Possible role of a B-cell mitogen in hypergammaglobulinaemia in malaria and trypanosomiasis.

Hyperreactive malarious splenomegaly (tropical splenomegaly syndrome)

The hyper-reactive malarial splenomegaly syndrome (HMS) is a leading cause of massive splenomegaly in malaria-endemic countries. HMS is caused by a chronic antigenic stimulation derived from the malaria parasite. Classic Fakunle’s major criteria for case definition are: persistent gross splenomegaly, elevated anti-malarial antibodies, IgM titre >2 SD above the local mean value and favourable response to long-term malaria prophylaxis. The syndrome is fatal if left untreated. The aim of this study is to systematically review the literature about HMS, particularly focussing on case definition, epidemiology and management. The search strategy was based on the following database sources: Pubmed, EmBase, Scopus. Search was done in March, 2014 and limited to English, Spanish, Italian, French, and Portuguese. Papers detected were 149, of which 89 were included. Splenomegaly was variably defined and the criterion of increased IgM was not always respected. The highest prevalence was reported in Papua New Guinea (up to 80%). In different African countries, 31 to 76% of all splenomegalies were caused by HMS. Fatality rate reached 36% in three years. The most frequent anti-malarial treatments administered were weekly chloroquine or daily proguanil from a minimum of one month to lifelong. In non-endemic countries, a few authors opted for a single, short anti-malarial treatment. All treated patients with no further exposure improved. Cases not completely fulfilling Fakunle’s criteria and therefore untreated, subsequently evolved into HMS. It seems thus appropriate to treat incomplete or ‘early’ HMS, too. For patients not re-exposed to endemic areas, a short course of treatment is sufficient, showing that eradicating the infection is sufficient to cure HMS. Longer (probably lifelong) courses, or intermittent treatments, are required for those who remain exposed. Splenectomy, associated with high mortality, should be strictly limited to cases not responding to medical treatment.

/pdf/the-hyper-reactive-malarial-splenomegaly-a-systematic-review-1eqk94ak9e.pdf

The hyper-reactive malarial splenomegaly: a systematic review of the literature.

The course of the tropical splenomegaly syndrome has been observed for periods of up to 6 1 2 years in 75 adults living in the Upper Watut Valley of New Guinea. During this time there were 27 deaths, 2 from septicaemia and another 8 from similar fulminating febrile illnesses. The mortality rate in those with Grade V splenomegaly was 57%, almost 3 times that of the remainder. Serial hospital assessment of 26 subjects demonstrated progression of the disease, characterized by further enlargement of the spleen and a fall in haemoglobin concentration in 9; increases in splenic red cell pool, in plasma volume and in serum IgM concentration were sometimes, but not invariably, associated. In none of the total group of 75 subjects was a decrease in spleen size observed. Thus the natural history of the tropical splenomegaly syndrome is that of a progressive disease with a high mortality in the fully developed case. Periodic fluctuations in the clinical severity of the disorder are frequently seen and are largely related to the occurrence of episodes of acute haemolysis; however, spontaneous remission has not been observed.

Tropical splenomegaly syndrome in New Guinea I. Natural history

Levels of species and class-specific malarial antibody were studied in 249 New Guineans with tropical splenomegaly syndrome (TSS) and in 87 control subjects living in the same area. Titres of IgG and IgM antibody to Plasmodium falciparum, P. vivax and P. malariae were estimated by indirect immunofluorescence. Both IgG and IgM antibody levels were higher in subjects with TSS than in controls; IgM titres were highest in those with the greatest splenic enlargement. Responses to all three species were comparable. It is concluded that there is no evidence from this study to incriminate any one species of malaria parasite in the production of tropical splenomegaly syndrome.

Malarial antibodies in tropical splenomegaly syndrome in Papua New Guinea.

Serum concentrations of IgA, IgG and IgM were estimated for 2,000 inhabitants of 2 malarious areas of New Guinea—Kaiapit, where spleen rates are high in children but splenomegaly occurs infrequently in adults and is never gross, and the Upper Watut Valley, where the tropical splenomegaly syndrome is particularly common, and 80% of adults and children have palpable spleens. Kaiapit adults had significantly higher IgM levels than children: IgM levels tended to increase throughout life, were higher in women than in men and in adults with splenomegaly. IgG and IgA levels showed no significant relation to increasing age above 10 years, to sex or to the presence or absence of splenomegaly. The youngest Watut children had higher IgM levels than Kaiapit subjects. IgM concentrations rose more rapidly with age, particularly in the first 20 years of life, so that the mean Watut adult level was more than twice that of Kaiapit adults. In Watut children splenomegaly was associated with significantly higher levels of all 3 immunoglobulin fractions, whereas adults with splenomegaly showed markedly higher levels of IgM, but significantly lower IgA concentrations than did subjects with impalpable spleens. The change in the pattern of immunoglobulin levels in association with splenomegaly occurred between the ages of 6 and 20 years, indicating that the transition from simple malarious splenomegaly to tropical splenomegaly syndrome probably occurs at this age. Subjects living near the valley floor had higher spleen rates than those living in high villages; IgM concentrations were also affected by altitude. The reason for this remains obscure, but it is suggested that both observations may be related to differences in intensity of operation of the factors responsible for the development of the tropical splenomegaly syndrome.

W.R. Pitney

Papers

Immunoglobulin levels in the Kaiapit and upper Watut areas of New Guinea: with special reference to the tropical splenomegaly syndrome