A Case of Hyper-reactive Malarial Splenomegaly. The Role of Rapid Antigen-detecting and PCR-based Tests

Abstract Hyper-reactive malarial splenomegaly (HMS) – originally referred to as tropical splenomegaly syndrome – is characterized by a massive splenomegaly, high titres of anti-malarial antibodies and polyclonal IgM hypergammaglobulinemia. It is believed to be a consequence of an aberrant immunological response to prolonged exposure to malarial parasites. Although it is a frequent disease in the tropics, it is infrequent in western countries and is only seen in long-term residents from endemic areas. We describe the case of a 67-year-old Spanish man, a missionary in Cameroon for 30 years, who presented with a clinical history that fulfilled the diagnosis of HMS. We discuss the role and importance of PCR-based techniques in demonstrating lowgrade malarial parasitemia and the usefulness of new rapid antigen-detecting dipstick tests.     

Hyper-reactive malarial splenomegaly in a patient with human immunodeficiency virus

Both hyperreactive malarial splenomegaly (HMS) and HIV infection are highly prevalent in sub-Saharan Africa, but the inter-relationships between the two conditions are not clearly defined. Diagnosis of HMS is particularly difficult in HIV-infected patients, and detection of circulating malaria parasites by polymerase chain reaction (PCR) may represent a useful diagnostic tool.     

Hyperreactive malarial splenomegaly in expatriates

Hyperreactive malarial splenomegaly, one of the major causes of splenomegaly in tropics, has been often reported in expatriates of non-tropical settings. Essential features are recurrent malarial infection, overproduction of IgM and hyperplasia of lymphoreticular system. The practice of diagnosing the condition by exclusion of obvious causes of splenomegaly in the tropics has been abandoned. There are specific criteria for the diagnosis. Huge splenomegaly >10 cm below costal margin, serum IgM more than 2 x standard deviation (2SD) above the local mean, high titre of malarial antibodies and response to antimalarial drugs are the cornerstones of the diagnosis. Splenic lymphoma with villous lymphocytes coexists with this condition and it should always be considered in the differential diagnosis of unresponsive or poorly responsive cases of hyperreactive malarial splenomegaly. Condition with fever and acute haemolysis in HMS has been termed as Fulminant tropical splenomegaly syndrome. Treatment of the condition depends on antimalarial (chloroquine/ proguanil/ pyrimethamine) chemoprophylaxis for 1 year or more.     

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.     

Hyperreactive malarial splenomegaly is associated with low levels of antibodies against red blood cell and Plasmodium falciparum derived glycolipids in Yanomami Amerindians from Venezuela

The immunological basis of the aberrant immune response in hyperreactive malarial splenomegaly (HMS) is poorly understood, but believed to be associated with polyclonal B cell activation by an unidentified malaria mitogen, leading to unregulated immunoglobulin and autoantibody production. HMS has been previously reported in Yanomami communities in the Upper Orinoco region of the Venezuelan Amazon. To investigate a possible association between antibody responses against Plasmodium falciparum and uninfected red blood cell (URBC) glycolipids and splenomegaly, a direct comparison of the parasite versus host anti-glycolipid antibody responses was made in an isolated community of this area. The anti-P. falciparum glycolipid (Pfglp) response was IgG3 dominated, whereas the uninfected red blood cell glycolipid (URBCglp) response showed a predominance of IgG1. The levels of IgG1 against Pfglp, and of IgG4 and IgM against URBCglp were significantly higher in women, while the anti-Pfglp or URBCglp IgM levels were inversely correlated with the degree of splenomegaly. Overall, these results suggest differential regulation of anti-parasite and autoreactive responses and that these responses may be linked to the development and evolution of HMS in this population exposed to endemic malaria. The high mortality rates associated with HMS point out that its early diagnosis together with the implementation of malaria control measures in these isolated Amerindian communities are a priority.     

Hyperreactive malarial splenomegaly in a European returning from 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 macroglobulinemia, 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.     

