Leoni et al.

Malaria Journal (2015) 14:185

DOI 10.1186/s12936-015-0694-3

RESEARCH Open Access

The hyper-reactive malarial splenomegaly:

a systematic review of the literature
Stefania Leoni1,2, Dora Buonfrate1, Andrea Angheben1, Federico Gobbi1 and Zeno Bisoffi1*

Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: Hyper-reactive, Malarial, Splenomegaly, Management, Treatment, Epidemiology, Review

Background immune complexes and cause persistent splenomegaly be-

Hyper-reactive malarial splenomegaly (HMS) represents cause of prolonged clearance from the reticuloendothelial
one of the leading causes of massive splenomegaly in tissue [3]. Cryoglobulins and autoantibodies, such as, for
malaria-endemic countries [1]. HMS is caused by an ab- instance, rheumatoid factor, contribute to the macroglobu-
errant immune response to a chronic antigenic stimula- linaemia [4]. A direct correlation between the spleen size
tion in subjects long exposed to malaria parasites [2]. and the IgM titre has been described [5-8]. Genetic factors
Previously defined as tropical splenomegaly syndrome are likely to be involved in the development of HMS.
(TSS), HMS has long been considered distinct from a Studies carried out in Papua New Guinea reported a
splenomegaly directly resulting from malarial parasit- higher incidence in individuals with HLA-DR2 haplotype
aemia. The syndrome is characterized by macroglobulinae- or with HLA heterozygosity [9,10]. Moreover a retrospect-
mia with overproduction of immunoglobulin, especially of ive study carried out in Ghana evidenced that the relatives
the IgM class, which aggregate into high molecular of patients with HMS were more likely to have spleno-
megaly than population controls [11].
Diagnostic criteria for HMS were proposed by Fakunle in
* Correspondence: [email protected]
1
Centre for Tropical Diseases, S Cuore Hospital, 37024, Negrar Verona, Italy 1981 [12]. Major criteria are: persistent gross splenomegaly
Full list of author information is available at the end of the article

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Leoni et al. Malaria Journal (2015) 14:185 Page 2 of 11

extending more than 10 cm below the costal margin, with- Methods

out any other apparent cause, elevated anti-malarial anti- Searching
bodies, IgM titre >2 standard deviations (SD) above the The search strategy was based on the following database
local mean value and favourable clinical and immunological sources: Pubmed, EmBase, Scopus, with no limitation as
response to long-term malaria prophylaxis [13]. Minor for the year of publication. The oldest paper retrieved
diagnostic criteria are: hepatic sinusoidal lymphocytosis, was published in 1966. Our searching strategy was based
normal cellular and humoral immune responses to anti- on these keywords (using of course the specific language of
genic challenge, including phytohaemagglutinin stimulation each database): asymptomatic malaria, chronic malaria,
(PHA), hypersplenism, lymphocyte proliferation, occur- malarious splenomegaly, splenomegaly syndrome, spleno-
rence within families or tribes. megalic syndrome, tropical splenomegaly, malarial spleno-
Other laboratory findings are related to hypersplenism, megaly. Additional search terms used were: epidemiology,
such as variable degrees of pancytopaenia, especially an- prevalence, incidence, pathogenesis, diagnosis, case defin-
aemia. The underlying mechanism causing anaemia is ition, prognosis, mortality, fatality, management, treatment.
the plasma volume expansion and the spleen sequestration The search was restricted to ‘humans’ and to the fol-
along with an increased haemolysis. Reticulocytes and in- lowing languages: English, French, Spanish, Italian, and
direct bilirubin are often increased [14,15]. Acute episodes Portuguese. The search was carried out in March 2014.
of haemolysis can also occur and seem to be associated Reference lists of all the articles identified were also ex-
with an autoimmune, cold-agglutinin-mediated response amined and relevant cited references were reviewed
triggered by non-patent parasitaemia [16]. Sinusoidal lym- similarly.
phocytosis may be revealed by histologic examination of
liver biopsy, but it is not specific. The peripheral blood Types of study
smear in HMS subjects is most often negative. However, Surveys, epidemiological studies, case reports/series,
using more sensitive diagnostic methods, such as polymer- studies on etiology, pathogenesis, diagnosis and treat-
ase chain reaction (PCR), the proportion of positive cases ment of HMS were collected. Reviews were excluded
increases [17-19]. from the analysis.
The main, severe complications of HMS are acute in-
fectious illnesses, haemolytic anaemia (especially during Inclusion criteria
pregnancy) and splenic rupture. According to historical Articles had to deal with hyperactive malaria splenomeg-
data, the syndrome is often fatal if left untreated [20]. aly or its synonymous, such as tropical splenomegaly or
Some authors have hypothesized that HMS could be chronic malaria, as a main subject.
considered as a pre-malignant state that could evolve to
chronic lymphocytic or hairy cell leukaemia or splenic Exclusion criteria
lymphoma with villous lymphocytes, as a result of a Papers were excluded when primarily dealing with acute
multi-step process with a single clone selection in a set malaria or with other causes of splenomegaly (such as
of deregulated polyclonal expansion of lymphocytes EBV, CMV, HIV, schistosomiasis). All papers identified
[21-23]. Actually, HMS and lymphoproliferative disor- were assessed by two reviewers (SL and DB) who inde-
ders are often clinically indistinguishable. Serological pendently screened the titles and abstracts, using the cri-
similarities between HMS and splenic lymphoma with teria mentioned above. Then they read the full text of
villous lymphocytes (SLVL) have also been reported. In those retained after the first screening. In case of differ-
the latter condition, too, a markedly raised anti- ences, a final consensus was reached after discussion
malarial antibody and IgM level have been observed that included a third reviewer (ZB).
[24]. Spleen reduction after a prolonged anti-malarial Data were extracted from all finally retained papers
treatment is one of the main criteria used to diagnose and specific fields of an Excel spreadsheet were popu-
HMS. Failure to respond makes an alternative diagno- lated. The spreadsheet was previously created on the
sis more likely [25]. basis of the study’s purpose. With available data the ana-
Despite a comparatively large amount of literature on lysis was focused first on epidemiology, such as gender
malaria, only a few papers deal with this particular com- and age of patients, country where the study was con-
plication. Moreover, diagnostic criteria are not uniform, ducted and country of origin of the patients, prevalence
epidemiological data are scarce and the clinical manage- of the syndrome in a given area, mortality rate, etc. Then
ment has been variable. This aim of this review was to we filled the section on diagnostic criteria and in par-
retrieve the relevant literature on HMS, focusing in par- ticular if they followed the Fakunle’s criteria or not. Fi-
ticular on three key aspects: diagnostic criteria for the nally data were extracted considering the type and
case definition, epidemiology (prevalence and mortality) duration of the treatment and when available, also data
and management. on outcome at follow-up. Finally, the reported treatment
Leoni et al. Malaria Journal (2015) 14:185 Page 3 of 11

