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Acta Medica Mediterranea, 2015, 31: 1127
HELICOBACTER PYLORI INFECTION IN MULTIPLE FORMS OF DERMATOSIS
Emine Colgecen1, Seyhan Karacavus2, Cigdem Kader3, Kemal Ozyurt4, Mehmet Celikbilek5
1
Bozok University Medical Faculty, Department of Dermatology, Yozgat - 2Bozok University Medical Faculty, Department of
Nuclear Medicine, Yozgat - 3Bozok University Medical Faculty, Department of Infection Diseases and Clinical Microbiology,
Yozgat - 4Kayseri Training and Research Hospital, Department of Dermatology, Kayseri - 5Bozok University Medical Faculty,
Department of Gastroenterology, Yozgat, Turkey
ABSTRACT
Introduction: Chronic spontaneous urticaria (CSU), idiopathic generalized pruritus (IGP), and rosacea are significant dermatological diseases of unknown etiology that adversely affect patients’ quality of life. The aim of this study was to determine the
frequency of Helicobacter pylori (HP) infection in patients with CSU, IGP, and rosacea and to establish whether signs of dermatological disease improve with anti-HP eradication treatment in HP-positive patients.
Materials and methods: Sixty patients (22 CSU, 17 IGP, and 21 rosacea) and 30 healthy individuals were enrolled. The 14Curea breath test (14C-UBT) was administered for diagnosis of HP. Patients with positive 14C-UBT results were administered amoxicillin 1 g, clarithromycin 500 mg and lansoprazole 30 mg twice daily for 2 weeks. At the end of this treatment, lansoprazole was
maintained alone for another 2 weeks. Patients were examined for signs of clinical improvement at the 2nd week and the 1st, 3rd, and
6th months after this treatment.
Results: Nineteen (86.4%) patients with CSU, 13 (76.5%) patients with IGP, and 16 (76.2%) patients with rosacea tested
positive for HP on the basis of 14C-UBT. Fourteen (46.7%) individuals in the control group tested positive for HP on the basis of
14
C-UBT. Statistical analysis revealed greater HP positivity in the patient group compared to the control group (p < 0.05). Almost
complete improvement of clinical signs was observed after eradication treatment for HP in 3 (15.8%) patients with CSU, 3 (23.1%)
with IGP and 6 (15.8%) with rosacea.
Conclusion: HP may play a role in the etiopathogenesis of CSU, IGP, and rosacea. In selected cases, HP eradication may
have beneficial effects on the course of the disease.
Key words: Chronic spontaneous urticaria, Helicobacter pylori, idiopathic generalized pruritus, rosacea.
Received April 27, 2015; Accepted October 14, 2015
Introduction
Helicobacter pylori (HP) is a gram negative
microaerophilic bacterium found in the mucosal
lining covering the gastric epithelium. Human to
human contact via the fecal-oral route is the primary mode of transmission, making it one of the most
widespread bacterial pathogens worldwide. HP
infection occurs across a broad range of demographic characteristics of populations (such as age,
socioeconomic status and race) and geographical
areas worldwide.
The prevalence is higher in developing countries, where levels as high as 70% have been reported. The prevalence in developed countries is
approximately 40%. Colonization of HP infection
begins in childhood, and unless eradication treatment is administered this persists throughout the
patient’s entire life. HP plays a significant role in
the etiology of gastritis, peptic ulcer, gastric carcinoma, and gastric lymphoma(1, 2).
In recent years, HP has been associated with
various diseases outside the gastrointestinal system
possibly including some hematologic, cardiovascu-
1128
lar and dermatological diseases. Various theories
have been proposed to account for extraintestinal
findings associated with HP infection. These
include atrophic gastritis, increased gastric vascular
permeability, released inflammatory mediators,
molecular mimicry and systemic immune
response(3-5). Reports have suggested that HP may
trigger lesions in chronic skin diseases, may be a
cause of deterioration in disease, and/or may lead to
increased resistance and chronic manifestation(1, 4, 5).