A case of Plasmodium vivax malaria complicated with pancytopenia due to hypoplasia of the bone marrow

The patient is a 39 year-old Japanese male who had traveled to Southeast Asia from March 14, 1987 and returned on April 2. On April 3 and 5, he had a high fever with chills and he was admitted to our hospital. Despite initial treatment with antibiotics, a high fever over 39 degrees C appeared with a 48 hour periodicity. On the 8th day after admission, malarial parasites were identified on the peripheral blood smear after repeated trials. Combined with a raised serum antibody titer, Plasmodium vivax malaria was diagnosed. He was successfully treated with the sulfadoxine 500 mg and pyrimethamine 25 mg (Fansidar) and body temperature was normalized after the 12th day. More interestingly, the patient showed pancytopenia without splenomegaly. The bone marrow aspiration revealed hypoplasia of erythroblasts, granulocytes and megakaryocytes. Because of this pancytopenia in the peripheral blood and hypoplasia of the bone marrow which improved after recovery from malarial infection, it was indicated that they were caused by the malarial infection. Generally, it is considered that anemia in malarial patients is caused by destruction of the blood cells by parasites and/or hypersplenism and compensatory hyperplasia of the bone marrow is seen. On the contrary, this case showed pancytopenia accompanied with hypoplasia of the bone marrow probably due to the malarial infection suggesting a new aspect of pathogenesis in the hematological abnormality of the malarial infection.     

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.     

Hyper-reactive Malarial Splenomegaly (HMS) in malaria endemic area in Eastern Sudan

Hyper-reactive Malarial Splenomegaly (HMS) is massive enlargement of the spleen resulting from abnormal immune response to repeated attacks of malaria. The present study was carried out in Kassala city, Eastern Sudan where HMS is considered as highly prevalent. The objectives of this study were to determine the incidence of HMS in Eastern Sudan, and to identify basic laboratory and clinical characteristics of this condition in Sudanese patients. In the period between January and March 2004, a cross-sectional study was carried out in four health centers in Kassala city. In the current study 114 out 1010 (11%) medical cases examined were found to have enlarged spleens, 87 (9%) of them were diagnosed as HMS. Sixty-three percent of HMS cases were males and the rest were females. The mean age of HMS patients was 28 years. Clinical investigations showed that all cases suffered from abdominal pain in the upper left quadrant and all had a palpable firm spleen (10-26cm) below the costal margin. Laboratory examinations showed that 74% of the cases were anaemic and the mean white blood count for all cases was 4237cell/mL(3). Serum concentration of IgM in all subjects was above the threshold of the mean value plus 2 S.D. for 35 asymptomatic controls. In more than 70% of the HMS patients (53 individuals) the spleens were impalpable after the third month of the treatment. Our data indicate that HMS is one of the major causes of tropical splenomegaly in Eastern Sudan.     

Malarial placental infection and low birth weight babies.

Two-hundred fifty-six mothers and their newborns were subjected to clinical and haematological tests for the evidence of malaria. Placentae of these were examined histopathologically for malarial parasites and malarial pigment. Forty six placentae showed scanty malarial pigment ingested by monocytes. These appearances were associated with focal syncytial necrosis and proliferation of cytotrophoblastic cells. Plasmodium falciparum was found in cord blood of six cases. The mean weight of newborns born to mothers having no evidence of malarial placental infection was 2.763 kg, while mean weight of newborns belonging to infected placentae was 2.143 kg. The difference was highly significant.     

The epidemiology of malaria in Bolifamba, a rural community on the eastern slopes of Mount Cameroon: seasonal variation in the parasitological indices of transmission

The prevalences of malarial parasitaemia, fever, splenomegaly and anaemia and the levels of parasitaemia were investigated, through part of one wet season (in 2001) and the following dry season (in 2002), in 2157 subjects in the village of Bolifamba, in south-western Cameroon. Overall, 55.9% of the villagers checked in the wet season but only 49.5% of those examined in the dry season were found smear-positive for malaria (P<0.0001). Rainfall was found to be significantly associated with the mean level of parasitaemia (P=0.001). The prevalences of fever (40.3% v. 19.6%), splenomegaly (37.4% v. 4.0%) and marked splenomegaly (i.e. a Hackett's score of 2 or higher; 25.8% v. 2.4%) were all significantly higher in the wet season than in the dry (P<0.0001 for each). No seasonal difference was observed, however, in the prevalence of anaemia. Parasitaemia, fever, splenomegaly and anaemia were all significantly more common in the young children investigated (i.e. those aged < 5 years) than in the older subjects.When the data were subjected to a multiple logistic regression, age-group, anaemia, fever, and month of examination were all found to be significantly associated with the presence of malarial parasitaemia. The results of this large-scale study, the first of its kind in the Buea district of Cameroon, indicate the intense transmission of malarial parasites in rural Bolifamba, with young children at greatest risk. The data collected provide a useful 'base line' for an ongoing study to assess the immune status of the residents of Bolifamba.     

