Tropical Splenomegaly Syndrome Research Articles

Bcl-2 and Immunoglobulin Gene Rearrangements in Patients with Malaria Related Chronic Splenomegaly

Two cases of malaria related chronic splenomegaly, one with tropical splenic lymphoma with villous lymphocytes (TSLVL) and the other with hyperreactive malarial splenomegaly (HMS) were analyzed by cytology, histology, karyotyping, immunophenotyping, and polymerase chain reaction (PCR) for detection of bcl-2/JH and FR3/JH rearrangements on blood and bone marrow samples, at diagnosis and 12 months after malarial prophylaxis. The reported data suggest that the detection of FR3/JH rearrangement might contribute to the diagnosis of TSLVL in patients with malaria related chronic splenomegaly, for whom bcl-2/JH rearrangement may be a common molecular event.

Is ultrasound a useful adjunct for assessing malaria patients?

The value of ultrasonography as an adjunct for diagnosis and monitoring malaria was investigated. In all, 118 patients (male/female 65/53; age 2-78 years, median 29 years) with malaria underwent a standardised abdominal ultrasound examination at baseline. In 62 out of 118 patients, ultrasonography was repeated 21 days later. In the results at baseline, huge splenomegaly with firm organ consistency, consistent with hyperreactive malarious splenomegaly syndrome, was observed in two Cameroonese children. In the other 116 patients, the most common finding was non-specific splenomegaly (96/116, 82.76%), occurring more frequently in non-immune patients (71/78, 91.03%) than in patients who had grown up in malaria-endemic areas (25/38, 65.79%; P<0.002). No correlation was found between liver or spleen size and any clinical parameter. The results on day 21 show that, although splenomegaly after therapy persisted more frequently in patients with malaria recrudescence or relapse (8/8, 100%) than in patients cured (32/54, 59.26%; P<0.0421), the practical value of this finding is questionable. Ultrasonography cannot be regarded as a first-line diagnostic method in patients with malaria.

The Spleen in Myelofibrosis With Myeloid Metaplasia

The differential diagnosis of massive splenomegaly, operationally defined as a palpable spleen that extends below the transumbilical line, includes myelofibrosis with myeloid metaplasia (MMM), chronic myeloid leukemia, lymphoma, hairy cell leukemia, hyperreactive malarial splenomegaly, kala-azar (visceral leishmaniasis), Gaucher disease, splenic cystic lymphangiomatosis, systemic lupus erythematosus, and sarcoidosis. In MMM, splenomegaly is secondary to extramedullary hematopoiesis. Progressive splenomegaly in MMM is associated with mechanical discomfort, early satiety, episodes of severe left upper quadrant pain from splenic infarcts, profound cachexia, increased red blood cell transfusion requirement, thrombocytopenia, and complications of portal hypertension. Spleen-directed management in MMM includes chemotherapy (initial choice), surgical removal of the spleen (in drug-resistant cases), and splenic irradiation (in poor surgical candidates). In a retrospective study of 223 consecutive splenectomies in MMM, the median spleen mass was 2700 g (range, 380-7735 g). Splenectomy in MMM does not alter the natural history of the disease but benefits a proportion of patients with the aforementioned spleenrelated symptoms.

Low-grade parasitaemias and cold agglutinins in patients with hyper-reactive malarious splenomegaly and acute haemolysis.

A cluster of 16 cases of hyper-reactive malarious splenomegaly (HMS) with severe, acute haemolysis, from an isolated, Venezuelan, Yanomami population, was prospectively investigated. Nine (69%) of the 13 HMS sera investigated but only one (7%) of 14 control sera (P < 0.005) contained elevated titres (of at least 1:32) of complement-fixing IgM cold agglutinins (CA). The CA detected had specificity for both the I and i blood-group antigens (with a relative predominance of anti-I) and wide thermal stability. The mean reciprocal CA titre was much higher for the HMS sera than for the control samples (59.16 v. 2.28; P < 0.001). Indirect tests for antiglobulin were positive for two of the 13 HMS cases (but none of 14 controls) investigated; all of the direct tests for antiglobulin gave negative results. The seven HMS cases checked, using an assay based on a nested PCR which amplified species-specific ribosomal sequences from Plasmodium vivax or P. falciparum, each yielded the PCR product that indicated P. vivax infection. However, only six (25%) of the 24 control samples (collected, at the same time as the HMS samples, from asymptomatic adults from the same Yanomami population) were PCR-positive (P < 0.001). In some cases at least, the acute severe episodes of haemolysis occasionally seen in HMS appear to be associated with an auto-immune, cold-agglutinin-mediated response triggered by non-patent parasitaemias.

