European Journal of Clinical Microbiology & Infectious Diseases

https://doi.org/10.1007/s10096-019-03793-8

REVIEW

Blastocystis, urticaria, and skin disorders: review of the current

evidences
Fares Bahrami 1 & Erfan Babaei 2 & Alireza Badirzadeh 3 & Tahereh Rezaei Riabi 4 & Amir Abdoli 5,6

Received: 6 November 2019 / Accepted: 5 December 2019

# Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Blastocystis is one of the most common intestinal protozoan parasites worldwide, which is linked to cutaneous lesions and
urticaria. In a setting of systematic review, the data on the association of Blastocystis infection with cutaneous lesions were
searched in order to summarize the main clinical symptoms, diagnostic methods, treatment, and outcome of the patients. The
search identified 28 eligible articles, including 12 cross-sectional studies and 16 case reports/case series (including 23 cases). A
diverse spectrum of skin symptoms, mainly urticaria, rash, and itching, was reported from the studies. Of the 23 infected cases
with the skin symptoms, gastrointestinal symptoms were reported from the 16 cases, whereas 7 cases with urticaria had
asymptomatic infection. The most frequent subtypes were ST1, ST2, and ST3, respectively. Metronidazole, paromomycin,
and tinidazole were the most prescribed drugs in patients with single Blastocystis infection. Notably, urticaria and other cutaneous
symptoms of all treated patients were resolved after treatment. In conclusion, this study indicates that Blastocystis infection can
be a neglected cause of urticaria and skin disorders. Since the treatment of Blastocystis infection is simple, screening and
treatment of this infection should be considered in patients with urticaria and other skin disorders.

Keywords Blastocystis . Urticaria . Cutaneous lesions . Skin disorders

Introduction of human and animals and is transmitted through fecal-oral

Blastocystis is one of the most common intestinal parasites
worldwide [1] that was first described by Alexeieff over
100 years ago [2]. The parasite resides in the large intestine
* Amir Abdoli
a.abdoli25@gmail.com; a.abdoli@jums.ac.ir
1
Zoonoses Research Center, Research Institute for Health
Development, Kurdistan University of Medical Sciences,
Sanandaj, Iran
2
Department of Immunology & Hematology, Kurdistan University of
Medical Sciences, Sanandaj, Iran
3
Department of Parasitology and Mycology, School of Medicine, Iran
University of Medical Sciences, Tehran, Iran
4
Department of Medical Parasitology and Mycology, School of
Medicine, Shahid Beheshti University of Medical Sciences,
Tehran, Iran
5
Department of Parasitology and Mycology, Jahrom University of
Medical Sciences, Jahrom, Iran
6
Zoonoses Research Center, School of Medicine, Jahrom University
of Medical Sciences, 74148-46199, Ostad Motahari Ave,
Jahrom, Iran
route (Figs. 1 and 2) [1, 3]. Despite recent development about
the biology and pathogenesis of Blastocystis [4], there are
controversial issues about clinical manifestations of this para-
site [3, 5, 6]. While Blastocystis is a commonly reported par-
asite in some healthy individuals without gastrointestinal
symptoms [6, 7], the parasite is also detected in patients with
irritable bowel syndrome (IBS) [8], patients with urticaria and
skin disorders, and immunocompromised patients [9]. So,
clinical symptoms of the infection are diverse and vary from
asymptomatic infection to acute diarrhea, abdominal pain,
nausea, and mild chronic abdominal discomfort [7, 10].
Despite these gastrointestinal symptoms, it is interesting that
this infection was reported from individuals with reactive ar-
thritis, urticaria, and other skin disorders (e.g., rash, itch,
palmoplantar, or diffuse pruritus) [1, 11–14].
Studies have shown that Blastocystis can act as an obligate
eukaryotic microorganism of the gut microbiota in some indi-
viduals [15]. However, the eukaryotic parasite appears more
common in healthy people than in individuals with various
bowel disorders. Recent findings suggest that the
Blastocystis is associated with certain intestine microbiota
profiles and could have roles as health indices [15, 16].