HMS-related hemolysis after acute attacks of Plasmodium vivax malaria

Among a cohort of 1,213 cases treated for Plasmodium vivax malaria from an isolated Papua New Guinean population, seven adults with severe and sustained hemolytic anemia after clearance of the peripheral parasitemia were prospectively investigated. All the patients fulfilled the criteria for hyper-reactive malarial splenomegaly and in 2 of 7 cases an IgG warm antibody was identified. Hereditary hemolytic anemia was excluded in 5 of 5 patients. All treated cases improved after an initial high dose of prednisone and antimalarial chemoprophylaxis. The persistence of marked anemia in a patient with splenomegaly after a P. vivax attack should raise the suspicion of hyper-reactive malarial splenomegaly.     

Hyperreactive malarial splenomegaly in pregnancy

Hyperreactive malarial splenomegaly (HMS) is common in many tropical areas and particularly affects women of reproductive age. It is associated with anaemia which can be debilitating in patients already compromised by anaemia due to poor nutrition and pregnancy. The course of the disorder in pregnancy is commonly punctuated by episodes of haemolytic anaemia which can be life-threatening to the mother and cause increased fetal morbidity and loss. Management of the chronic state consists of lifelong anti-malarial therapy supplemented by haematinics. Blood transfusions may be required to treat episodes of severe haemolysis.     

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.     

Diagnosis of malaria by allele-specific PCR]

Malaria is relatively rare in Japan. Of 13 patients referred to our laboratory for malarial screening in the past 4 years, malarial parasites were detected in 8. Conventional screening procedures commonly detect hepatic dysfunction, thrombocytopenia, elevated LDH activity, and increased CRP levels in malaria patients. More notably, the 8 malaria patients identified by our laboratory also demonstrated reactive lymphocytosis. In the absence of additional clinical information, reactive lymphocytosis alone may be enough to warrant laboratory blood smear tests on the suspicion of malaria. Conventional microscopic methods have often proved inconclusive in identifying malarial parasite species or detecting mixed infections. However, by combining the methods of DNA analysis with those of microscopy, we were able to conclusively diagnose all cases of suspected malaria. As a test of their skills, 9 laboratory technicians relatively inexperienced with malarial parasites were asked to screen 6 samples: 3 containing malarial parasites, and 3 that were malaria-free. Although none of the technicians were able to accurately identify the samples without additional clinical information, 4 accurately identified all malarial samples when that information was provided. Experience is a crucial determinant of ability to detect malarial parasites by microscopic methods alone. Nonetheless, the findings of our study suggested the diagnostic accuracy of laboratory screening procedures for malaria can be significantly improved if combined with minimal clinical data and the techniques of DNA analysis.     

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.     

Hyperreactive malarial splenomegaly in Venezuela

A cross-sectional seroepidemiological survey seeking hyperreactive malarial splenomegaly was carried out in isolated Yanomami hamlets in Amazonas Territory in Venezuela. All 110 inhabitants greater than 1 year of age were evaluated clinically and 98 were studied immunologically. The spleen index for individuals greater than 10 years of age was 44%. Only 3 patients had Plasmodium spp. on thick blood smears. All had serological evidence of infection with Plasmodium falciparum and P. vivax. Twenty-three patients were considered to show hyperreactive malarial splenomegaly. Clinical manifestations of the syndrome did not differ from those described in other parts of the world.     

