Tropical Splenomegaly Syndrome

Hyperreactive malarial splenomegaly (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]

Frequency

United States

Hyperreactive malarial splenomegaly (HMS) has been reported only in people who have resided in or who have visited areas where malaria is endemic.[12]

International

Hyperreactive malarial splenomegaly (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.[13]

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%.[14]

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.[15]

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.[16]

Mortality/Morbidity

The natural history of hyperreactive malarial splenomegaly (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,[17] with a mortality of 85% in hospitalized patients.[6] However, other series found a much lower mortality rate.[18]

HMS is not a premalignant condition, although an overlap with chronic lymphocytic leukemia has been noted.[19] 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.[20, 21]

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 splenomegaly (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, 22]

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.[23]

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.[24]

Sex

Overall, hyperreactive malarial splenomegaly (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.[25]

Age

Hyperreactive malarial splenomegaly (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.[26]

The most common presenting symptoms of hyperreactive malarial splenomegaly (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.

A history of chronic splenic enlargement differentiates HMS from simple malarial splenomegaly. Extensive travel history should be taken, including travel in the distant past to endemic areas, in patients who present with massive splenomegaly. HMS may develop years after returning home in expatriates and visitors.

Almost all patients report weight loss.

Many patients do not have any symptoms and are capable of normal daily activity. Patients adapt physiologically to chronic anemia and are symptomatic only when it is severe. Weakness, loss of energy, and headache may signify severe anemia.

Rarely, patients have intermittent fever. Persistent, severe fever should raise the possibility of an alternative diagnosis.[26]

Bleeding complications such as epistaxis are uncommon because thrombocytopenia is usually not severe.

Susceptibility to 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.[27]

Patients with hyperreactive malarial splenomegaly (HMS) 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 moderate-to-massive splenomegaly. Few spleens (around one third) are tender, and almost all have a smooth surface, soft consistency, and sharp border.[25] 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.

Extensive travel history should be taken, including travel in the distant past to endemic areas, in patients who present with massive splenomegaly. HMS may develop years after returning home in expatriates and visitors.

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.

The most important predisposing factor for hyperreactive malarial splenomegaly (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.

A study by Gai et al found that in the southern Indian city of Mangaluru (Mangalore), the rate of splenomegaly in patients with malaria caused by Plasmodium falciparum (29.6%) was higher than that in patients with Plasmodium vivax malaria (16.6%).[28]

Diagnostic criteria for hyperreactive malarial splenomegaly

In nonendemic areas, the diagnosis of hyperreactive malarial splenomegaly (HMS) can be a challenge. Extensive testing may be needed to exclude conditions that cause massive splenomegaly and are more prevalent. However, the mere exclusion of other disease processes causing splenomegaly is insufficient to establish a diagnosis of 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

• 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 B-12, 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

Patients with HMS have high titers of malarial antibodies.

Titers of cold agglutinins, rheumatoid factor, antinuclear factor, cryoproteins, and thyroglobulins may be high.[29]

Serologies for cytomegalovirus (CMV), toxoplasmosis, Epstein-Barr virus (EBV), human herpesvirus 6 (HH6), parvovirus B19, and schistosomiasis may be false-positive.[30]

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

Demonstration of (malarial) parasitemia is not a required diagnostic criterion for the diagnosis of hyperreactive malarial splenomegaly (HMS). Parasitemia may be absent or undetectable, at extremely low levels; hence, direct demonstration of malarial parasites in the patient’s blood is neither useful nor required to diagnose HMS.

Indirect immunologic evidence of antigen presence may be detectable by rapid diagnostic tests (RDTs). Although these methods have been available for several years, they have not proved superior to direct microscopic examination, which still is the criterion standard for the diagnosis of (acute) malaria.

Parasite nucleic acids can also be detectable by polymerase chain reaction (PCR)[31] and may be more sensitive than direct microscopy, but the cost and turnaround time are prohibitive to be used widely in the developing countries. PCR is very useful to identify the species after the diagnosis has been established by alternative means.

Indirect immunofluorescence (IFA) or enzyme-linked immunosorbent assay (ELISA) may be useful in the detection of antibodies.

Most of these tests have been used in the diagnosis of acute malaria. Data regarding their applicability and usefulness in HMS are lacking.[32]

However, Genderini et al did describe a case in which HMS was diagnosed in a patient aged 16 years using loop-mediated isothermal amplification (LAMP) of DNA.[33]

A phytohemagglutination stimulation test may be helpful for differentiating HMS from lymphomas and chronic lymphocytic leukemia, for which the result is abnormal.[30]

Other tests can be conducted as indicated to exclude other etiologies of massive splenomegaly.

Liver biopsy is not required to establish the diagnosis and 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.

Therapy is based on the use of antimalarial drugs. A literature review by Leoni et al indicated that a short therapy course is sufficient treatment for HMS in patients who, after exposure to malaria parasites, do not revisit areas where malaria is endemic. In such patients, according to the study, elimination of the infection effectively cures the splenomegaly. The investigators, who drew data from 89 papers, asserted that patients who continue to be exposed to malaria-endemic regions require intermittent therapy or possibly lifelong treatment.[34]  Addition of doxyxline to the antimalarial may be of benefit; Genderini et al administered dihydroartemisinin/piperaquine (320/40 mg three tablets/day for 3 days) with doxycycline 200 mg to a patient once a day for 6 weeks, with complete resolution of HMS.[33]  

A retrospective, longitudinal study by Bisoffi et al indicated that patients with early HMS should receive the same treatment as patients with the full-blown syndrome, since early HMS predisposes patients to the more advanced condition. The study found that among patients with early HMS, reexposure to malaria is a major risk factor for progression and stated that, while a single antimalarial treatment will probably prove adequate against early HMS, antimalarial prophylaxis should subsequently be used in reexposed patients.[35]

Splenectomy plays no role in the treatment of hyperreactive malarial splenomegaly (HMS) and should be avoided, as it can result in fulminant and overwhelming infections with high mortality.