Fig. 1 The life cycle of Blastocystis parasite. The classic form found in
human stools is the cyst, which varies tremendously in size from 6 to
40 μm . The thick-walled cyst present in the stools is believed to
be responsible for external transmission, possibly by the fecal-oral route
through ingestion of contaminated water or food . The cysts infect
epithelial cells of the digestive tract and multiply asexually ( , ).
Vacuolar forms of the parasite give origin to multi-vacuolar and
ameboid forms. The multi-vacuolar develops into a pre-cyst that
Urticaria or hives is a kind of skin rash with red,
raised, itchy bumps; often the patches of rash move
around. Typically, they last a few days and do not have
any scars or any skin changes. Less than 5% of urticaria
cases last for more than 6 weeks. Till now, several caus-
ative factors have known to be involved in the etiology
of urticaria, including allergic reaction, stress, infectious
agents, antibiotics, nonsteroidal anti-inflammatory drugs
(NSAIDs), insect bites, food additives, physical stimuli,
and systemic disorders [17–19].
Eur J Clin Microbiol Infect Dis
gives origin to a thin-walled cyst , thought to be responsible for auto-
infection. The ameboid form gives origin to a pre-cyst , which de-
velops into a thick-walled cyst by schizogony . The thick-walled cyst
is excreted in feces . Image courtesy of DPDx, Centers for Disease
Control and Prevention (https://www.cdc.gov/dpdx). Source: https://
www.cdc.gov/parasites/blastocystis/biology.html
A correlation between Blastocystis infection and cu-
taneous lesions, particularly urticaria, has been frequent-
ly reported [1, 5]. Multiple case reports or cross-
sectional studies have been suggested a causal link be-
tween Blastocystis infection and urticaria. Hence, the
main objective of this study is a systematic review re-
garding the association of Blastocystis infection with
urticaria and other skin disorders in order to summarize
the main clinical manifestations, diagnosis, treatment,
and outcome of the cases.
Eur J Clin Microbiol Infect Dis
Fig. 2 Light microscopy images
of Blastocystis.a Blastocystis in
culture. Using Robinson’s and
other media. b and c Blastocystis
in fecal smears, stained with iron
hematoxylin. Reproduced from
the Ref [3] with permission from
Elsevier
Methods
This review was performed according to the preferred
reporting items for systematic review and meta-analysis
(PRISMA) protocol [20] (Fig. 3). An electronic search was
conducted using three main databases, including PubMed,
Medline, and Scopus until 4 December 2019. The search
was conducted according to the keywords as follows:
Blastocystis and “urticaria” or “skin allergies” or “skin disor-
ders” or “pruritus” or “cutaneous” or “itch”. Case reports, case
series, or cross-sectional studies which mentioned the associ-
ation of urticaria or skin disorders with Blastocystis infection
were initially selected for further evaluation. Publication with
full text or abstracts in English language was eligible for initial
inclusion, and non-English language without English abstract
was excluded. The references of all selected articles were
hand-searched to finding other relevant articles or their cita-
tions by searching in Google Scholar. All selected articles
were imported into the EndNote X8 software (Thomson
Reuters, New York, USA), and duplicated articles were
checked and then removed.
The inclusion criteria were the association of
Blastocystis with urticaria or skin disorders. Included
studies were screened according to the article’s title and
abstract data by two authors (FB and EB) separately. Any
articles that did not mention this association or review
articles were excluded. Then, full text of qualified studies
was evaluated by all authors (FB, EB, AB, TRR, and AA)
and tabulated according to the country, year, type of stud-
ies, diagnostic methods, gastrointestinal or other symp-
toms, urticaria and other skin disorders, coinfection with
other pathogens, treatment, and outcomes.
Results
Three hundred and thirty-six articles were retrieved from the
initial search of the databases, 275 articles were removed due
to duplication, and after screening of the remaining 61 articles,
26 irrelevant and 8 ineligible articles were excluded. Finally,
28 articles met the inclusion criteria (Fig. 3). Among them,
twelve articles were cross-sectional studies [21–32], and 16
articles were case reports or case series (Tables 1 and 2) [13,
33–47]. The majority of the studies was reported from Turkey
(n = 6, 21.4%), Italy (n = 4; 14.3%), and Germany (n = 3;
10.7%) (Fig. 4).
As demonstrated in the Fig. 5, alongside the routine stool
examination, other methods have been used for identification
of Blastocystis infection among 28 selected articles, including
PCR for initial detection in 7.14% (2/28) [29, 39], stool cul-
ture in 28.5% (8/28) [21, 22, 25, 31, 33, 39, 43, 47], as well as
subtype identification by molecular methods in 25.0% (7/28)
of the studies [21, 22, 25, 29, 31, 32, 41].
A variety of cutaneous symptoms were reported in
Blastocystis-infected patients, such as urticaria, rash, and
itching (Tables 1 and 2). From the 23 case reports (Table 2),
gastrointestinal symptoms were not reported in 7 cases [13,
36, 38, 40, 43], while 16 cases had a different spectrum of the
symptoms, from the minor gastrointestinal symptoms to diar-
rhea, abdominal pain, flatulence, nausea, and vomiting
(Fig. 6) [33–35, 37, 39, 41, 42, 44–47]. Among the cross-
sectional studies (Table 1), gastrointestinal symptoms were
reported from the majority of Blastocystis-infected individ-
uals. For instance, gastrointestinal-related symptoms were re-
ported in 73.75% of 80 Hungarian patients with Blastocystis
infection, including abdominal pain (n = 40, 50%), abdominal