Treatment of Suspected Hyper-Reactive Malarial Splenomegaly (HMS) in Pregnancy with Mefloquine

Malaria infections in pregnancy are associated with adverse outcomes for both mother and child. There are few data on hyper-reactive malarial splenomegaly, an aberrant immunological response to chronic or recurrent malaria in pregnancy. This retrospective assessment reviewed the impact of mefloquine treatment on pregnant women with suspected hyper-reactive malarial splenomegaly in an area of low malaria transmission in the 1990s, showing significant reductions in spleen size and anemia and anti-malarial antibody titers without any notable negative effect on treated women or their newborns.Malaria infections in pregnancy are associated with distinct epidemiological, pathophysiological, and clinical features, including a greater risk of complications during the acute course of the illness and adverse outcomes for both the mother and her child.^1,2 Hyper-reactive malarial splenomegaly (HMS; historically known as Tropical Splenomegaly Syndrome” [TSS] or “Big Spleen Disease”) is one of the most common causes of a markedly enlarged spleen in malaria-endemic regions, whereas uncomplicated malaria and schistosomiasis are common causes of splenomegaly.^3,4 HMS is thought to represent an abnormal polyclonal B-cell-mediated response to recurrent or chronic malaria infection,^5–7 which results in marked splenomegaly and functional hypersplenism.⁵ Although there is no single diagnostic test, cases can be identified using a defined set of clinical, laboratory, and histological criteria including gross splenomegaly (spleen size ≥ 10 cm below the costal margin), elevated immunoglobulin M (IgM) titers (often defined as ≥ 2 SD above the local mean), the presence of high titers of anti-malarial antibodies, evidence of a lymphocytic hepatic sinusoidal infiltrate on liver biopsy, absence of evidence of a neoplastic lymphoproliferative disorder, and a reduction in spleen size (≥ 40% over 6 months) in response to effective anti-malarial treatment.⁸ HMS is more common in certain ethnic groups (e.g., 80% prevalence in some tribes in New Guinea), and the association of severe HMS with HLA-DR2 is further evidence in support of an underlying host predisposition.⁹ Treatment consists of prolonged courses of effective anti-malarial therapy. Reduction in splenic mass is associated with a reduction in serological parameters.^10,11There are few data in the literature addressing HMS in pregnancy,^12,13 which is of particular relevance given the susceptibility of pregnant women to malaria, the risk of splenomegaly in pregnancy in terms of anemia, thrombocytopenia, and increased susceptibility to infection, and the anxiety related to the safe administration of anti-malarial medication to pregnant women. This retrospective analysis aimed to characterize the effects of mefloquine treatment on spleen size and maternal IgM, IgG, and anti-malarial antibodies in pregnant women with splenomegaly in an area of low seasonal transmission on the Thai-Myanmar border.This survey was undertaken at the Shoklo Malaria Research Unit (SMRU), Mae Sot, Thailand, between May 1994 and February 1997. Pregnant women were screened weekly for malaria by blood smear and every second week for anemia by hematocrit. Spleen size measurement was part of the routine obstetric examination. Any woman with significant splenomegaly (defined locally as ≥ 5 cm enlargement) and with a negative malaria film was given 5 mg/kg mefloquine weekly (Lariam, Roche Pharmaceuticals, Basel, Switzerland) as part of standard clinical practice to reduce anemia. A venous blood sample (3 mL) was sent to the Mae Sot Hospital for hemoglobin electrophoresis for detection of β-thalassemia (no test was available for α-thalassemia at that time). If during subsequent follow-up the spleen became impalpable, treatment was given for a further 2 weeks and then stopped; if the splenomegaly was unresponsive, treatment was stopped at 12 weeks. Women were followed up to delivery and neonatal outcomes were recorded.Thirty-six women with suspected HMS were identified and treated as described; residual plasma samples from routine blood counts were stored for 31 of these women at the time of diagnosis and each time the woman was followed up. These samples were taken as part of routine clinical care. One hundred and twenty-nine samples (median samples per individual interquartile range [IQR]: 5 [3–6]) were processed for total IgM and IgG (Minineph, The Binding Site, Birmingham, UK); anti-malarial antibody titers (ELISA, DiaMed, Switzerland) were measured in a smaller subset of 87 samples taken from 23 cases (median samples per individual [IQR]: 4 [3–5]; mean value for duplicate tests obtained on 57 samples). Single samples taken from 29 malaria-smear negative pregnant women without splenomegaly from the same geographical area, population, and collected within the same time frame, were used as unmatched controls; total IgM and IgG were measured on all of these samples, and anti-malarial antibodies in a subset of five (mean value for duplicate tests obtained on all samples).Concomitant rates of splenomegaly in the 3,503 women enrolled to antenatal care during the same period were 3.8% (134) for splenomegaly of any size and 1.0% (36) for splenomegaly ≥ 5 cm. By contrast, from May 2007 to September 2010 these proportions had dropped markedly to 0.5% (69 of 12,067) and 0.3% (40), respectively; which corresponded with a reduction in the incidence of Plasmodium falciparum malaria in the population.