Causes of massive tropical splenomegaly in Ghana.

The causes and diagnosis of massive tropical splenomegaly are not well studied, especially with modern investigative methods. We aimed to identify features that would help local clinicians differentiate between the underlying conditions. We collected prospective clinical and laboratory data on 221 Ghanaian patients with spleen size of at least 10 cm. We identified conditions associated with massive splenomegaly with molecular and immunological investigations as well as routine tests. Patients were assigned to diagnostic categories on the basis of these test results and predetermined criteria. Hyper-reactive malarial splenomegaly (HMS; 91 patients [41%]) and B-lymphoproliferative disorders (48 [22%]) were the most common disorders associated with massive splenomegaly. Of the remaining patients, 32 (14%) had haematological disorders, and in 50 (23%) we could not identify the cause of splenomegaly. Male sex predominated in all diagnostic groups except HMS and tropical splenic lymphoma. Age less than 40 years and absolute lymphocyte count (less than 10 x 10(9)/L) were the only useful and widely available discriminators for distinguishing patients with HMS from those with lymphoproliferative disorders. B-lymphoproliferative disorders are a previously unrecognised cause of massive tropical splenomegaly. This finding has major implications for management of massive splenomegaly. Diagnosis of the less common causes of this disorder is usually straightforward, but differentiating between B-lympho proliferative disorders and HMS can be difficult. HMS is associated with younger age, a higher proportion of women, and lower absolute lymphocyte counts than lympho proliferative disorders.

B-lymphotropic viruses in a novel tropical splenic lymphoma.

Peripheral blood from patients with a novel tropical splenic lymphoma, characterized by splenomegaly and circulating naïve CD5-negative villous B lymphocytes, has been screened for evidence of an association with the B-lymphotropic viruses, Epstein--Barr virus (EBV), hepatitis C virus (HCV) and human herpesvirus 8 (HHV8). No increased prevalence of EBV, HCV and HHV8 was demonstrated using serological and molecular techniques, compared with a geographical, age-matched control group. However, lymphoma patients had markedly raised EBV antibody levels without a concomitant increase in the rate of detection of viral genomes in the peripheral blood. This phenomenon also occurred in patients with hyper-reactive malarial splenomegaly, a condition that occurs in the same geographical area and that is clinically indistinguishable from tropical splenic lymphoma, adding further weight to the suggestion that there may be an aetiological association between these two disorders.

Spur cell anaemia and acute haemolysis in patients with hyperreactive malarious splenomegaly. Experience in an isolated Yanomamo population of Venezuela

A prospective study, aimed to investigate the aetiology of an unusual clustering of cases of severe acute haemolytic anaemia affecting a high percentage of the adult population, was carried out in two isolated Yanomamo communities of the Upper Orinoco basin in Venezuela. Twenty-six patients with active or recent episodes of severe haemolysis were evaluated. All of them exhibited massive liver and spleen enlargement and fulfilled the diagnostic criteria of the hyperreactive malarious splenomegaly (HMS) syndrome. In four cases with advanced non-alcohol-related chronic liver disease, hypersplenism, severe haemolytic anaemia and acanthocytosis, the characteristic clinical and laboratory findings of spur cell anaemia were documented. Chronic infection by the HBV and HCV was present in three of them. However, in most of the 22 additional HMS cases, the acute haemolytic condition appeared associated with the occurrence of a cold agglutinin-mediated autoimmune response. The clustering of a significant number of cases of severe acute haemolysis in HMS patients from this small isolated aboriginal community is most unusual, and represents a serious complicating factor for a population already beleaguered by a high prevalence of malaria due to multiresistant strains of Plasmodium falciparum. Moreover, the coexistence of HMS and severe chronic HBV or HCV infection may further aggravate the course of the haemolytic disorder, because of the occurrence of spur cell anaemia.