Fig. 3 PRISMA diagram through
the different phases of the review
pain with blood in their stool (n = 17, 21.25%), meteorism
(n = 15, 18.75%), weight loss (n = 8, 10%), perianal pain or
itching (n = 6, 7.5%), stool with mucus (n = 5, 6.25%), and
vomiting and fever (n = 2, 2.5%) [27]. Interestingly, 40% of
the infected patients also suffered from other chronic gastro-
intestinal diseases, such as gastroesophageal reflux (20%),
IBS (12%), diverticulosis (12%), IBD (9%), lactose intoler-
ance (6%), colon tumors (4%), and celiac disease (3%) [27].
Subtypes of the parasite were determined in six cross-
sectional studies [21, 22, 25, 29, 31, 32]. In this regard,
Cakir et al. [21] assessed the frequency of Blastocystis infec-
tion and their subtypes among 264 patients with urticaria or
gastroenteritis and 81 stool samples as healthy control in
Turkey. The results found that the infection rate was 22.5%
of patients with urticaria, 22.2% of patients with malignancies,
and 16.15% in patients with gastroenteritis. The frequency of
Blastocystis subtypes was ST1 = 33.3%, ST2 = 16.7%, and
ST3 = 23.8% among patients with urticaria [21]. In other stud-
ies, the most frequent genotype in patients with urticarial was
ST3 [22, 25, 29, 31].
Among the case reports, the most prescribed drugs in pa-
tients with single Blastocystis infection were metronidazole (8
cases) [35, 38–40, 42–46], paromomycin [13, 36, 37, 40] (5
Eur J Clin Microbiol Infect Dis
cases), metronidazole plus paromomycin (2 cases) [40, 41],
and tinidazole in a case series of six patients [47]. As such,
anti-helminth drugs praziquantel and albendazole were pre-
scribed to patients who coinfected with helminth infections
[33, 34]. Notably, the cutaneous symptoms of all treated pa-
tients were resolved after treatment (Table 2). Among the 12
cross-sectional studies, treatment and outcome were reported
in three studies [27, 30, 31], which three of them prescribed
metronidazole [27, 31, 32], and one study only reported “an-
tiparasitic medications” [30]. In patients who received metro-
nidazole, gastrointestinal and cutaneous symptoms were re-
solved after treatment [27, 31, 32] (Table 1).
Discussion
Urticaria has been considered as a disease of unknown origin
(“idiopathic”). Although, it resembles allergen-mediated
hives, there is no identifiable specific antigen that precipitates
episodes of hives, and it is just as likely to occur in non-atopic
individuals as in those with a personal or family history of
allergic rhinitis, asthma, or eczema (atopic dermatitis) with
Table 1 Study which found association between Blastocystis, urticaria, and other skin disorders

Country/year, Diagnostic methods Findings Gastrointestinal/other Urticaria and Coinfection in stool Treatment and outcome Outcome Ref.
study aims, and symptoms other skin samples
population disorders

►Turkey/2019 ►Routine stool ►Frequency of ►Not reported the types of ►Chronic ► Not reported ►Not reported ►ST1 and ST2 subtypes [21]
►To assess the examination Blastocystis infection gastrointestinal urticaria were higher in the
frequency of ►Lugol and was 16.15% in patients symptoms symptomatic group, and
Eur J Clin Microbiol Infect Dis

Blastocystis trichrome staining with GI, 22.5% of ST3 was higher in the
subtypes in ►Parasite culture in patients with urticaria, control group
patients with Jones’ medium 22.2% of patients with
chronic urticaria, ►Positive isolates malignancies
immunosup- were subjected to ►Frequency of
pressed PCR for subtypes Blastocystis subtypes
individuals, and determination was
gastrointestinal ►In urticaria patients,
complications ST1 = 33.3%,
(GIS) ST2 = 16.7%,
►A total of 345 ST3 = 23.8%
stool samples ►In GIS patients,
(264 patients with ST1 = 25.0%,
urticaria or ST2 = 33.3%,
gastroenteritis and ST3 = 31.0%
81 stool samples ►In chemotherapy group,
as healthy ST1 = 33.3%,
control) ST2 = 41.7%,
ST3 = 11.9%
►Turkey/2019 ►Routine stool ►In the control group, two ►The symptoms were ►Itching and ►Giardia coinfection in ►750 mg of ►All infected patients [32]
►To investigate the examination patients (1.6%) were followed as: itching urticaria lesions one patient metronidazole orally were successfully
role of ►Lugol and plosive (16/16), gas (11/16), for 10 days treated
Blastocystis trichrome staining ►In the patient group, bloating (9/16), nausea ►Urticaria lesions cleared
infection with ►Parasite culture Blastocystis was found (6/16), abdominal pain after treatment
gastrointestinal ►PCR and DNA in 12.0% of the patients (5/16), constipation
symptoms in sequencing for (16/133), including (5/16), diarrhea (3/16),
acute and chronic Blastocystis 5.3% and 6.8% vomiting (1/16), and
urticaria patients subtype infection rate in acute weight loss (1/16)
and determination identification and chronic
of the Blastocystis urticaria, respectively
subtypes ►In acute urticaria, three
►Patients included subtype 1 (ST1), one
as group I ST2, and three ST3
(N = 137 patients, were detected
subdivided into ►In chronic urticaria
acute (72) and patients, one ST1 and
chronic urticaria eight ST3 were detected
patients (65)) and
group II as control
individuals
(N = 129)
►Egypt/2019 ► Not reported ► Not reported ►Not reported [22]
Table 1 (continued)

Country/year, Diagnostic methods Findings Gastrointestinal/other Urticaria and Coinfection in stool Treatment and outcome Outcome Ref.
study aims, and symptoms other skin samples
population disorders