outcome of studies with more than 10 recruited subjects Sixty-three papers described cases observed or studies
was summarized. The studies were obviously heteroge- conducted in endemic areas. In particular, 50/63 (80%)
neous but, because of the extreme poverty of papers in Africa, 8/63 (12%) in Asia [26-33], and 5/63 (8%) in
dealing with HMS, it was aimed to provide the most South America [16,34-37]. Of the 26 papers from non-
comprehensive picture of the main reported aspects of endemic countries, 22 (85%) concerned patients ob-
the syndrome since the first publication until now. served in Europe, the others were case reports from
Israel [38], the USA [39,40] and Hong Kong [41]. Apart
Results from two retrospective studies [42,43] and one prospect-
The electronic search identified 331 papers from ive longitudinal study [19], the other papers were case
Pubmed, 60 From EmBase and 75 from Scopus. Sixty- reports/case series. These included immigrants (15 pa-
eight duplicates were discarded. After an evaluation of pers), expatriates (ten papers) or both groups (one
language, titles and abstracts, a total of 152 papers were paper). The range of age of subjects under study fell
detected that may relate to this review. Thirteen were from birth [44] to a maximum of 77 years [45] and most
not retrieved. On the basis of the full text, 51 papers of the patients with HMS were young adults. According
were discarded since they did not deal with HMS. to some studies a male gender prevalence was noted but
The remaining 89 papers were included. The flow is analysing the literature no significant gender difference
summarized in Figure 1 (PRISMA flow chart). was observed.

Figure 1 PRISMA flow chart.

Leoni et al. Malaria Journal (2015) 14:185 Page 4 of 11

Diagnostic criteria for case definition the publication of Fakunle’s criteria, Mardsen and Crane
Fakunle’s criteria were mostly used, but adherence to had suggested the following: persistent splenomegaly,
them was variable. Most authors declaring to follow hepatic sinusoidal lymphocytosis, disproportionate eleva-
Fakunle’s criteria considered as splenomegalic a patient tion of serum IgM levels and high anti-malarial antibody
with spleen size bigger than 10 cm below the costal mar- titre, without considering the response to the therapy [55].
gin (Figure 2), but lower measures were also reported In other papers, the exclusion of other causes of spleno-
[34,46]. Overall, the range of the spleen size reported to megaly in an endemic area was sufficient to consider a
define splenomegaly was extremely variable, from 3 [27] patient as affected by HMS [56,57].
to 30 cm [47] below the costal margin. Both palpatory
and echographic methods were used. Some authors pre- Epidemiology in endemic countries
ferred to use Hackett’s spleen size classification There are scanty data regarding the prevalence of the
[16,20,29,35,48-50], which is based on palpation. They syndrome in the general population. Studies performed
considered as splenomegalic a patient with spleen size in Papua New Guinea reported an extraordinarily high
classified at least in the II or III grade (Table 1). Other prevalence of the syndrome (85% in five years old chil-
authors did not define splenomegaly, but described the dren and 80% in adults) among inhabitants of the Upper
spleen as “gross” [13] or “huge” [39]. The increase in Watut Valley [58]. The relationship between the parasite
IgM titre was not always respected. Some authors con- rate and the spleen size varied with age: in children the
sidered it neither specific nor necessary [51,52]. In five spleen size appeared to be directly related to the parasite
studies the syndrome was also diagnosed in absence of rate, while in adults the opposite occurred [44].
raised IgM [1,32,37,52,53]. Studies conducted in The Gambia reported a much
In other studies the case definition relied on at least two lower prevalence: 1.6 per 1,000 subjects aged ten years
out of the three major criteria (leaving aside anti-malarial or older [44,59]. Other authors studied the proportion of
antibody titre that is invariably raised), besides excluding splenomegaly caused by HMS. In northern Nigeria, 30
other causes of splenomegaly [28,42,43,54]. It was observed splenomegalic patients out of 75 (40%) were classified as
that some of those patients, if further exposed to malaria, having HMS, and so were 137 out of 334 subjects in
evolved to the complete syndrome, and this suggested the northern Zambia (again, 40%), 38 patients out of 131
possibility to make the diagnosis at an early stage [43]. (31%) in Kenya, 91/221 (41%) in Ghana and 87/114
Moreover, a direct correlation between the splenomegaly (76%) in eastern Sudan [1,48,60-62].
class and the IgM level has been demonstrated, suggesting In Papua New Guinea, the overall mortality rate in a
a continuum in the syndrome evolution [42]. series of 75 untreated patients during a 72-month period
Another approach to the diagnosis of HMS was a was 36%, reaching 57% in patients with grade V spleno-
combination of major and minor criteria. In 1976, before megaly [20]. In another study, the reported mortality

Figure 2 African patient with splenomegaly seen at the Centre for Tropical Diseases, Negrar.
Leoni et al. Malaria Journal (2015) 14:185 Page 5 of 11