The use of PCR in the diagnosis of hyper-reactive malarial splenomegaly (HMS).

Between August 1997 and September 1998, 14 cases of hyper-reactive malarial splenomegaly (HMS) were diagnosed in the Instituto de Salud Carlos III in Madrid, Spain. These cases, from Equatorial Guinea and Cameroon, were identified using the diagnostic criteria established by Y. M. Fakunle in 1981: gross splenomegaly; high levels of anti-malarial antibodies; IgM in serum at least two standard deviations above the local mean; and clinical and immunological response to antimalarial treatment. Although malarial parasites were only detected in the Giemsa-stained blood films of four of the cases, these four and four others were found to have the DNA of such parasites in their blood when tested using a method based on a semi-nested, multiplex PCR. These result indicate that malarial parasitaemias may be more prevalent in HMS than is usually recognized.

Hyperreactive malaria in expatriates returning from sub-Saharan Africa.

The extreme presentation of hyperreactive malaria is hyperreactive malarial splenomegaly syndrome (HMS). Some patients present with a less pronounced syndrome. To investigate whether the degree of splenomegaly correlates with the degree of immune stimulation, whether prophylaxis or recent treatment play a role, and whether short therapy alone is effective, we examined retrospectively the medical records of expatriates with exposure to P. falciparum who attended our outpatient department from 1986 to 1997, particularly subacute symptoms or signs, strongly elevated malarial antibodies and elevated total serum IgM. We analysed duration of stay, prophlyaxis intake, spleen size, serum IgM levels and response to antimalarial treatment. Serum IgM levels were significantly higher in patients with larger splenomegaly. The use of chloroquine alone as treatment for presumptive or proved malaria attacks was correlated with larger spleen size. Short adequate antimalarial therapy resulted in marked improvement or complete recovery. In nine patients the hyperreactive response reappeared after re-exposure, in four of them twice. We conclude that patients with subacute symptoms but without gross splenomegaly may have very high levels of IgM and malarial antibodies, and relapse on re-exposure, suggesting the existence of a variant of the hyperreactive malarial splenomegaly syndrome without gross splenomegaly.

Malaria and Immunoglobulins in Pacific Prehistory

The role of malaria in Pacific prehistory has been the subject of considerable study and supposition. In this manuscript, I attempt to clarify the research and reasoning that has led me to suggest that the Austronesian-speaking peoples had a selective advantage in malarious environments. In particular, I hope to dispel any notion that that advantage was due to resistance to malaria and to re-affirm my actual assertion that the genetic basis for the Austronesian advantage was resistance to developing the hyperimmune disease, hyperreactive malarious splenomegaly. I believe that an appreciation of this distinction will ultimately prove to be essential to understanding the role of malaria in facilitating the spread of the Austronesians—in the form of people, languages, and/or genes—throughout the Pacific. [Pacific prehistory, malaria, natural selection, Austronesians, immunoglobulins]

VH gene sequences from a novel tropical splenic lymphoma reveal a naive B cell as the cell of origin.

The prevalence of malaria and other infections in tropical Africa provides a setting for the emergence of B-cell tumours distinct from that in Western countries. Attempts to draw comparisons with Western lymphomas have led to difficulties, with so-called African chronic lymphocytic leukaemia (CLL) having a different pattern of incidence from Western CLL. Splenomegaly is common in African CLL, and this has posed diagnostic problems in differentiating the tumour from malaria-associated hyper-reactive malarial splenomegaly (HMS). One feature of the splenomegalic form of African CLL is that the tumour cells often possess short but fine cytoplasmic projections reminiscent of those observed in Western splenic lymphoma with villous lymphocytes (SLVL). Analysis of Ig VH genes both facilitates discrimination between clonal B-cell tumours and HMS, and reveals the differentiation status of the cell of origin. This study indicated that VH genes of nine cases of clonal splenic B-cell tumours with villous lymphocytes from Ghana were relatively unmutated, consistent with an origin from a naive B cell. These features differ from SLVL which arises from a post-follicular antigen-selected B cell. One possibility is that these splenic B-cell tumours derive from a splenic T-independent B cell, with malaria infection as a potential influence.