►To evaluate the ►Routine stool ►Blastocystis was ►IBS was seen in 84.6% ►Urticaria was
relationship examination detected in 65 (43.3%) (55/65) of asthmatics observed in
between ►Parasite culture out of 150 asthmatics and 71.4% (25/35) of 15.4% (10/65)
Blastocystis ►Positive isolates and 35 (23.3%) out of non-asthmatic children of asthmatics
genotypes were subjected to 150 non-asthmatic and 8.6%
With total and PCR for subtypes children (3/35) of
specific IgE to determination ►Of 100 cases of non-asthmatic
intestinal ► Total and specific blastocystosis, 84 were children
allergens and the IgE and C-3 were genotype-3, and 16
levels of measured in were genotype-4
complement-3 patients’ serum ►Positive C-3 serum
(C-3) in patients’ with ELISA levels were in 46
serum (54.81%) of genotype-3
►Cross-sectional and 2 (12.5%) of
study of 150 genotype-4
asthmatics and ►High total IgE levels
150 were in 30 (35.7%) out
non-asthmatic of 84 cases of
children genotype-3 and 4 (25%)
out of 16 cases of
genotype-4
►Positive specific IgE
was in 25 (29.8%) of
genotype-3 and 3
(18.75%) of genotype-4
►Turkey/2018 ►Routine stool ►Of 37,108 stool ► Gastrointestinal ►Urticaria was ►Not reported ►Not reported ►Not reported [23]
►To evaluate the examination samples, 2573 (6.93%) symptoms were seen among
relationship positive detected among 68.4% 30.1% (776
between (1761 out of 37,108 samples) of the
Blastocystis samples) patients patients
infection with
urticaria and
intestinal
symptoms
►Stool examination
of 37,108 samples
►Spain/2016 ►Retrospective ►From the 418 positive ►Of the 92 patients with ►Cutaneous ► Not reported ► Not reported ►Not reported [24]
►To describe the records cases, 234 (56%) symptoms not manifestations
epidemiological patients were attributable to other were seen in 9
and clinical completely etiologies except for (9.8%) of the
characteristics of asymptomatic, 92 Blastocystis infection, infected
patients with (22%) patients had the most frequent patients
Blastocystis symptoms, and 92 symptoms were
infections (22%) patients had diarrhea (61 patients,
symptoms that could be
Eur J Clin Microbiol Infect Dis
Table 1 (continued)

Country/year, Diagnostic methods Findings Gastrointestinal/other Urticaria and Coinfection in stool Treatment and outcome Outcome Ref.
study aims, and symptoms other skin samples
population disorders

►Retrospective attributed to other 66.3%) and abdominal

observational causes pain (34 patients, 37%).
study of 418
Eur J Clin Microbiol Infect Dis

patients
►Turkey/2015 ►Routine stool ►44 (72.1%) out of 61 ►The most common ►Pruritus was ►Not reported ►Not reported ►Not reported [25]
►To assess the examination isolates were positive symptoms of infected seen in 36.1%
clinical symptoms ►Parasite culture in ►Blastocystis subtypes cases were abdominal (22/61) of the
of patients with Jones’ medium were ST3 in 17 pain (n = 24, 39.4%), infected
Blastocystis ►Positive isolates (38.6%), ST2 in 13 pruritus (n = 22, patients
infection and their were subjected to (29.5%), ST1 in 9 36.1%), diarrhea (n = 4,
subtypes PCR for subtypes (20.5%), ST1 + ST3 in 6.6%), and constipation
►A total of 61 cases determination 4 (9.1%), and (n = 2, 3.3%),
was included (40 ST1 + ST2 in one respectively
males, 21 (2.3%) of the samples
females; age
range,
5–69 years, mean
age,
35 ± 19.1 years)
►Turkey/2015 ►Routine stool ►Blastocystis was ►Gastrointestinal ►Anal itching, ►Not reported ►Not reported ►Not reported [26]
►To assess the examination detected in 275 out of symptoms were skin itching,
clinical symptoms 50,185 samples which abdominal pain (27.3%) and skin rash
and prevalence of was (0.54%) and diarrhea (19.6%) were detected
Blastocystis ►Distribution of the followed by anorexia among 7.6%,
infection infection was higher in (8.7%), nausea (7.6%), 3.3%, and 0.4%
►Stool samples of 7–13 aged children vomiting (5.8%), of the patients
50,185 patients (34.9%) constipation (4.0%),
were obtained in a ►The infection rate was bloody diarrhea (3.6%),
5 years period higher among heartburn (3.3%), and
symptomatic patients halitosis (1.1%)
(70.2%) compared with ►Other symptoms were
asymptomatic patients growth retardation
(29.8%) (9.0%), fever (8.7%),
► saliva (8.4%), dysuria
(6.2%), chest pain
(5.8%), headache
(3.3%), weakening
(2.9%), listlessness
(2.5%), cough (1.8%),
dizziness (0.7%),
hemoptysis (0.7%)
►Hungary/2014 ►Routine stool ►The frequency of ►Gastrointestinal ►9 out of 80 ►Coinfection with ►Metronidazole was ►Gastrointestinal [27]
►To investigate the examination Blastocystis infections symptoms were (11.25%) cases Blastocystis was found prescribed in eight symptoms and skin
prevalence, ►Out of 80 was 6.0% of 3255 reported in 73.75% of exhibited skin in 18.75% of the cases, patients with cutaneous manifestation of all
clinical patients 80 patients, including manifestations including symptoms, although
Table 1 (continued)