Appropriate consultation with oncologists and metabolic and infectious disease specialists may be sought to rule out diseases that mimic hyperreactive malarial splenomegaly (HMS).

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.

In regions where malaria is endemic, travelers should take precautions to prevent mosquito exposure and the development of malaria, including the following:

• Wearing long-sleeved clothing and pants tucked into socks
• Using N,N-diethyl-meta-toluamide (DEET) spray 25-35%
• Using bed nets
• Using antimalarial medications for chemoprophylaxis

For local inhabitants of endemic areas, the mosquito population can be reduced by eliminating standing water and using insecticide near the home. The local population should also follow the travelers' precautions listed above.

Antimalarial drugs have been the only drugs to be used in hyperreactive malarial splenomegaly (HMS) and have been shown to be effective in treatment. Clinical trials that address the drug of choice, efficacy, or duration of treatment or prophylaxis are lacking. 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 may need to be long term, although the exact duration is unknown and has not been studied. Response may take weeks to months and relapses are common when therapy is discontinued. The therapy may have to be continued for months to years, but the exact duration or endpoint are not established. In expatriates with HMS, brief courses of treatment may be adequate.[24]

Chloroquine and proguanil appear to be equally effective. Eradication of parasitemia may be the underlying mechanism. Pyrimethamine may be an alternative.[36]

Owing to the emergence of drug resistance, drugs that have been efficacious in the past may no longer be effective. Unfortunately, no reliable data are available and clinical trials have not been performed. Fixed-dose drug combinations may be an alternative if response is not seen to the above drugs and if drug resistance is suspected. Atovaquone-proguanil (Malarone) or artemether-lumefantrine (Coartem) and can be used in children. Other combinations include quinine sulfate plus doxycycline or tetracycline or clindamycin.

Use of mefloquine may be considered but this drug may rarely cause severe neuropsychiatric reactions.

The success of these alternative antimalarial drugs in treating acute drug-resistant malaria may not be reflected in treating HMS.[32]

The age to initiate chemoprophylaxis in endemic areas, which population to prophylax, and the duration of prophylaxis are unknown.

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.

Class Summary

Because epidemiologic and other data suggest that HMS is related to malarial infection, antimalarial drugs have been used and have been effective.

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.

Atovaquone/proguanil (Malarone)

Atovaquone selectively inhibits parasite mitochondrial electron transport. Proguanil metabolite cycloguanil disrupts deoxythymidylate synthesis by inhibiting dihydrofolate reductase in the malaria parasite.

Mefloquine

Can have significant side effects, including night terrors. Used only for chloroquine resistance and as a last-line option.

Quinidine gluconate

For severe parasitemia and complicated malaria. Intensive care unit (ICU) admission and cardiac monitoring are required.

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.

Sulfonamides act in synergy with pyrimethamine; used together. Administer with folinic acid to decrease adverse effects. Employed primarily as a prophylactic medication for malaria and toxoplasmosis.

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.

Because of the extended length of treatment often needed for hyperreactive malarial splenomegaly (HMS), 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

Antimalarials are the mainstays of treatment for hyperreactive malarial splenomegaly (HMS) (see Medication). These drugs often need to be continued long-term (months to years). However, the exact length of treatment has not been ascertained.

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.

For travelers to endemic areas, antimalarial prophylaxis is essential to minimize the risk of hyperreactive malarial splenomegaly (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.[37] A recent report of a phase 3 trial of RTS,S/AS01 malaria vaccine showed modest protection (50% reduction) against clinical and severe malaria in African infants.[38]

Long-term follow-up and studies are needed on whether a reduction in incidence of acute infection will lead to a decrease in the incidence of HMS.[32]

Complications of hyperreactive malarial splenomegaly (HMS) 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.

A study by Zambrano et al looking at unresolved HMS in Congolese refugees recently resettled in the United States reported that the likelihood of a hematologic abnormality, including anemia, thrombocytopenia, or leukopenia, was 39% greater in those who had splenomegaly at any time after arrival. Moreover, in persons with persistent splenomegaly, there was a 60% greater chance of a hematologic abnormality, especially thrombocytopenia (five-fold higher risk), with elevated alkaline phosphatase also being found (57% greater likelihood).[39]

Hyperreactive malarial splenomegaly (HMS) is a chronic disease with mortality rates from 20-57% based on the degree of splenomegaly.[17] Higher mortality rates are associated with treatment noncompliance.[18] Bleeding and infection are the most common complications.[17]

Splenectomy should be avoided because it increases the risk of fulminant infections.

The exact risk of development of malignancy has not been established.

The importance of antimalarial prophylaxis during visits to endemic areas should be emphasized to travelers.

Symptoms should be promptly attended to and evaluated, even if they occur in travelers who received prophylaxis. Hyperreactive malarial splenomegaly (HMS) may present months to years after leaving an endemic area.