You are in: eMedicine Specialties > Pediatrics: General Medicine > Hematology Tropical Splenomegaly SyndromeArticle Last Updated: Nov 19, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP, Assistant Professor of Pediatric Hematology-Oncology, Department of Pediatrics, Children's Hospital at Albany Medical Center Vikramjit S Kanwar is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology Coauthor(s): Mudra Kumar, MD, MBBS, MRCP, Associate Professor, Department of Pediatrics, University of South Florida College of Medicine Editors: J Martin Johnston, MD, Director of Pediatric Hematology/Oncology, Backus Children's Hospital, Memorial Health University Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine Author and Editor Disclosure Synonyms and related keywords: tropical splenomegaly syndrome, TSS, Bengal splenomegaly, big spleen disease, idiopathic splenomegaly, African macroglobulinemia, cryptogenic splenomegaly, hyperreactive malarial syndrome, HMS, massive splenomegaly, hepatomegaly, hepatosplenomegaly, splenic enlargement, hypersplenism, enlarged spleen, large spleen, Plasmodium falciparum, P falciparum, Plasmodium vivax, Plasmodium malariae, malaria, sickle cell trait, anemia, hemoglobinopathies, lymphoreticular disorders, schistosomiasis, hepatic cirrhosis, leishmaniasis, typhoid, tuberculosis, chronic lymphocytic leukemia, CLL, splenic lymphoma with villous lymphocytes, SLVL, chronic antigenic stimulation INTRODUCTIONSection 2 of 11
  BackgroundSeveral 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 This condition was later redefined as hyperreactive malarial syndrome (HMS) using more clear diagnostic criteria.2 PathophysiologyHMS 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 malariae.3 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. 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.5 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. FrequencyUnited StatesHMS occurs only in people who have resided in or who have visited areas where malaria is endemic.6 InternationalHMS 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:
Exact and accurate assessment of the incidence of HMS is difficult because many conditions that cause splenomegaly and similar symptoms are prevalent in areas where malaria is endemic. These conditions include hemoglobinopathies, lymphoreticular disorders, schistosomiasis, hepatic cirrhosis, leishmaniasis, typhoid, and tuberculosis. Mortality/MorbidityThe natural history of HMS is not well documented. HMS is associated with a high mortality rate in untreated individuals, and overwhelming infections are the leading cause of death. A 5-year mortality rate of 50% was reported in Uganda and New Guinea,10 with a mortality as high as 85% in hospitalized patients.3 Other series found a much lower mortality rate.11 HMS is not considered a premalignant condition, although an overlap with chronic lymphocytic leukemia is noted.12 Whether HMS can undergo clonal evolution to splenic lymphoma with villous lymphocytes (SLVL) is unclear. The entities appear to independently evolve in response to chronic antigen stimulation. RaceCertain racial and immunologic factors may be important in the pathogenesis of HMS, although results of phenotypic studies of human lymphocyte antigens have not been entirely 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.13 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 no or intermittent prophylaxis against malaria.14 SexHMS is more common in female individuals, especially lactating mothers, than in male individuals. The female-to-male ratio is 2:1. AgeHMS 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.15 These observations support the theory that prolonged chronic antigenic stimulation is an important factor in the development of HMS. CLINICALSection 3 of 11
History
Physical
Causes
DIFFERENTIALSSection 4 of 11
Brucellosis Felty Syndrome Histiocytosis Infectious Mononucleosis Leishmaniasis Malaria Salmonella Infection Schistosomiasis Sickle Cell Anemia Thalassemia Trypanosomiasis Tuberculosis
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Drug Name | Chloroquine phosphate (Aralen Phosphate) |
|---|---|
| Description | 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. |
| Adult Dose | 1 g salt (600 mg base) PO initially and 300 mg base 6, 24, and 48 h later; then, 300 mg base qwk for months to >1 y until response occurs |
| Pediatric Dose | 10 mg/kg base PO and 5 mg/kg 6, 24, and 48 h later; then, 5 mg/kg base qwk for months to >1 y until response occurs |
| Contraindications | Documented hypersensitivity; retinal and visual field defects; hepatic disease; psoriasis; porphyria |