Country/year, Diagnostic methods Findings Gastrointestinal/other Urticaria and Coinfection in stool Treatment and outcome Outcome Ref.
study aims, and symptoms other skin samples
population disorders

manifestations, Blastocystis-posit- ► Out of 80 confirmed abdominal pain in 40 mainly on the Campylobacter jejuni three patients received patients resolved after
and skin ive specimens, cases, infected patients cases, abdominal pain females, (n = 3) additional doxycycline antimicrobial treatment
symptoms of 41.1% contained with skin symptoms had with blood in their stool including Candida albicans (n = 3) due to coinfection (e.g.,
confirmed cases few parasites, significantly higher in 17 cases, meteorism urticaria, Clostridium difficile A Borrelia burgdorferi,
of Blastocystis 5.5% had levels of CRP in 15 cases, weight loss papular skin and/or B toxin(s)(n = 2) Mycoplasma
infections moderate amount, (p = 0.038), leucocytes in 8 subjects, perianal lesions, and Campylobacter lari pneumoniae, and
►Routine and 53.4% (p = 0.024), neutrophil pain or itching in 6 itching skin (n = 1) Escherichia coli
microscopic contained a high granulocytes, and its subjects, stool with plaques Non-toxin-producing infections)
parasitological number of the percentage ratio mucus in 5 cases, Clostridium difficile
examination of parasites (p = 0.007, p = 0.012), vomiting and fever in 2 (n = 1)
3255 patients who thrombocytes cases, respectively Candida glabrata (n = 1)
admitted to clinics (p = 0.002), and red ►Additionally, 40% of Geotrichum candidum
between 2005 and blood cell distribution Blastocystis-positive (n = 1)
2013. width (RDW, p = 0.025) patients also suffered Entamoeba coli (n = 1)
►Data of 80 ►Conversely, the value of from other chronic Entamoeba histolytica
confirmed lymphocytes gastrointestinal and Clostridium
positive cases (p = 0.011) and diseases, such as difficile
with Blastocystis monocytes (p = 0.023, gastroesophageal reflux A and/or B toxin(s) (n = 1)
infections were p = 0.011) and their (20%), IBS (12%), Entamoeba histolytica
assessed for percentage ratios were diverticulosis (12%), with Geotrichum
cutaneous and higher in patients IBD (9%), lactose candidum (n = 1)
gastrointestinal without skin lesions intolerance (6%), colon
symptoms ►Eosinophil counts did tumors (4%), and
not have significant coeliac disease (3%)
difference in infected
patients
►Italy/2003 ►Routine stool ►Overall, protozoans and ►Gastrointestinal ►The presence of ► Not reported ► Not reported ►Not reported [28]
►Evaluation of a examination helminths were symptoms were Giardia lamblia
possible link ►Formalin-ethyl recovered from the reported in 18 patients in the stools
between intestinal acetate technique stools of 48 allergic (p = 0.023) was
parasites and patients and 23 controls significantly
allergy (p = 0.004) associated with
►218 patients with ►Protozoans and allergic skin
chronic urticaria, helminths were manifestations
atopic dermatitis, recovered from 35 (p = 0.030)
or pruritus of (16.1%) and 13 (6.0%)
unknown origin cases, respectively
were included ►The most prevalent
parasite was
Blastocystis (12 cases
5.5%) and Giardia
lamblia (10 cases,
4.58%)
►Argentina/2015 ►Routine stool ►Blastocystis was ►Gastrointestinal ►Chronic ►Of 67 patients with ►Not reported ►Blastocystis multiple [29]
examination reported in 67 patients symptoms like diarrhea, urticaria Blastocystis infection, subtypes (STs) were
Eur J Clin Microbiol Infect Dis
Table 1 (continued)

Country/year, Diagnostic methods Findings Gastrointestinal/other Urticaria and Coinfection in stool Treatment and outcome Outcome Ref.
study aims, and symptoms other skin samples
population disorders

►Assessment of the ► PCR ►The most frequent constipation, abdominal 17 co-infections were associated with
relationship genotype of Blastocystis pain, and bloating reported with other urticaria, and the
between in urticaria patients was parasitic infections, presence of a particular
Eur J Clin Microbiol Infect Dis

Blastocystis ST3 including Endolimax allele (a34) significantly

infection and ►In asymptomatic nana (5/17), associated with urticaria
urticaria individuals and patients Dientamoeba fragilis patients was detected
►A total of 270 with gastrointestinal (5/17), Giardia
symptomatic and symptoms, ST1, ST2, intestinalis (5/17),
asymptomatic ST3, and ST6 genotypes Entamoeba coli (3/17),
control (n = 28). were reported Entamoeba hartmanni
(3/17), Enterobius
vermicularis (3/17),
Cystoisospora belli
(1/17), Chilomastix
mesnili (1/17),
Iodamoeba butschlii
(1/17)
►Turkey/2016 ►Routine stool ►Parasites were detected ►Nausea/vomiting, ►Urticaria ►Other intestinal ►Antiparasitic ►The parasites were [30]
►To investigate the examination in 10% (21/211) patients abdominal pain, parasites medications for removed after treatment
prevalence of ►The most common gastrointestinal 10 days ►Among the patients who
parasitic parasite was symptoms received antiparasitic
infection-related Blastocystis in 12 (Blastocystis-positive) treatment, urticaria
urticaria in chil- samples, followed by continued in 5, reduced
dren Giardia intestinalis in 6, and disappeared in
►211 children with (n = 5), Dientamoeba 10 patients. In the
chronic urticaria fragilis (n = 3), follow-up, urticaria did
Enterobius vermicularis not recur in these 10
(n = 3), and Entamoeba patients, and they were
spp. (n = 1) considered cases of
parasitic
infection-related urticar-
ia (4.7%)
►The causative parasites
related to urticaria were
detected as B. hominis
(n = 5), G. intestinalis
(n = 4), and D. fragilis
(n = 1)
Table 2 Summary of the case reports that found association between Blastocystis, urticaria, and other skin disorders