Splénomégalie malarique hyperréactive chez un Européen revenant d'Afrique

Hyper-reactive malarial splenomegaly in a European patient after residence in Africa. Introduction. — Hyper-reactive malarial splenomegaly (HMS) syndrome related to abnormal immunologic response to repeated malarial infections is unusual in European expatriates. Exegesis. — We report the case of a 72-year-old white male patient who had been residing in the Congo and developed a typical clinical features of hyperactive malarial syndrome characterized by massive splenomegaly with hypersplenism, high titers of malarial IgM antibodies, IgM macroglonulinemia, liver and medullary lymphocytic proliferation, and a clinical and immunological response to long-term chloroquine therapy. Conclusion. — Criteria for the diagnosis of hyper-reactive malarial splenomegaly are useful. However, making a distinction from malignant lymphoproliferative disorders is difficult, as a sustained response to chloroquine is required. Therefore, chloroquine appears to have a regulatory effect on the immune system.

Serological similarities between hyperreactive malarial splenomegaly and splenic lymphoma in West Africa

In West Africa hyperreactive malarial splenomegaly (HMS) and splenic lymphoma with villous lymphocytes (SLVL) are demographically and clinically indistinguishable. Determination of lymphocyte clonality is needed to differentiate clearly between these 2 disorders. To obtain evidence to support our hypothesis that HMS and SLVL are aetiologically related we studied the serological profile of malaria-related antibodies in HMS and SLVL in West Africa. We found that in SLVL total immunoglobulin M and antimalarial antibody levels were markedly raised, a combination which is characteristic of HMS. These findings strongly support a developmental relationship between HMS and SLVL in tropical Africa and implicate malaria in this process.

Chronic malaria and splenic lymphoma: clues to understanding lymphoma evolution.

In west Africa, splenic lymphoma with villous lymphocytes and hyper-reactive malarial splenomegaly have many clinical and immunological features in common suggesting an aetiopathological link. We hypothesize that in hyper-reactive malarial splenomegaly the dysregulated immune response to repeated malaria infections results in a stimulated, proliferating pool of B cells in which perturbation of cell growth and apoptosis by environmental and other factors promotes the development of SLVL. In Africa these factors are likely to include infectious agents several of which have already been associated with B-cell non-Hodgkin's lymphomas.

Circulating villous lymphocytes—a link between hyperreactive malarial splenomegaly and splenic lymphoma

Significant numbers of villous lymphocytes were noted in the blood of patients with a clinical diagnosis of hyperreactive malarial splenomegaly (HMS) in Ghana. Demographic and haematological data were recorded from 22 patients with massive splenomegaly. Additional investigations included lymphocyte immunophenotyping, protein electrophoresis and immunoglobulin gene rearrangements. Although all patients had over 30% villous lymphocytes and no leucocytosis, 7 had no evidence of a monoclonal disorder. Immunophenotyping and the presence of monoclonal lymphocytes identified 3 further patients with B-cell splenic lymphoma with villous lymphocytes (B-SLVL). HMS and SLVL co-existed in the same, predominantly female, patient population and were indistinguishable except by molecular analysis of lymphocytes. The discovery of the uncommon villous lymphocytes in both non-malignant and malignant disorders in the same geographical area suggested that HMS and SLVL are pathophysiologically related. In Caucasians with SLVL the malignant cells arise from B-cells that have undergone antigen selection. We postulate that the excessive proliferation of polyclonal B-lymphocytes, driven by frequent exposure to malaria, predisposes to the emergence of a malignant lymphoma, B-SLVL, in tropical West Africa.