Table 1 Hackett’s spleen size classification under lifelong chloroquine prophylaxis showed an im-
Spleen grade Description of the spleen grade provement of all, with a partial regression of splenomegaly
0. Spleen not palpable even on deep inspiration. and an increase of haemoglobin level over a period of 12-
I. Spleen palpable below costal margin, usually on
18 months. However, in no case a normalization of the
deep inspiration. spleen size was observed. The prophylactic regimen halved
II. Spleen palpable, but not beyond a horizontal line halfway the mortality rate over ten years compared to untreated
between the costal margin and umbilicus, measured in a patients [79]. Other studies confirmed the efficacy of this
line dropped vertically from the left nipple. regimen [27,31,71]. The most recent one was carried out
III. Spleen palpable more than halfway to umbilicus, but in Sudan in 2013 and reported, after a three-month ther-
not below a line horizontally running through it. apy, a complete normalization of the spleen size in 14 pa-
IV. Palpable below umbilicus but not below a horizontal tients out of 21 [69]. In Nigeria, 10/39 subjects fully
line halfway between umbilicus and pubic symphysis.
recovered and 29/39 improved after daily proguanil ad-
V. Extending lower than class 4. ministered for two to 12 months [76].
Two papers reported improvement after a single, short
rate in adults was 26% at ten years follow-up, but it fell course of anti-malarial treatment followed by oral ster-
to 13% in subjects under chloroquine prophylaxis [2]. oid therapy [50,80]. However, other authors observed
The main causes of death were infectious diseases, acute that the syndrome tended to quickly relapse once anti-
haemolysis and multi-organ failure (MOF) [35,63,64]. malarial therapy was stopped [75,78]. Only one study in
Sudan [18] opted (for the 33 patients included) for a
Non-endemic countries short course anti-malarial treatment (various regimens)
The first case of HMS in a Caucasian who lived in Africa as for an acute falciparum malaria. For most of the pa-
was described in 1970 [65]. Only two case series were tients, other treatments were administered during the
retrieved describing more than ten expatriates returning follow-up (for 15 to 24 months). However, no prophy-
to Europe [42,43]. Most patients had lived for at least laxis was administered during the different treatments.
five years in an endemic area. Both series (in Belgium Thirty-six patients had improved and 12 had worsened
and Italy, respectively) included patients fully responding at the end of the follow-up period, while six were re-
to the classic criteria (17/49 and 29/57, respectively) and ported as unchanged. Table 2 summarizes the main re-
patients with an incomplete syndrome. The clinical out- sults of the studies including more than ten patients.
come at follow-up was favourable for all patients who Only few data are available on HMS treatment in
remained in Europe and presented at follow-up. The only pregnancy. A recent retrospective study carried out in
other case series described in Europe is a prospective Thailand reported the efficacy of weekly mefloquine, ad-
study in Spain [19] on 14 immigrants (from Equatorial ministered for two to 25 weeks (median nine weeks) to
Guinea or Cameroon), all responded to Fakunle’s criteria. 31 pregnant women with suspected HMS, without any
Four had a positive blood film, and four additional major adverse event. Those presenting only one or two
patients were positive at PCR. major criteria of the conventional definition of HMS
A six years old child was the youngest immigrant from were also treated and showed on average a spleen size
Africa diagnosed with HMS [66]. A seven years old child, reduction of more than 40% [28].
born in UK to Ghanaian parents, was diagnosed with
HMS after three short trips to Ghana (eight weeks in Therapy in non-endemic countries
total), the last one eight months before presentation. Des- The management of HMS in non-endemic areas has
pite the absence of fever or fever history, Plasmodium been heterogeneous. Overall, the drugs used were:
falciparum trophozoites and gametocytes were found in chloroquine, quinine plus clindamycin or doxycycline
her blood [67]. or pyrimethamine-sulphadoxine, proguanil, mefloquine,
atovaquone-proguanil, halofantrine, and artemisinin de-
Therapy in endemic countries rivatives. A few authors preferred to prescribe a short
The most frequent anti-malarial treatments adminis- course (≤seven days) of anti-malarial treatment, while
tered in endemic countries were weekly chloroquine the majority opted for longer therapy. Overall, the
[2,26,31-34,37,49,61,62,68-71] or daily proguanil [13,25, follow-up period ranged from six weeks to 36 months.
52,57,60,64,71-78]. Other regimens were chloroquine In six studies out of 21 a short course of treatment (as
plus primaquine [27,70], mefloquine [28], quinine [18], for an acute malaria episode) was administered
pyrimethamine [56], artemether [18], and sulphadoxine/ [17,42,43,66,81,82]. In the Belgian study (Table 3) [42]
pyrimethamine [18,50]. Overall, the duration of therapy all 49 expatriates received a short course of anti-
ranged from a minimum of one month [13,56] to a life- malarial therapy. Thirty-nine patients were followed up
long treatment [2]. The largest cohort of patients (148) for at least two weeks after treatment (median six
 Leoni et al. Malaria Journal (2015) 14:185
Table 2 Treatment outcome: studies conducted in malaria endemic countries with >10 patients and follow up data available
Study Country N patients Type of treatment Duration Follow up Outcome
Pryor 1967 [49] New Guinea 99 CLQ 1500 mg/3 days, then 300 mg/wk NR average 4.1 mths in hospital No change in spleen size,
plus 6-23 mths out general benefit
Sagoe 1970 [57] Nigeria 43 PG 100 mg/day ≥6 mths 6 mths 32 improved 11 worsened
Bagshawe 1970 [13] Kenya 28 PG 100 mg/day 1 - 26 mths 1 -6 mths 16 improved 11 worsened 8
unchanged
Stuvier et al. 1971 [27] India 14 PQ 15 days, then CLQ 300 mg/wk 6-14 mths once/mths for ≥6 mths 11/14 spleen size ↓50%
Stuvier et al. 1974 [71] Uganda 41 CLQ 300 mg/wk or PG 100 mg/day NR 4- 20 mths all improved
Bryceson et al. 1976 [60] North Nigeria 30 PG 100 mg/day 3 - 12 mths 3 mths 12/13 improved (17 lost)
Fakunle and Greenwood 1980 [64] Nigeria 69 PG 100 mg/day 3 mths 10 wks 2 /40 died plus 8/29 defaulters
De Cock et al. 1986 [52] Kenya 38 PG 100 mg/day or CLQ 300 mg/wk NR NR 13/18 improved (20 lost)
Crane 1986 [2] Papua NG 148 CLQ 300 mg/wk lifelong 12-18 mths 146 improved (2 lost)
Gupta et al. 1987 [31] India 54 CLQ 300 mg, 1 or 2/wk 2 yrs 2 yrs 54 Improved
Mac Onuigbo and Mbah 1992 [76] Nigeria 39 PG 100 or 200 mg 2 - 12 mths 2 - 12 mths All improved (10 cured)
Manenti et al. 1994 [79] Tanzania 312 PMT 25 mg/wk 1 mths 3 mths 208 improved 104 unchanged
A-Elgayoum et al. 2011 [18] Sudan 54 Single short term treatment 1 d to 1 wk (often repeated) 15 –24 mths 36 improved 12 worsened 6
(various regimens) unchanged
Alkadarow et al. 2013 [69] Sudan 33 CLQ 300 mg/wk 3 mths 3 mths 14/21 improved (12 lost)
(CLQ = chloroquine; PG = proguanil; PQ = primaquine; PMT = pyrimethamine; NR = not reported).