Country/year Cases Diagnostic methods and laboratory Gastrointestinal/other Urticaria and other skin Coinfection Treatment Outcome Ref.
findings symptoms disorders

►Poland/2019 ►44-year-old ►Stool exam and thick smear by ►Diarrhea ►Fever and skin rash ►Schistosoma ►Praziquantel ►Decrease eosinophil [33]
man Kato-Miura method (Blastocystis-positive) sp., (2400 mg in one levels and
►High eosinophilia Strongyloid- daily dose) and elimination of
►Trichuris trichiura eggs, es albendazole parasites
Strongyloides stercoralis eggs, stercoralis, (2 × 400 mg per
rhabditiform larvae (Harada-Mori and day for 2 weeks).
stool culture), and Blastocystis Trichuris
vacuolar forms and cysts were trichiura
detected in stool
►The Schistosoma sp. infection was
diagnosed with serological tests
(ELISA/Western blot)
►Bulgaria/2019 ►Case series of ► Routine stool examination ►Minor ►Urticaria ►No other ►Tinidazole (four ►Complete clearance [47]
six adults ►Parasite culture in Robinson’s gastrointestinal ►Histological examination pathogens doses of 500 mg, of skin lesions up to
(mean age medium symptoms showed mild perivascular every 12 h in 2 3 days after
31.64 years, ►Skin biopsy and interstitial consecutive days) receiving the total
varying from inflammation with for all patients cumulative dose
18 years to scattered eosinophils (mean 2.84 days)
64 years) consistent with urticaria ►The minor
gastrointestinal
symptoms had also
disappeared
►The 1-month
follow-up stool
analysis was
negative for
Blastocystis sp.
►No relapse of
urticaria was seen in
any of the patients
after the parasite
eradication
►Poland/2018 ►5-year-old boy ►Routine stool examination ►Abdominal pain ►Periodical urticaria ►Ascaris ►Mebendazole ►The symptoms [34]
►High serum immunoglobulin E and flatulence lumbricoides 100 mg 2 times resolved after
(IgE) (Blastocystis-positive) daily for 3 days treatment
►Albendazole
400 mg once
daily for 3 days
(for ascariasis)
►Due to persisting
symptoms,
metronidazole
250 mg 3 times
daily for 5 days
Eur J Clin Microbiol Infect Dis
Table 2 (continued)

Country/year Cases Diagnostic methods and laboratory Gastrointestinal/other Urticaria and other skin Coinfection Treatment Outcome Ref.
findings symptoms disorders

►USA/2013 ►71-year-old ►Stool examination ►Mild diarrhea for ►With 1-week history of ►Not reported ►Metronidazole ►Rash had improved [35]
male patient ►skin biopsy 3 days pruritic rash, which (750 mg tablet 3 within next 3 days
(Blastocystis-positive) started on his forehead times a and was completely
and quickly spread to his day/10 days) resolved by the end
Eur J Clin Microbiol Infect Dis

entire body of 7 days

►Germany/2002 ►35-year-old ►Stool examination (microscopy) ►No gastrointestinal ►Palmoplantar (urticarial) ►Not reported ►Paromomycin at ►Skin lesions were [36]
female patient symptoms itching at night a dose of about cleared after
(Blastocystis-positive) 25 mg/kg treatment
bodyweight
(three times
500 mg
daily/7 days)
►Germany/2002 ►60-year-old ►Stool examination (microscopy) ►No gastrointestinal ►Four-year history of ►Not reported ►Paromomycin ►All urticaria [13]
female symptoms anaphylactoid reactions, symptoms cleared
(Blastocystis-positive) severe asthma,
generalized urticaria
►Italy/2004 ►45-year-old ►Stool examination (microscopy) ►Mild gastroenteric ►History of remitting and ►Not reported ►Paromomycin ►All urticarial and [37]
female complaints relapsing bouts of (1000 mg twice a gastrointestinal
(Blastocystis-positive) erythematous and day) and symptoms cleared
pruriginous lesions metronidazole after treatment
extended at trunk and (750 mg/10 days)
limbs without
angioedema
►Italy/2002 ►32-year-old ►Stool examination (microscopy) ►No gastrointestinal ►History of allergic rhinitis ► Not reported ►Metronidazole ►Signs improve [38]
female symptoms and chronic urticaria, (1.5 g/10 days) within 2 weeks and
(Blastocystis-positive) swelling in pressure sites disappeared
Skin lesions on the feet with 4 weeks later fecal
marked pain analyses
►Greece/2007 ►19-year-old ►Stool examination (microscopy) ►Abdominal pain for ►Hives presented with ►Not reported ►Metronidazole ►Complete resolution [39]
male ►Stool culture 2.5 months itchy wheals over body (750 mg 3 times of symptoms
►PCR (Blastocystis-positive) and extremities a day).
►Italy/2004 62-year-old ►Stool examination (microscopy) ►No gastrointestinal ►History of itching ►Not reported ►Paromomycin ►One month after [40]
female symptoms localized initially to the (25 mg/kg body treatment, it
(Blastocystis-positive) trunk and subsequently weight/10 days). completely subsided
anywhere
►Italy/2004 ►34-year-old ►Stool examination (microscopy) ►No gastrointestinal ►Generalized urticaria and ►Not reported ►Paromomycin ►After 2 months, the [40]
female patient symptoms pruritus (25 mg/kg body patient became
(Blastocystis-positive) weight) symptom-free
►Metronidazole Subsequent stool
(500 mg three examinations were
times per negative for
day/10 days) Blastocystis infec-
tion
►Italy/2004 ►Stool examination (microscopy) ►Not reported [40]
Table 2 (continued)