¹⁴Of the 31 of 36 women with suspected HMS for whom blood samples were available, 7 (23%) had splenomegaly of ≥ 10 cm at enrollment, 17 (55%) a serum IgM concentration ≥ 2 SD above the local controls, and 18 (58%) responded to treatment with a reduction in spleen size of ≥ 40%. Three (10%) women met all of these criteria and 13 (42%) only two.² Minor criteria defined as hepatic sinusoidal lymphocytosis, normal lymphocyte response to phytohemagglutinin stimulation, lymphocyte proliferation, were not assessed.¹A median of 9 (2–25) weekly mefloquine treatments were provided per woman. Pre-mefloquine treatment plasma titers for cases were significantly higher than controls for all measurements (Figure 1): total IgM was 6.1 (95% confidence interval [CI] 3.8–8.5) versus 2.1 (95% CI 1.8–2.4) IU/mL, P = 0.001; total IgG was 17.6 (95% CI 15.9–19.3) versus 12.5 (95% CI 11.5–13.6) IU/mL, P < 0.0001; and anti-malarial antibody index values were 9.1 (95% CI 8.1–10.2) versus 2.6 (95% CI 0.43–4.85), P < 0.0001. Significant reductions in spleen size (linear regression: co-efficient −0.14; SE 0.03; [95% CI −0.20–0.07]; P < 0.0001) and in anti-malarial antibody index values (linear regression: co-efficient −0.69; SE 0.03; [95% CI −0.13–0.01]; P = 0.02) were observed with mefloquine treatment. Decreases in IgM and IgG titers were also observed, although these did not reach statistical significance. Five women had complete resolution of splenomegaly. Splenic reduction (median [range]) was observed in women with and without abnormal hemoglobin-typing (available for 30 women): 4 (0–8) cm with normal hemoglobin typing (N = 16), 2.5 (1–6) cm with homozygote β-thalassemia (N = 4); 3 (1–7) cm with β-thalassemia trait, N = 9; and no change in one with hemoglobin-E disease (P = 0.381). The proportion of women with splenic reduction ≥ 40% was 75% (12 of 16) of women with normal hemoglobin typing and 57.1% (8 of 14) of women with abnormal hemoglobin typing, P = 0.442.Open in a separate windowFigure 1.Values of control and pre-mefloquine treatment (for cases) total immunoglobulin M (IgM), IgG, and anti-malarial antibody index results.Women with suspected HMS were significantly older and of higher gravidity, with a mean age of 30 versus 24 years (P = 0.0009) and 5 versus 3 pregnancies (P = 0.019), and on average, had a 17% proportional reduction in hematocrit at the start of antenatal screening than contemporary controls: 28.8% (95% CI 26.6–31.0%) versus 34.8% (95% CI 33.3–36.4%; P < 0.0001). The mean hematocrit before delivery in women treated with mefloquine (5 mg/kg/week) increased to 31.5% (95% CI 26.6–31.0%; P = 0.05) from baseline, whereas the hematocrit values in control women fell significantly to 32.6% (95% CI 31.2–34.0%; P = 0.009). There was no difference in mean birth weights between the two groups: 2,910 g (95% CI 2,704–3,118 g) in cases versus 2,989 g (95% CI 2,856–3,123 g; P = 0.50) in controls. One baby in the group with splenomegaly was born prematurely (< 37 weeks). All babies in both groups had normal post-natal assessments (N = 50).There are limitations to this retrospective analysis: the sample size was small reflecting the relative rarity of HMS in this population (prevalence ~1%); the control group was contemporary but unmatched; and there were no malaria polymerase chain reaction data that have been used in other settings to confirm low-density parasitemias in putative HMS patients,¹⁵ thereby confirming active malaria infection as the direct cause of splenomegaly. Other causes of splenomegaly were also not explicitly ruled out, although there is no schistosomiasis in the area, the rate of human immunodeficiency virus and syphilis remains very low (< 0.4%), and none of these women died of malignancy-related maternal deaths. The raised anti-malarial antibody titer results presented here are similar to a series of 50 Hmong refugees from Thailand examined in Minnesota, North America, with a spleen > 2 cm.¹⁶ Despite these limitations, we show that in a group of women with a spleen size ≥ 5 cm and negative malaria films, treatment with mefloquine led to reduction in spleen size and decrease in anemia, without any adverse outcomes. Splenic reduction of ≥ 40%⁸ was also seen in women who did not meet all the conventional criteria for HMS: in this analysis it was a feature of 5 of 7 (71%) and 10 of 13 (77%) of women with one and two major criteria of HMS, respectively; and in women with abnormal hemoglobin typing. This suggests that in a malarious area mefloquine is useful even when splenomegaly is thought to be caused by hemoglobinopathy.Total IgM and IgG titers were elevated in women with splenomegaly, and anti-malarial antibodies were inevitably present. Statistically significant decreases were not observed in all of the serological parameters on treatment, perhaps because of the relatively short period of follow-up (range for last follow-up sample: 5–29 weeks). Weekly mefloquine can be used for the treatment of HMS in pregnancy in areas where P. falciparum parasites remain sensitive to the drug.     

