickle disease who do suffer from malaria and develop HMS remain functionally asplenic and do not appear to benefit from expansion of marginal zone B-cells and macrophages in the enlarged spleen, although prospective data are needed to confirm this clinical observation. [8]
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. [9] 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. Plasma levels of interleukin 10 (IL-10) and interferon gamma (IFNγ) are significantly increased. [10]
Effective malarial chemoprophylaxis and eradication measures have been associated with a decrease in the incidence of HMS. Antimalarial treatment is shown to be effective in decreasing splenomegaly, correcting anemia and lymphocytosis, and decreasing serum IgM in patients with HMS. However, withdrawal of prophylaxis in patients from malaria-endemic regions has been associated with relapse anywhere from 2-18 months after initial diagnosis. [11]
Epidemiology
Frequency
United States
Hyperreactive malarial syndrome (HMS) has been reported only in people who have resided in or who have visited areas where malaria is endemic. [12]
International
Hyperreactive malarial syndrome (HMS) is restricted to native residents and visitors of 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 Algiers, Congo, Madagascar, Ivory Coast, Sudan, New Guinea, Nigeria, India, Philippines, Brazil, China, Uganda, Yemen, Bangladesh, Ethiopia, Hong Kong, Ghana, Somalia, Zambia, and Chile. 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%. [13]
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. [14]
In a review of patients with massive splenomegaly in Ghana, 41% were diagnosed to have HMS; the rate in Sudan was 9%. [10] The second most common diagnosis was B-lymphoproliferative disorders. Even with relatively modern investigative techniques, no diagnosis could be established in about a fourth (23%) of the patients. HMS was associated with a younger age, female sex, and lower absolute lymphocyte counts than lymphoproliferative disorders. [15]
Mortality/Morbidity
The natural history of hyperreactive malarial syndrome (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, [16] with a mortality of 85% in hospitalized patients. [6] However, other series found a much lower mortality rate. [17]
HMS is not a premalignant condition, although an overlap with chronic lymphocytic leukemia has been noted. [18] 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 immunocompromised patients from malaria-endemic regions who have HIV infection and lung carcinoma, following the exclusion of other disease entities, such as Epstein-Barr virus, cytomegalovirus, or lymphoproliferative disorders. [19, 20]
Race
Generally, the distribution of malaria in the tropical areas of the world also predisposes individuals of certain racial origin such as African American, Asian, and Pacific Islander to hyperreactive malarial syndrome (HMS).
Inheritance of a genetic trait in individuals who develop HMS has also been described. Interestingly, X-linked segregation implicated in the pathogenesis of HMS tends to present with strong familial patterns that have been identified in residents of Papua New Guinea, but not Ghana. [12, 21]
Furthermore, a genetic component of the immune response implicated in HMS has been described. Specifically, less heterozygosity of human lymphocyte antigens (HLAs) has been hypothesized to be associated with a less robust immune response to recurrent malaria infection than in individuals with more heterozygous HLA. [22]
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. [23]
Sex
Overall, hyperreactive malarial syndrome (HMS) is more common in females, especially lactating mothers, than in males, with a female-to-male ratio of 2:1. Only one study in Eastern Sudan showed men to have a higher incidence. [24]
Age
Hyperreactive malarial syndrome (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. [25]
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Young patient with hepatomegaly and massive splenomegaly.