Country/year Cases Diagnostic methods and laboratory Gastrointestinal/other Urticaria and other skin Coinfection Treatment Outcome Ref.
findings symptoms disorders

►69-year-old ►No gastrointestinal ►Generalized urticaria and ►Paromomycin ►Complete resolution

male patient symptoms pruritus (25 mg/kg body of symptoms
(Blastocystis-positive) weight/10 days)
►Germany/2010 ►20-year-old ►Stool examination (microscopy) ►Diarrhea and ►Generalized urticarial and ►No other ►Combination ►All urticaria [41]
male patient ►Subtype identification by nausea flatulence pathogens therapy with symptoms cleared
molecular methods (Blastocystis-positive) paromomycin
►Blastocystis ST2 genotype was (3 g/d) and
detected metronidazole
(1.8 g/d/10 days)
►Jamaica/1990 ►29-year-old ►Stool examination (microscopy) ►History of diarrhea, ►History of morning ►Not reported ►Metronidazole ►After 2 weeks, knee [42]
female patient ►Synovial fluid examination abdominal pain, stiffness, pain, and (400 mg/2- inflammation
from the left knee and vomiting swelling of joints, elbows, weeks) subsided, and all
ankles, knees abdominal pain and
diarrhea were
cleared
►Bosnia and ►49-year-old ►Stool cultures ►No gastrointestinal ►Urticaria ►Not reported ►Metronidazole ►All parasitological [43]
Herzegovina/ male symptoms (100 μg twice a and bacteriological
2014 (Blastocystis-positive) week) stool cultures were
negative
►Australia/2006 ►24-year-old ►Stool examination (microscopy) ►History of chronic ►History of urticaria and ►Not reported ►Metronidazole ►The patient’s [44]
female diarrhea, IBS hives (750 mg/10- diarrhea and
(Blastocystis-positive) days) abdominal pain had
disappeared
►USA/2012 ►24-year-old ►Stool examination (microscopy) ►Six-week history of ►Urticaria ►Endolimax ►Metronidazole ►Complete resolution [45]
male diffuse abdominal nana (500 mg/3 times of symptoms
pain and diarrhea a day/10 days) 10 days later
►Denmark/2008 ►40-year-old ►Stool examination (microscopy) ►Hospitalized due to ►Urticaria ►Not reported ►Metronidazole ►All symptoms [46]
female severe diarrhea and (400 mg three cleared
fever times a
(Blastocystis-positive) day/10 days) and
cotrimoxazole
Eur J Clin Microbiol Infect Dis
Eur J Clin Microbiol Infect Dis
Fig. 4 World map of included
studies in the current systematic
review
immunoglobulin E (IgE)-mediated type I allergic reactions
[17–19, 48].
Several protozoan and helminth parasites can be involved
in the pathogenesis of urticaria [49]. Nonetheless, Blastocystis
is one of the most frequent parasites among symptomatic and
asymptomatic individuals. There are different reports regard-
ing the link between Blastocystis infection and urticaria. Many
case reports have found a link between Blastocystis and acute/
chronic urticaria (Tables 2 and 3 and Fig. 7). There are various
reports on the association between delayed pressure urticaria,
angioedema, and palmoplantar pruritus with Blastocystis in-
fection [5, 12, 13]. Cutaneous manifestations of Blastocystis
infection are often associated with a particular phenotype [14]
or subtype of the parasite [1, 5]. Analysis of the SSU rDNA of
Blastocystis led to identify at least 17 different STs in a wide
range of mammalian and nonmammalian hosts. Some sub-
types have host specificity and variability in geographic dis-
tribution. However, the main STs reported in human are ST1
through ST4 [3, 6, 16].
Fig. 5 Diagnostic method for detection of Blastocystis infection
The mechanisms of Blastocystis-induced cutaneous lesions
are not clear, but this abnormality is probably due to immune
responses or alterations of certain gut microbiota [4, 10, 15].
On the surface of the intestinal tract, an immune response
against carbohydrate antigens surrounding the amoeboid
forms of the parasite was reported [10, 14]. Various evidences
have been shown that the amoeboid form of ST1, ST2, and
ST3 subtypes of the parasite could closely participate in
chronic urticaria [22, 25, 29, 31]. One of the major mediators
in these processes is histamine, which can be released by
immigrant cells, activate mast cells and basophils, and cause
urticaria [17, 48]. The recent report of a cross-sectional study
of 150 asthmatics and 150 non-asthmatic children in Egypt
shed light on the involvement of Blastocystis infection with
some autoimmunity and skin disorders [22]. The results re-
vealed the infection rates were 43.3% and 23.3% among asth-
matics and non-asthmatic children, respectively, and urticaria
was observed among 15.4% and 8.6% of the same patients,
respectively. The prevalence of ST3 genotype was 84%, and
Fig. 6 Percentages of gastrointestinal symptoms in infected patients with
skin disorder