| Interactions | Cimetidine may increase serum levels and possibly levels of other 4-aminoquinolones; magnesium trisilicate may decrease absorption of 4-aminoquinolones |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | GI effects include epigastric discomfort, nausea, vomiting, abdominal cramping, and weight loss (decrease by taking drug with meals); pruritus, skin pigmentation, and lightening of hair color may occur; prolonged use may exacerbate various dermatoses; visual disturbances with blurring of vision, difficulty focusing, and accommodation may occur; retinopathy reported when high doses used for long period; prolonged use may cause nerve deafness (may be irreversible); headache, nervousness, depression, and psychic changes reported; peripheral neuritis and myopathy may occur Neuromyopathy occurs with prolonged use (reversible); cardiovascular effects most common with high doses and include EEG changes, hypotension, and cardiomyopathy; can precipitate hemolysis in G-6-PD deficiency; regular ophthalmologic (eg, slit lamp, funduscopic, visual field) examinations recommended; monitor for myopathy; accidental ingestion may be fatal in children, even with small doses; patients with acute toxicity present within half hour with nausea, vomiting, headache, drowsiness, arrhythmias, cardiovascular collapse, seizures, hypokalemia, and cardiopulmonary arrest |
| Drug Name | Proguanil (Paludrine) |
|---|---|
| Description | 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. |
| Adult Dose | 200 mg/d PO |
| Pediatric Dose | <1 year: 3 mg/kg/d or 25 mg PO qd 1-4 years: 50 mg PO qd 5-8 years: 100 mg PO qd 9-14 years: 150 mg PO qd >14 years: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Coadministration with chloroquine may increase incidence of mouth ulcers or diarrhea; may decrease immune response to typhoid vaccine; high protein binding may displace warfarin (monitor INR) |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Best taken after meals at same time every day; for children, can be mixed with honey, milk, or jam; must adjust dosage in renal failure; in rare cases, causes pancytopenia or thrombocytopenia, neutropenia, or anemia (generally reversible with discontinuation); mouth ulcers and diarrhea reported; can cause cholestatic liver disease (reversible); urticaria, phototoxicity, and exanthems reported |
| Drug Name | Pyrimethamine and sulfadoxine (Fansidar) |
|---|---|
| Description | 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. |
| Adult Dose | Acute episode: 50-75 mg (based on pyrimethamine component) PO qd for 3 d is curative Prophylaxis: 25 mg (based on pyrimethamine component) PO qwk |
| Pediatric Dose | Not well established; may need tailored according to data available for acute episodes and for prophylaxis or transmission control; dosages are based on pyrimethamine component <2 months: Contraindicated Acute episode: 4-10 years: 12.5 mg/d PO for 3 d >10 years: 25-50 mg/d PO for 3 d Alternative dose: <10 kg: 6.25 mg/d PO for 3 d 10-20 kg: 12.5 mg/d PO for 3 d 20-40 kg: 25 mg/d PO for 3 d Prophylaxis: <4 years: 6.25 mg PO qwk 4-10 years: 4-10 mg PO qwk >10 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; megaloblastic anemia due to folate deficiency; age <2 mo |
| Interactions | Concurrent use of antifolic acids (eg, methotrexate) may increase risk of bone marrow suppression (discontinue if signs of folate deficiency develop); mild hepatotoxicity may occur with concomitant administration of lorazepam and pyrimethamine |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Use of sulfonamides near term may increase risk of kernicterus in newborns; can minimize adverse reactions (eg, abdominal pain, nausea, vomiting, diarrhea) by taking with food; can cause exfoliative dermatitis, photosensitivity, pruritus, vasculitis, and toxic epidermal necrolysis; urticaria may be first sign of more serious reaction (eg, Stevens-Johnson syndrome); discontinue at first appearance of rash; agranulocytosis and thrombocytopenia common, especially at high doses (reversible with leucovorin); CNS effects include ataxia, tremors, and weakness; seizures possible, especially with preexisting seizure disorder; caution in alcoholism, anemia (especially if megaloblastic), asthma, bone marrow suppression, dental disease, folate deficiency, hepatic disease, renal disease, and seizure disorder |
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.
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, are now commonplace in most hospitals.
| Media file 1: Young patient with hepatomegaly and massive splenomegaly. | |
 | View Full Size Image | Media type: Photo |
Tropical Splenomegaly Syndrome excerpt
Article Last Updated: Nov 19, 2007