In terms of dermatological diseases, HP has been
reported to be associated with recurrent aphthous
stomatitis, rosacea, chronic urticaria (CU), pruritus,
Behcet’s disease, lichen planus, Sjögren syndrome,
Henoch-Schönlein purpura, and alopecia areata(2, 5-9).
The aim of this study was (I) to determine the
frequency of HP infection in patients with chronic
spontaneous urticaria (CSU), idiopathic generalized
pruritus (IGP), and rosacea using 14C-urea breath
test (14C-UBT); and (II) to evaluate whether dermatological disease signs improve with anti-HP eradication treatment in HP-positive patients.
Materials and methods
Patients
Sixty patients over the age of 18 admitted to
the Bozok University Faculty of Medicine
Dermatology Clinic and 30 age-matched healthy
individuals with similar sociocultural demographics
to those of the patient group were enrolled. The
patient group consisted of 22 patients with CSU, 17
with IGP and 21 with rosacea. Local ethics committee approval was obtained before the study began.
Sex, age, drug use history, food anamnesis,
presence of systemic and dermatological diseases,
and the presence of gastrointestinal complaints
were investigated and recorded for all individuals in
the patient and control groups. Individuals who had
been using antibiotics and proton pump inhibitors
during the previous four weeks were excluded.
HP infection assessment and treatment
All patients swallowed 37 kBq (1μCi) of an
encapsulated form of 14C-urea/citric acid composition (HelicapTMNoster System, Stockholm,
Sweden) in 25 mL water after overnight fasting.
Breath samples were collected using a special dry
cartridge system (HeliprobeTMBreathCardTM;
Noster System) after 10 min. Patients exhaled gently into the cartridge mouthpiece until the indicator
membrane changed colour from orange to yellow.
Emine Colgecen, Seyhan Karacavus et Al
Activity was measured on a Geiger-Müller counter
(HeliprobeTM Analyzer; Noster System) for 250 s.
Results were expressed both as counts per min
(cpm) and as grade (0= not infected, <25 cpm; 1=
equivocal, 25-50 cpm; 2= infected,>50 cpm), as
recommended by the manufacturer depending on
the counts obtained from the cartridges.
Patients with positive 14C-UBT results were
administered amoxicillin 1 g, clarithromycin 500
mg, and lansoprazole 30 mg twice daily over 2
weeks. At the end of this treatment, lansoprazole
was maintained alone for a further 2 weeks.
Patients were examined for signs of clinical
improvement at the 2nd week and at the 1st, 3rd, and
6th months after this treatment.
Statistical analysis
All analyses were performed using Statistical
Package for the Social Sciences (SPSS) 15.0 software (SPSS Inc., Chicago, IL, USA). Results were
reported as mean ± standard deviation (SD) or percentages. The Chi-square test was performed to
compare categorical variables. Student’s t-test was
used to determine significance at comparison of
means of continuous variables in the two groups. A
p-value of less than 0.05 was considered statistically significant.
Results
Of the 22 patients with CSU, 16 were female
and 6 male, with a mean age of 41.7 ± 11.2. Nineteen
(86.4%) patients with CSU tested positive for HP
based on 14C-UBT. Of the 17 patients with IGP, 10
were female and 7 female, with a mean age of 44.6 ±
12.6. Thirteen (76.5%) patients with IGP tested positive for HP based on 14C-UBT. Of the 21 patients
with rosacea, 19 were female and 2 male, with a
mean age of 45.3 ± 10.8. Twelve of the patients with
rosacea had papulopustular rosacea (PPR) and 9 had
erythematotelangiectatic rosacea (ETR). Sixteen
(76.2%) of these patients tested positive for HP
based on 14C-UBT. All the patients had gastric symptoms.
The control group consisted of 30 subjects, 16
female and 14 male, with a mean age of 44.3 ± 13.6.
No gastric symptoms were observed in the control
group. Fourteen (46.7%) individuals in the control
group tested positive for HP based on 14C-UBT.