Page 6 of 11
 Leoni et al. Malaria Journal (2015) 14:185
Table 3 Treatment outcome: studies conducted in non endemic countries with >10 patients and follow up data available
Study Country N patients Treatment Duration Follow up Outcome
Van den Ende et al. 2000 [42] Belgium 39 Caucasians, 17 fully responding Single, short term treat for Pf 1 day to 1 week according ≥2 wks (average 6 wks) All not re-exposed improved
to Fakunle criteria malaria (various regimens) to drug or fully recovered
Eseme et al. 2004 [43] Italy 49 Caucasians (29 fully responding Single, short term treatment 1- 4 days according to drug 6-36 mths All not re-exposed improved
to Fakunle criteria) plus 8 Africans for falciparum malaria or fully recovered
(different countries) (various regimens)
Puente et al. 2001 [83] Spain 14 Africans (13 from E. Guinea, Quinine standard dose for 3- 9 mths (mean = 4.3 mths) 3 - 9 mths (mean = 4.3 All not re-exposed improved
1 from Cameroon) 1 wk then CLQ mths) or fully recovered

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Leoni et al. Malaria Journal (2015) 14:185 Page 8 of 11

weeks) showing improvement or a complete recovery. do not respond to medical treatments [29,93]. One study
The Italian study (Table 3) [43] (57 patients, mostly analysing short- and long-term outcome of splenectomy
European Caucasians, of which 28 with an incomplete reported a peri-operative mortality rate of about 31% ris-
‘early’ stage HMS) confirmed the efficacy of short treat- ing to 39% at long-term (41-74 months) follow-up [94].
ment in absence of re-exposure, and showed 100% im- The most frequent peri-operative complications de-
provement at follow-up (six to 36 months after therapy). scribed were major bleeding and infections. The latter
The remaining four papers are case reports. Two of them were the main cause of death in the following months.
reported a global improvement at follow-up visits, two and Most surviving patients improved. However, the liver
24 months after treatment, respectively [17,82]: one used tended to progressively enlarge, probably related to per-
quinine plus doxycycline and the other one mefloquine. sistence of the antigenic stimulus [95]. In non-endemic
Conversely, one case was described with no improvement areas, therapeutic splenectomy has been reported in
eight months after a three-day course of atovaquone- Venezuela, Sri-Lanka, Hong Kong [30,39,41] and the
proguanil [46]. USA (for haemolytic anaemia complicating HMS) [40].
The prospective study in Spain (Table 3) [19], that was
conducted on 14 African subjects, besides using a short Discussion
course of anti-malarial treatment just as in the Belgian The literature available on HMS consists of some case
and Italian studies referred to above [42,43], also added reports and a few case series. Parameters considered by
weekly chloroquine for a longer period, ranging from different authors are often heterogeneous and hardly
three to nine months, basically obtaining the same clin- comparable. However some key points are identifiable.
ical results (in those not re-exposed) as in the two previ- First of all, HMS should be taken into consideration in
ous studies. Most other authors opted for long-term all patients with splenomegaly living/having lived in mal-
treatment following, in some cases only, a short anti- arious areas. Strict adherence to Fakunle’s criteria is
malarial course [84,85]. The duration of therapy varied questionable. Some authors observed that cases not
from one [46] to 12 months or until recovery [83,86]. completely fulfilling the criteria can subsequently evolve
Intermittent therapy was also used, with quinine [45] or into the full-blown, ‘classical’ HMS [42,43], thus repre-
with chloroquine plus proguanil [87]. senting an early stage of the syndrome. Considering the
The most common prescription, just as in endemic high fatality rate of this condition, if left untreated, as
countries, was chloroquine alone [54,83,85,88], or in com- well as the wide availability of effective anti-malarial
bination with doxycycline [46], with proguanil [42,85,89] drugs, it seems appropriate to treat HMS even in case
or with primaquine [90], or preceded by a short course of the classical triad of splenomegaly, raised IgM and anti-
quinine [19,83,88] or halofantrine [83]. Other regimens malarial antibodies is only partially satisfied. Clearly, in-
used for long-term treatment were proguanil [67,85,86], vestigations of other possible causes of splenomegaly
mefloquine [91] or quinine plus doxycycline [17]. should be carried out, in particular, but not limited to,
All patients with no further exposure and with avail- considering lymphoproliferative disorders.
able follow-up data improved. It is not clear whether a The treatments administered have been heterogeneous
mere withdrawal of exposure, without treatment, could and do not permit recommending a first choice regimen
be sufficient to obtain HMS resolution: only a few case yet, considering the lack of randomized clinical trials.
reports debate on this aspect. One described the persist- However, for patients who move from endemic to non-
ence of HMS in a eight years old Caucasian boy, who endemic areas, there is circumstantial evidence support-
had been on chloroquine prophylaxis while in Africa, ing the fact that an adequate short-course treatment is
after an 18-month stay in Europe [91]. Another case of effective [42,43]. This contrasts with the more common
HMS was diagnosed in an Ethiopian immigrant after a 19- choice of a long-term anti-malarial course in these cases,
month stay in Israel [38]. On the contrary, a spontaneous too, which is the classical approach that has been sug-
resolution of the syndrome was reported in a Guinean pa- gested and followed for decades. It reflects the view that
tient after two months of residence in a malaria-free area, the syndrome tends to evolve even though malaria para-
with a regression of the spleen size from 20 cm to 3-4 cm sites are no longer present in blood. This particular as-
below the costal margin and a normalization of all labora- pect was described in a study showing a progressive
tory findings [92]. The main results of the three case series enlargement of the liver after splenectomy in a patient
described in Europe with more than ten patients are sum- with negative thick blood films. This occurrence was at-
marized in Table 3. tributed to persistence of the underlying stimulus to
reticulo-endothelial system [95]. According to the most
Splenectomy cited authors [2], the absence of parasitaemia is one of
Splenectomy in HMS is generally suggested for patients the diagnostic criteria. This view does not hold any lon-
with huge splenomegaly and disabling symptoms, who ger. On the one hand, recent reports showed that more
Leoni et al. Malaria Journal (2015) 14:185 Page 9 of 11

