IgM is polyclonal and there is no evidence to attribute the syndrome to any malaria species in particular [1], althoughPlasmodium falciparumis by and large the predominant species in the countries where the syndrome continues to be described [4]. clinical outcome at following appointments was analysed in relation to re-exposure to malaria, and to treatment (only part of the patients with e-HMS were treated with a single anti-malarial treatment and advised to follow an effective anti-malarial prophylaxis, in the event that re-exposed). The association from the outcome with all the main impartial variables was first assessed with univariate analysis. A stepwise logistic regression model was then performed to study the association from the outcome with all the main impartial variables. == Results == One hundred and twenty-six topics with e-HMS were retrieved. Eighty-one had at least one follow-up visit. Of 46 re-exposed to malaria for a variable period, 21 (46 %) had progressed, including 10/46 (22 %) evolving to full-blown HMS, while of 29 patients not re-exposed, 24 (93 %) had improved or cured and five (7 %) progressed (p < 0. 001). At logistic regression re-exposure was confirmed as a major risk factor of progression (OR 9. 458, CI 1 . 76750. 616) while treatment at initial visit was protecting (OR 0. 187, CI 0. 0540. 650). == Conclusion == e-HMS should be regarded as a clinical condition predisposing to HMS. Although the case definition may include fake positives, e-HMS should be treated just as the full-blown syndrome. A single anti-malarial treatment is most likely adequate, followed by effective prophylaxis for patients exposed again to malaria transmission. == Electronic supplementary material == The N-Acetylglucosamine online edition of this article (doi: 10. 1186/s12936-015-1015-6) contains supplementary material, which is available to certified users. Keywords: Hyper-reactive malarial splenomegaly, Hyperreactive malarial splenomegaly, Tropical splenomegaly, Tropical splenomegaly syndrome, HMS, Early hyperreactive malarial splenomegaly, e-HMS, Chronic malaria, Malaria, Plasmodium falciparum == Background == The hyperreactive malarial splenomegaly (HMS), previously known as tropical splenomegaly or tropical splenomegaly syndrome (TSS) is a chronic problem of malaria. Patients possess high levels of anti-malarial antibody [1, 2], because of the chronic antigenic activation, which seems to be an important factor in the development of the syndrome. Although the exact mechanism is uncertain, evidence suggests that repeated or chronic exposure to malaria elicits exaggerated activation of polyclonal B lymphocytes, leading to extreme and partially uncontrolled production of immunoglobulin M (IgM) as the initiating event [3]. IgM is polyclonal and there is no evidence to feature the N-Acetylglucosamine syndrome to any malaria species in particular [1], althoughPlasmodium falciparumis by and large the predominant species in the countries where the syndrome has been explained [4]. A history of chronic splenic enlargement [5, 6] differentiates HMS from the splenomegaly observed in acute malaria. At the very beginning patients might not have any symptoms. If HMS is not cured most patients report unspecific symptoms like asthenia, abdominal discomfort and other. Patients adapt physiologically to chronic anaemia, which develops due to hypersplenism [7, 8] and become symptomatic when it is severe. Hepatomegaly is also common. Main complications are represented STMN1 by an increasing frequency of infectious diseases and haemolytic disorders, and mortality may exceed 50 % if the syndrome is left untreated [9]. In particular, especially pregnant women are susceptible to episodes of massive haemolysis, which N-Acetylglucosamine are usually preceded by febrile episodes [10]. After excluding other known reasons for splenomegaly, tropical splenomegaly syndrome (the former name of HMS) was defined as a separate entity and Fakunle arranged clear diagnostic criteria in 1981 [11], that were subsequently reviewed by Bates et al. [12]. The major diagnostic criteria include: massive splenomegaly, high N-Acetylglucosamine anti-malarial antibody titre, high IgM value (local mean +2SD) and a clinical-immunological response to prolonged anti-malarial treatment or to a prophylactic regimen [13]. HMS has also been diagnosed in expatriates after a prolonged period of publicity in endemic areas [14]. At the centre to get tropical diseases (CTD), in the last 25 years, a relevant number of cases have been observed, both in immigrants from malaria endemic areas.