Immunoglobin M and malarial antibody levels in hyper-reactive malarial splenomegaly

In a study of chronic splenomegaly in Kenya, hyper-reactive malarial splenomegaly, our preferred name for tropical splenomegaly syndrome, was diagnosed in 38 patients. This diagnosis was based on exclusion of other conditions and observations of hepatic sinusoidal lymphocytosis on liver biopsy. To assess the previously recommended diagnostic criterion of elevation of serum IgM, to two standard deviations (s.d.) above the local mean, serum IgM levels were measured in patients and in 90 geographically matched controls. Patients with IgM levels 2 s.d. above the local mean were compared with those with lower levels. No differences were found other than higher malarial antibody titres in the group with higher IgM levels. Agreement is required concerning diagnostic criteria for hyper-reactive malarial splenomegaly; other features of the syndrome may occur in the absence of marked IgM elevation.     

Evaluation of clinical pallor in the identification and treatment of children with moderate and severe anaemia

BACKGROUND: Anaemia from malaria is a common problem in developing countries. Blood transfusion in developing countries is available in few hospitals. Children who are severely anaemic and may require urgent blood transfusion usually present to peripheral first-level health facilities from where they must be referred to hospitals. Since most peripheral facilities do not determine haemoglobin levels, the decision on referral has to be made on clinical grounds. OBJECTIVES: To evaluate the sensitivity and specificity of clinical pallor of the palms, nailbeds, conjunctivae, buccal mucosa or tongue against haemoglobin values and their reproducibility among health workers. METHODS: A total of 2540 children 2 months to 5 years of age presenting to a rural health centre in Ethiopia were enrolled. Clinically detected pallor was compared with measured blood haemoglobin concentrations. RESULTS: Any anaemia (haemoglobin < 11 g/dl) was found in 61% of the children. Severe anaemia (haemoglobin < 5 g/dl) was found in 4%. The presence of any pallor clinically correlated with moderate anaemia (haemoglobin level < 8 g/dl) could be detected with a sensitivity of 95% and a specificity of 64-68% when the palm and nailbeds were used and a sensitivity of 84% and a specificity of 81% when the conjunctivae were used. Severe anaemia was detected clinically as severe pallor in 50-56% of cases (with a specificity of 95-96%). Agreement between physicians was highest for conjunctivae and nailbed pallor (87%) and lowest for palm pallor (73%). Using multivariate analysis, identification of a systolic ejection murmur or altered sensorium, the presence of splenomegaly or malarial parasitaemia were independently predictive of severe and moderately severe anaemia. CONCLUSIONS: Moderate and severe anaemia can be identified clinically in most cases for treatment and referral purposes. A systolic ejection murmur, altered sensorium, the presence of splenomegaly or malarial parasitaemia may be used as additional tools in considering urgent referral for blood transfusion.