sensitive diagnostic tools have found a higher proportion of Received: 29 December 2014 Accepted: 14 April 2015
malarial infection in HMS patients [17]. This suggests that
Plasmodium is present, albeit often at sub-microscopic
parasite density. On the other hand, the full response to a References
1. Bedu-Addo G, Bates I. Causes of massive tropical splenomegaly in Ghana.
short course of anti-malarial therapy indicates that the Lancet. 2002;360:449–54.
eradication of the infection is usually sufficient to cure 2. Crane G. Recent studies of hyperreactive malarious splenomegaly (tropical
HMS [28,42,43]. Therefore, the presence of Plasmodium in splenomegaly syndrome) in Papua New Guinea. P N G Med J. 1986;29:35–40.
3. Fakunle YM, Onyewotu II, Greenwood BM, Mohammed I, Holborow EJ.
blood is necessary for a further development of the syn- Cryoglobulinaemia and circulating immune complexes in tropical
drome. This is also suggested by the unusual case of HMS splenomegaly syndrome. Clin Exp Immunol. 1978;31:55–8.
reported above [67]: a child who still had circulating 4. Ziegler JL. Cryoglobulinaemia in tropical splenomegaly syndrome. Clin Exp
Immunol. 1973;15:65–78.
Plasmodium eight months after her last short-term visit to 5. Wells JV. Serum immunoglobulin levels in tropical splenomegaly syndrome
a malaria-endemic country. in New Guinea. Clin Exp Immunol. 1968;3:943–51.
6. Wells JV. Immunological studies in tropical splenomegaly syndrome. Trans R
Soc Trop Med Hyg. 1970;64:531–46.
Conclusion 7. Stuiver PC. [Tropical splenomegaly] (in Dutch). Tijdschr Gastroenterol.
Lifelong effective malaria prophylaxis or intermittent 1972;15:238–47.
treatments are probably necessary for those who remain 8. Crane GG. The pathogenesis of tropical splenomegaly syndrome–the role of
immune complexes. P N G Med J. 1977;20:6–13.
exposed to malaria transmission. Chloroquine seems to 9. Bhatia K, Crane G. HLA and tropical splenomegaly syndrome in the Upper
still be partially effective, even if P. falciparum resistance Watut Valley of Papua New Guinea. Hum Immunol. 1985;13:235–42.
has developed. Possibly this regimen acts not only as an 10. Bhatia KK, Crane GG. HLA heterozygosity and hyperreactive malarious
splenomegaly in the Upper Watut Valley of Papua New Guinea. P N G Med
anti-malarial, but also as an immunomodulating and im- J. 1989;32:277–86.
munosuppressant therapy [47,96], as it is suggested by 11. Martin-Peprah R, Bates I, Bedu-Addo G, Kwiatkowski DP. Investigation of
the regression of the spleen size even in patients with familial segregation of hyperreactive malarial splenomegaly in Kumasi,
Ghana. Trans R Soc Trop Med Hyg. 2006;100:68–73.
lymphoproliferative disorders [60]. The choice of the 12. Fakunle YM. Tropical splenomegaly. Part 1: Tropical Africa. Clin Haematol.
drug should consider the local pattern of P. falciparum 1981;10:963–75.
drug susceptibility, as well as the availability and cost 13. Bagshawe AF. Long-term proguanil therapy in idiopathic tropical
splenomegaly. East Afr Med J. 1970;47:622–6.
of the different regimens. Splenectomy is potentially 14. Pryor DS. The mechanism of anaemia in tropical splenomegaly. Q J Med.
associated with high mortality, therefore it should be 1967;36:337–56.
strictly limited to cases that do not respond to medical 15. Ringelhann B, Miller H, Konotey-Ahulu FI. The origin of anaemia in tropical
splenomegaly syndrome. Acta Med Acad Sci Hung. 1973;30:331–41.
treatment [94,97]. 16. Torres JR, Villegas L, Perez H, Suarez L, Torres VMA, Campos M. Low-grade
parasitaemias and cold agglutinins in patients with hyper-reactive malarious
splenomegaly and acute haemolysis. Ann Trop Med Parasitol. 2003;97:125–30.
Competing interests
17. Mothe B, Lopez-Contreras J, Torres OH, Munoz C, Domingo P, Gurgui M. A
The authors declare that they have no competing interests.
case of hyper-reactive malarial splenomegaly. The role of rapid
antigen-detecting and PCR-based tests. Infection. 2008;36:167–9.
Authors’ contributions 18. A-Elgayoum SME, El-Rayah EA, Giha HA. Validation of PCR for detection and
ZB conceived of the study, provided major contribution to the study design, characterization of parasitaemia in massive splenomegaly attributed
revised critically the different versions of the draft manuscript, contributed to clinically to malaria infection. Diagn Microbiol Infect Dis. 2011;70:207–12.
performing the systematic review, was in charge of the last version of the 19. Puente S, Rubio JM, Subirats M, Lago M, Gonzalez-Lahoz J, Benito A. The
manuscript. SL contributed to the study design, performed the systematic use of PCR in the diagnosis of hyper-reactive malarial splenomegaly (HMS).
review, wrote the first version of the manuscript. DB provided major Ann Trop Med Parasitol. 2000;94:559–63.
contribution to the study design, performed the systematic review, revised 20. Crane GG, Wells JV, Hudson P. Tropical splenomegaly syndrome in New
critically the different versions of the draft manuscript. AA provided major Guinea. I. Natural history. Trans R Soc Trop Med Hyg. 1972;66:724–32.
contribution to the study design, revised critically the different versions of 21. Bates I, Bedu-Addo G, Rutherford TR, Bevan DH. Circulating villous lymphocytes
the draft manuscript. FG contributed to the study design, revised critically - a link between hyperreactive malarial splenomegaly and splenic lymphoma.
the different versions of the draft manuscript and contributed to the final Trans R Soc Trop Med Hyg. 1997;91:171–4.
version. All authors have given final approval of the version to be published 22. Bates I, Bedu-Addo G, Bevan DH, Rutherford TR. Use of immunoglobulin
and agree to be accountable for all aspects of the work in ensuring that gene rearrangements to show clonal lymphoproliferation in hyper-reactive
questions related to the accuracy or integrity of any part of the work are malarial splenomegaly. Lancet. 1991;337:505–7.
appropriately investigated and resolved. 23. Jimmy EO, Bedu-Addo G, Bates I, Bevan D, Rutherford TR. Immunoglobulin
gene polymerase chain reaction to distinguish hyperreactive malarial
splenomegaly from ‘African’ chronic lymphocytic leukaemia and splenic
Acknowledgements lymphoma. Trans R Soc Trop Med Hyg. 1996;90:37–9.
The authors, as well as the manuscript preparation, were funded by Sacro 24. Wallace S, Bedu-Addo G, Rutherford TR, Bates I. Serological similarities
Cuore Hospital, Negrar, Verona. The funding body had no role in the between hyperreactive malarial splenomegaly and splenic lymphoma in
study design, in the collection, analysis and interpretation of data, in the West Africa. Trans R Soc Trop Med Hyg. 1998;92:463–7.
writing of the manuscript, and in the decision to submit the manuscript 25. Bedu-Addo G, Rutheford T, Bevan D, Bates I. Splenic lymphoma with villous
for publication. lymphocytes should be included in the differential diagnosis of massive
splenomegaly. Croat Med J. 1998;39:412–8.
Author details 26. Verma S, Aggarwal A. Hyper-reactive malarial splenomegaly: rare cause of
1
Centre for Tropical Diseases, S Cuore Hospital, 37024, Negrar Verona, Italy. pyrexia of unknown origin. Indian J Pediatr. 2007;74:409–11.
2
Internal Medicine Department, Verona University, Piazzale L A Scuro, 10, 27. Stuiver PC, Ziegler JL, Wood JB, Morrow RH, Hutt MS. Clinical trial of malaria
37134 Verona, Italy. prophylaxis in tropical splenomegaly syndrome. BMJ. 1971;1:426–9.
Leoni et al. Malaria Journal (2015) 14:185 Page 10 of 11