the ST4 genotype was 16% in infected children. Positive se-
rum levels of complement-3 (C-3) were detected in 54.81% of
the ST3 and 12.5% of the ST4 genotype-infected individuals.
Indeed, a high total IgE level was detected in 35.7% and 25%
of the ST3 and ST4 genotypes, respectively, and specific IgE
to food allergens (cow’s milk, egg whites, peanuts, wheat, and
sesame seeds) was positive among 29.8% of the ST3 and
18.75% of ST4-infected children. IBS symptoms was seen
in 84.6% of asthmatics and 71.4% of non-asthmatic children
as well [22]. It should be noted that Blastocystis infection is
also associated with the IBS, especially; the ST1 and ST3
were known to be a potential risk factor for IBS according to
a recent systematic review [50]. Increased serum comple-
ments C3 and C4 have been related to the severity of chronic
urticaria [51]. Production of autoantibodies against the α sub-
unit of the IgE receptor is a cause of histamine release and
allergic symptoms in patients with chronic urticaria [52–54].
Interestingly, a significantly higher level of the inflammatory
biomarker C-reactive protein (CRP), leukocytes, neutrophil
granulocytes and its percentage ratio, and thrombocytes was
detected in Blastocystis-infected patients with cutaneous
symptoms [27] (see details in the Table 1). Increased throm-
bocyte volume [55] and the CRP concentration [55–57] have
been reported in patients with chronic urticaria as well. These
evidences suggest the involvement of Blastocystis infection
with the immune system to cause urticaria and other cutaneous
symptoms.
Recent studies revealed that alterations of gut microbiome
may be involved in the pathogenesis of various diseases [58],
including urticaria [59]. Gut microbiome may be playing a
role in the pathogenesis of Blastocystis infection [15]. In this
regard, an assessment of gut microbiome among chronic urti-
caria patients and healthy individuals revealed that the relative
Fig. 7 Various forms of
cutaneous lesions in individuals
with Blastocystis infection. a
Extensive papulopustular skin
lesions with eosinophilic
cellulitis. b Numerous 5–10-mm
diameter-sized, sporadically
confluent, itching, urticariform-
papular skin lesion on back and
gluteal region. c Several centime-
ters diameter-sized erythematic,
itching skin plaque on right side
of the forehead. d Widespread
urticarial skin lesions on the trunk
and extremities. Figs. A, B, and C
reprint from the ref. [27] with
permission from Springer-Nature.
Fig. D reprint from the ref. [41]
with permission from Elsevier
Eur J Clin Microbiol Infect Dis
amounts of the Enterobacteriaceae family in the stool samples
of chronic urticaria patients were more than that of healthy
controls; instead, the frequencies of Akkermansia muciniphila,
Clostridium leptum, and Faecalibacterium prausnitzii in
healthy individuals were significantly more than chronic urti-
caria patients [59]. Another study among Chinese patients
with chronic urticaria demonstrated a high abundance of the
pathogenic bacteria Escherichia coli and a significantly lower
frequency of F. prausnitzii, Prevotella copri, and Bacteroides
sp. in the patient group than healthy controls [60]. In an Italian
population with intestinal protozoan infection, a significantly
higher frequency of F. prausnitzii was detected in
Blastocystis- and Entamoeba-infected patients, while
Escherichia coli was more frequent in Giardia-positive pa-
tients [61]. Andersen et al. [62] have shown that infected in-
dividuals with Blastocystis alone or coinfected with
Dientamoeba fragilis typically had high relative abundances
of Prevotella and levels of Bacteroides and clostridial cluster
XIVa [62]. It seems that the relationship of Blastocystis-mi-
crobiota and their interaction may have pivotal roles in the
pathogenesis of Blastocystis infection, although it needs fur-
ther investigations. Inasmuch as the gut microbiome is in-
volved in the pathogenesis of skin disorders [63],
Blastocystis infection may have an indirect role in the etiology
of these disorders via gut microbiota alterations [15, 16].
Another evidence that showed the link between
Blastocystis infection and cutaneous symptoms is related
to resolution of skin disorders after eradication of the
parasite (Table 2). Metronidazole [27, 31, 35, 38–40,
42–46] and paromomycin [13, 36, 37, 40] are two com-
mon drugs that successfully eradicate the parasite and
consequently resolved gastrointestinal and cutaneous
symptoms of the infected patients.
Eur J Clin Microbiol Infect Dis
Conclusion
The results revealed that Blastocystis infection can be in-
volved in the etiopathogenesis of urticaria and other skin
symptoms. Hence, it is suggested that early diagnosis and
treatment of Blastocystis infection can prevent both gastroin-
testinal and cutaneous symptoms. However, further investiga-
tions are required to elucidate the effects of different
Blastocystis subtypes and the impact of coinfection with other
pathogens in the etiopathogenesis of Blastocystis-induced cu-
taneous symptoms.
Acknowledgments We give thanks to Dr. Zahra Asadgol (Department of
Environmental Health Engineering, School of Public Health, Iran
University of Medical Sciences, Tehran, Iran) for her great technical as-
sistance in designing some graphs.
Funding sources This study was supported by Kurdistan University of
Medical Sciences, Sanandaj, Iran, and Jahrom University of Medical
Sciences, Jahrom, Iran.
Authors’ contributions FB and AA conceived the study design and per-
formed the initial search for inclusion; FB and EB screened the articles
according to title and abstract; FB, EB, AB, and TRR prepared the tables;
FB and AA designed the figures; FB and EB wrote the draft of the paper;
FA, AB, and AA revised the paper according to the reviewer’s comments;
and AA performed a final revision for submission.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval Not applicable.
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