Hyperreactive malarial splenomegaly and AIDS: proguanil prevents recurrent pneumonia

An Ethiopian immigrated to Israel and gave a positive test result for human immunodeficiency virus. Soon after, he was thrice admitted to hospital in 3 months for severe pneumonia. Acquired immunodeficiency syndrome was diagnosed, as was hyperreactive malarial splenomegaly (HMS). Thereafter, during maintained proguanil treatment for HMS, the patient remained well for 16 months. Then, after another pneumonic illness, pneumococcal vaccine was administered. Proguanil was maintained for another 10 months and, despite declining CD4 cell counts, good health continued for a further 18 months.

IGHG3 G and the Pathogenesis of Hyperreactive malarious splenomegaly

Hyperreactive malarious splenomegaly is an aberrant response to chronic malarial infection, defined by persistent gross splenomegaly and elevated serum IgM and IgG. The populational and familial patterns of this disorder suggest genetically based, immune incompetence. In Papua New Guinea, the disease occurs among populations characterized by high frequencies of IGHG3 G haplotypes. Elsewhere, the distribution and prevalence of hyperreactive malarious splenomegaly is consistent with the distributions of IGHG3 alleles. Drawing upon this relationship, I suggest that expression of the G3 M G phenotype is a necessary precondition for hyperreactive malarious splenomegaly, consistent with the pathogenesis of malaria and the functions of the immune system.

Immunoglobulin gene polymerase chain reaction to distinguish hyperreactive malarial splenomegaly from ‘African’ chronic lymphocytic leukaemia and splenic lymphoma

Hyperreactive malarial splenomegaly (HMS) is found in geographical association with B cell lymphoproliferative disorders such as ‘African’ chronic lymphocytic leukaemia (CLL) and splenic lymphoma with villous lymphocytes (SLVL). It is sometimes not easy to make a differential clinical diagnosis between these conditions. We have previously used Southern blotting as a definitive method for the diagnosis of monoclonal lymphoproliferation in these disorders, but this is expensive, lengthy and technically difficult. In the present paper we have compared Southern blotting with polymerase chain reaction (PCR) amplification of the immunoglobulin heavy chain gene. We found an excellent correlation between the 2 methods in demonstrating monoclonal populations of lymphocytes in patients with a clinical diagnosis of CLL or SLVL. We have further demonstrated monoclonality in a patient who could not be classified as CLL or SLVL on clinical criteria alone. In contrast, patients with well defined HMS or with non-B cell proliferations all showed polyclonal rearrangements. We propose that the immunoglobulin gene PCR is a useful tool for the investigation of tropical splenomegaly of uncertain origin.

Non-Invasive Diagnosis of Tropical Splenomegaly Syndrome

A study of 41 clinically diagnosed cases of possible tropical splenomegaly syndrome (TSS) was undertaken in Mulago Hospital, Kampala, Uganda, to determine the appropriateness of liver ultrasonography in confirming a diagnosis of TSS. Definitive diagnosis of TSS was made on liver biopsy in 35 (85%) cases. Abdominal ultrasound showed that 30 of the confirmed cases of TSS had normal liver echo-texture and portal vein diameter, and five had abnormally increased liver echo-texture. The combination of massive splenomegaly and hepatomegaly, together with normal ultrasound features of the liver was highly suggestive of TSS. The sensitivity of this criterion was 86% and the specificity was 83%. This non-invasive approach to the diagnosis of TSS is associated with less hazards than liver biopsy, and a normal echogram could be used to make the diagnosis in over 80% of cases, in the field where histopathology may be lacking.

Massive splenomegaly responsive to proguanil and with features of hairy cell leukaemia

A recent Ethiopian immigrant to Israel presented with pneumococcal sepsis, massive splenomegaly and lymphadenopathy. Investigations revealed many features of both hairy cell leukaemia (HCL) and hyperreactive malarious splenomegaly (HMS). Proguanil therapy for HMS was followed by rapid, marked decrease in spleen size, disappearance of the tartrate-resistant acid phosphatase-positive cells characteristic of HCL, and increasing eosinophilia, but unchanged lymphadenopathy.