28. Jaroensuk J, Stoesser N, Leimanis ML, Jittamala P, White NJ, Nosten FH, et al. 54. Rovere PA, Bisoffi Z. The hyperreactive malarial splenomegaly syndrome in
Treatment of suspected hyper-reactive malarial splenomegaly (HMS) in Europeans: Is this more frequent than it appears? About three cases in Italian
pregnancy with mefloquine. Am J Trop Med Hyg. 2014;90:609–11. missionaries. Giornale di Malattie Infettive e Parassitarie. 1994;46:715–7.
29. Vriend WH, Hoffman SL, Silaban T, Zaini M. Splenectomy in massive tropical 55. Marsden PD, Crane GG. The tropical splenomegaly syndrome. A current
splenomegaly: two-to six-year follow-up in 14 patients. Trop Geogr Med. appraisal. Rev Inst Med Trop Sao Paulo. 1976;18:54–70.
1988;40:298–303. 56. Manenti F, Porta E, Esposito R, Antinori S. Treatment of hyperreactive
30. Nagaratnam N, De Silva DP, De Silva SP. Tropical splenomegaly syndrome in malarial splenomegaly syndrome. Lancet. 1994;343:1441–2.
Ceylon. J Trop Med Hyg. 1973;76:80–2. 57. Sagoe AS. Tropical splenomegaly syndrome: long-term proguanil therapy
31. Gupta HL, Vankataswar N, Aggarwal A, Bhutani P. Tropical splenomegaly correlated with spleen size, serum IgM, and lymphocyte transformation.
syndrome and the role of chloroquine prophylaxis. J Indian Med Assoc. BMJ. 1970;3:378–82.
1987;85:298–300. 58. Crane GG, Pitney WR, Hobbs JR, Gunn C. Immunoglobulin levels in the
32. Haider M, Nizami S, Qureshi A, Raza A, Mahar FK, Beg MA. Hyper-reactive malarial Kaiapit and Upper Watut areas of New Guinea with special reference to the
splenomegaly in the absence of raised IgM antibodies. Trop Doct. 2013;43:37–8. tropical splenomegaly syndrome. Trans R Soc Trop Med Hyg. 1971;65:795–807.
33. Hoffman SL, Piessens WF, Ratiwayanto S, Hussein PR, Kurniawan L, Piessens PW, 59. Greenwood BM, Groenendaal F, Bradley AK, Greenwood AM, Shenton F,
et al. Reduction of suppressor T lymphocytes in the tropical splenomegaly Tulloch S, et al. Ethnic differences in the prevalence of splenomegaly and
syndrome. N Engl J Med. 1984;310:337–41. malaria in The Gambia. Ann Trop Med Parasitol. 1987;81:345–54.
34. Torres RJ, Noya GO, Mondolfi GA, Peceno C, Botto AC. Hyperreactive 60. Bryceson AD, Fleming AF, Edington GM. Splenomegaly in Northern Nigeria.
malarial splenomegaly in Venezuela. Am J Trop Med Hyg. 1988;39:11–4. Acta Trop. 1976;33:185–214.
35. Torres RJR, Magris M, Villegas L, Torres VMA, Dominguez G. Spur cell 61. De Cock KM, Hodgen AN, Lucas SB, Jupp RA, Slavin B, Arap Siongok TK, et al.
anaemia and acute haemolysis in patients with hyperreactive malarious Chronic splenomegaly in Nairobi, Kenya. I. Epidemiology, malarial antibody and
splenomegaly. Experience in an isolated Yanomamo population of immunoglobulin levels. Trans R Soc Trop Med Hyg. 1987;81:100–6.
Venezuela. Acta Trop. 2000;77:257–62. 62. Allam MM, Alkadarou TA, Ahmed BG, Elkhair IS, Alansary EH, Ibrahim ME, et al.
36. Alecrim WD, Alecrim MDG, Albuquerque BC, McNeill M, Dourado H, Prata A, Hyper-reactive Malarial Splenomegaly (HMS) in malaria endemic area in Eastern
et al. [Tropical splenomegaly in the Ituxi River, Amazonas, Brazil] (in Sudan. Acta Trop. 2008;105:196–9.
Portuguese). Rev Inst Med Trop Sao Paulo. 1982;24:54–7. 63. Jones IG, Lowenthal MN. Fulminant tropical splenomegaly syndrome. Med J
37. Duarte MIS, Boulos M, Segurado AAC, Oliveira MS, Araujo ESA, Silva MA, Aust. 1975;2:645–7.
et al. Hyperreactive malarious splenomegaly: Immunohistochemical 64. Fakunle YM, Greenwood BM. Mortality in tropical splenomegaly syndrome.
demonstration of Plasmodium falciparum antigen in liver cells. Trans R Soc Trans R Soc Trop Med Hyg. 1980;74:419.
Trop Med Hyg. 1997;91:429–30. 65. Lowenthal MN, Hutt MS. Tropical splenomegaly syndrome in a caucasian in
38. Yermiyahu T, Maislos M, Shneider A, Ben Meir D, Lowenthal MN. Massive Africa. BMJ. 1970;3:262–3.
splenomegaly responsive to proguanil and with features of hairy cell 66. De Franceschi L, Sada S, Andreoli A, Angheben A, Marocco S, Bisoffi Z.
leukaemia. Trans R Soc Trop Med Hyg. 1995;89:194–6. Sickle cell disease and hyperreactive malarial splenomegaly (HMS) in young
39. Torres-Rojas JR, Rothschild H, Krotoski WA. Tropical splenomegaly syndrome immigrants from Africa. Blood. 2005;106:4415–7.
in a nontropical setting. Am J Trop Med Hyg. 1981;30:1–4. 67. Ladhani S, Dosekun E, Patel V, Shingadia D. Massive hepatosplenomegaly in
40. Ackerman L. Hyperreactive malarial syndrome. J Am Board Fam Pract. a child with malaria. Pediatr Infect Dis J. 2002;21:1090–2.
