Laboratory Studies
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:
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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 IgM level 2 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)
Minor criteria include the following:
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Hepatic sinusoidal lymphocytosis
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Normal cellular and humoral responses to antigenic challenge, including a normal phytohemagglutination response
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Hypersplenism
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Lymphocytic proliferation
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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 Studies
Imaging tests are of limited value. Ultrasonography of the abdomen may help to document and monitor hepatosplenomegaly.
Other Tests
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.
Histologic Findings
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.
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Young patient with hepatomegaly and massive splenomegaly.