1996;9:356–9. 68. Crane GG, Rowley MJ, Warburton MF, Mackay IR. Humoral immune
41. Chim CS, Wong SS, Lam CC, Chan KW. Concurrent hyperreactive malarial responses in the tropical-splenomegaly syndrome in New Guinea. Clin Sci.
splenomegaly and quartan malarial nephropathy - Plasmodium malariae 1972;43:869–79.
revisited. Haematologica. 2004;89:ECR21. 69. Alkadarou T, Musa A, Alkadarou A, Mahfouz MS, Troye-Blomberg M, Elhassan AM,
42. Van Den Ende J, Van Gompel A, Van Den Enden E, Taelman H, Vanham G, et al. Immunological characteristics of hyperreactive malarial splenomegaly syndrome
Vervoort T. Hyperreactive malaria in expatriates returning from sub-Saharan in sudanese patients. J Trop Med. 2013:961051. doi:10.1155/2013/961051
Africa. Trop Med Int Health. 2000;5:607–11. 70. De Morais JA. [Macroglobulinemic splenomegaly of Charmot or tropical
43. Eseme F, Lodesani C, Amicarelli E, Marocco S, Monteiro G, Anselmi M, et al. splenomegaly syndrome: report of the 1st case diagnosed in Angola and
Hyperreactive malarial splenomegaly in Europeans. Giornale Italiano di review of the world literature] (in Portuguese). An Inst Hig Med Trop (Lisb).
Medicina Tropicale. 2004;9:61–4. 1977;5:293–323.
44. Crane GG, Pryor DS. Malaria and the tropical splenomegaly syndrome in 71. Stuiver PC, Buttner DW, Mannweiler E. Immunodiagnostic studies in tropical
New Guinea. Trans R Soc Trop Med Hyg. 1971;65:315–24. splenomegaly syndrome in Uganda. Trop Geogr Med. 1974;26:121–5.
45. Garavelli PL. [Tropical splenomegaly. A case report] (in Italian). Recenti Prog 72. Adekile AD, Adeodu OO, Jeje AA, Odesanmi WO. Persistent gross
Med. 2005;96:609. splenomegaly in Nigerian patients with sickle cell anaemia: relationship to
46. Camara B, Kantambadouno JB, Martin-Blondel G, Berry A, Alvarez M, Benoit- malaria. Ann Trop Paediatr. 1988;8:103–7.
Vical F, et al. Hyperreactive malarial splenomegaly: Three clinical cases and 73. Fakunle YM, Greenwood BM, Fleming AF, Danon F. Tropical splenomegaly
literature review. Med Mal Infect. 2009;39:29–35. syndrome or chronic lymphatic leukaemia? Trop Geogr Med. 1979;31:353–8.
47. Dascalescu CM, Najman A. Tropical splenomegalies: Hyperreactive malarial 74. Khan MK, Kamruzzaman M, Quddus MR. Hyperreactive malarial
splenomegaly and tropical splenic lymphoma with villous lymphocytes. splenomegaly (HMS). Mymensingh Med J. 2006;15:204–7.
Hématologie. 2005;11:259–63. 75. Lowenthal MN. Tropical splenomegaly syndrome. Med J Zambia. 1982;16:14–5.
48. Lowenthal MN, Hutt MS, Jones IG, Mohelsky V, O’Riordan EC. Massive 76. Onuigbo MA, Mbah AU. Tropical splenomegaly syndrome in Nigerian
splenomegaly in Northern Zambia. I. Analysis of 344 cases. Trans R Soc Trop adults. West Afr J Med. 1992;11:72–8.
Med Hyg. 1980;74:91–8. 77. Ree GH. Tropical splenomegaly. Trans R Soc Trop Med Hyg. 1976;70:259.
49. Pryor DS. Tropical splenomegaly in New Guinea. Q J Med. 1967;36:321–36. 78. David-West AS. Relapses after withdrawal of proguanil treatment in tropical
50. Ouattara I, Ehui E, Tanon A, Eholie SP, Bissagnene E. [Hyperactive malarious splenomegaly syndrome. BMJ. 1974;3:499–501.
splenomegaly: diagnosis and therapeutic problems in adults] (in French). 79. Crane GG, Hudson P, Hudson BET. The effect of suppressive antimalarial
Bull Soc Pathol Exot. 2008;101:295–7. therapy in tropical splenomegaly syndrome in New Guineans. P N G Med J.
51. Kern P, Knobloch J, Riethmuller G, Dietrich M. Serological and 1973;16:46–50.
immunological investigations in patients with gross splenomegaly from the 80. Ssebabi EC, Jagwe JG, Nzaro E, Amsel S. Tropical splenomegaly syndrome:
Gabon. Tropenmed Parasitol. 1983;34:253–8. an immune complex disease. East Afr Med J. 1975;52:680–5.
52. De Cock KM, Hodgen AN, Jupp RA, Slavin B, Siongok TK, Rees PH, et al. 81. Tobena Rue M, Coll Usandizaga F, Moraga Llop FA, Toran Fuentes N, Garcia
Immunoglobin M and malarial antibody levels in hyper-reactive malarial Pena MP. [Hyper-reactive malarial splenomegaly in a 9 year-old Equatorial
splenomegaly. J Trop Med Hyg. 1986;89:119–21. Guinean child] (in Spanish). An Pediatr (Barc). 2011;75:80–1.
53. Gangneux JP, Vignes S, Poinsignon Y, Derouin F. Evolutive visceral malaria 82. De Iaco G, Saleri N, Perandin F, Gulletta M, Ravizzola G, Manca N, et al.
and hyperimmune palustral splenomegaly: a difficult distinction. Bull Soc Hyper-reactive malarial splenomegaly in a patient with human
Pathol Exot. 1999;92:27–8. immunodeficiency virus. Am J Trop Med Hyg. 2008;78:239–40.
Leoni et al. Malaria Journal (2015) 14:185 Page 11 of 11

83. Puente S, Subirats M, Benito A, Rubio JM, Gonzalez-Lahoz JM. Hyperreactive

malarial splenomegaly in Europeans: Report of five cases. J Travel Med.
2001;8:322–4.
84. Granier H, Vatan R, Nicolas X, Richecoeur M, Martin J. [Hyperreactive malarial
splenomegaly in a European returning from Africa] (in French). Rev Med
Interne. 1999;20:431–3.
85. Moraes MF, Soares M, Arroz MJ, Do Rosario VE, Pimenta DA Graca J,
Abecasis P. [New concepts in hyperreactive malarial splenomegaly]
(in Portuguese). Acta Medica Portuguesa. 2003;16:41–6.
86. Bhattacharya DN, Harries JR, Emerson PA. Tropical splenomegaly syndrome
(T.S.S.) in a European. Trans R Soc Trop Med Hyg. 1983;77:221–2.
87. Dascalescu CM, Rosenzwajg M, Bonte H, Mir IA, Aoudjhane M, Smadja NV,
et al. Bcl-2 and immunoglobulin gene rearrangements in patients with
malaria related chronic splenomegaly. Leuk Lymphoma. 2004;45:2093–7.
88. Chagnon A, Talard P, De Jaureguiberry JP, Mafart B, Pierre C, Carli P.
[Hyper-reactive malarial splenomegaly in an European returning from Central
Africa] (in French). Presse médicale. 1989;18:938.
89. Orus J, Martinez A, Corachan M, Valls ME. Hyperreactive malarial
splenomegaly syndrome in a European patient. Trop Doct. 1996;26:140–1.
90. Evans DI, Reddy PM, Wolman B. Tropical splenomegaly, sickle-cell trait, and
P. falciparum infection. Br Med J. 1972;1:250–1.
91. Van Den Ende J, Van Gompel A, Van Den Enden E, Colebunders R.
Development of hyperreactive malarious splenomegaly in an 8-year-old
caucasian boy, 18 months after residence in Africa. Ann Soc Belg Med Trop.
1994;74:69–73.
92. Vila N, Pallares L, Sierra C, Estruch R. Hyperreactive malarial splenomegaly.
Medicina Clínica. 1993;100:75.
93. Ajao OG. Enlarged spleen syndrome. J Natl Med Assoc. 1980;72:323–5.
94. Crane GG, Pryor DS, Wells JV. Tropical splenomegaly syndrome in New
Guinea. II. Long term results of splenectomy. Trans R Soc Trop Med Hyg.
1972;66:733–42.
95. Hamilton PJ, Stuiver PC, Ziegler JL. Splenectomy in tropical splenomegaly
syndrome–a five year follow-up. J Trop Med Hyg. 1971;74:230–2.
96. Betticher DC, Nicole A, Pugin P, Regamey C. The hyperreactive malarial
splenomegaly syndrome in a European: Has the treatment a modulatory
effect on the immune system? J Infect Dis. 1990;161:157–9.
97. Pryor DS. Splenectomy in tropical splenomegaly. BMJ. 1967;3:825–8.

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