Mean ages and sex distribution in the patient
and control groups are given in Table 1. Table 2
shows HP positivity in the patient groups (CSU, IGP,
Helicobacter pylori infection in multiple forms of dermatosis
1129
and rosacea) and the control group based on 14CUBT. Statistical analysis revealed greater HP positivity in the patient group compared to the control
group (p < 0.05).
Chronic
spontaneous urticaria
Idiopathic
generalized pruritus
Rosacea
Control
N
22
17
21
30
Age
19-69
18-64
26-72
18-72
Mean age
41.7 ± 11.2
44.6 ± 12.6
Signs of rosacea disappeared almost entirely at the
end of the 1st month in 5 patients, whereas one
patient exhibited recurrence of PPR lesions at 6th
month check-up. One patient with ETR exhibited
significant improvement in erythema at the 1st
month after eradication treatment although severe
relapse was observed at 3rd month check-up (Table
3).
45.3 ± 10.8 44.3 ± 13.6
Sex
Discussion
HP is the one of the most common infectious
agents worldwide(10). In addition to causing local
Male n (%)
6 (27.3)
7 (41.2)
2 (9.5)
14 (46.7)
tissue damage in the gastric mucosa, HP has also
been shown to be involved in various diseases that
Table 1: Mean age and gender distribution in the patient and
are not directly related to the gastrointestinal syscontrol groups.
tem. Several major dermatological diseases have
been reported to be associated with HP. Testing for
C-urea breath
C-urea breath
test positive
test negative
p
HP is frequently performed with non-invasive methn (%)
n (%)
ods such as 13 or 14C-UBT, stool antigen tests, and seroChronic spontaneous
19 (86.4)
3 (13.6)
0.003
logical tests. Histological examination and the urease
urticaria
test have higher diagnostic value, but are invasive
Idiopathic generalized
13 (76.5)
4 (23.5)
0.017
techniques(1, 4, 5, 11).
pruritus
In approximately 75-80% of cases of urticaria,
Rosacea
16 (76.2)
5 (23.8)
0.035
the
disease
takes the form of CU. This is more comControl
14 (46.7)
16 (53.3)
mon in middle-aged women, and no etiological agent
(12)
Table 2: Comparison of 14C-urea breath test positivity is identified in two-thirds of patients . A relationship between HP infection and CSU has been docubetween the patient and control groups.
mented in recent studies, and various mechanisms
Improvement
Recurrence
have been proposed as the underlying cause(13-17).
Cases
Cases
Following colonization of HP, increased gastric vasChronic spontaneous urticaria
3
0
cular permeability during infection results in
increased exposure to allergens ingested through
Idiopathic generalized pruritus
3
1
food consumption. More frequent allergic conditions
Rosacea
6
2
may therefore be expected in patients with duodenal
Papulopustular
5
1
ulcer. There are also studies suggesting that HP-speErythematotelangiectatic
1
1
cific immunoglobulin (Ig) E levels may increase in
Total
12
3
the gastric and duodenal mucosa and may thus be
involved in the pathogenesis of urticaria(4, 18). It has
Table 3: Dermatological responses after eradication in the
also been suggested that HP may trigger the producpatient groups.
tion of autoantibodies targeted against circulating
Three (15.8%) patients with CSU were
IgE and/or the IgE receptor FcεRI through molecular
observed to be free of signs of urticaria following
mimicry(19). Nonetheless, the role of HP infection in
eradication treatment, 2 in the 1st month and one in
CU is still uncertain. Chronic infection can also
the 3rd month. These were still healthy at 6th month
result in immunological stimulation through the
follow-up. Three (23.1%) patients with IGP respondrelease of various mediators, and in increased noned well to eradication treatment. Improvement
specific cutaneous vascular permeability. In addition
st
occurred in the 1 month after treatment in each of
to the virulence of HP, host-related and environmenthese cases. However, relapse was observed in one
tal factors are also implicated(5, 20). Some researchers
th
case at 6 month follow-up. Six (15.8%) (5 PPR and
have suggested that HP eradication may result in
1 ETR) patients with rosacea exhibited almost comimprovement in CU symptoms(15-17), while others
plete improvement of clinical signs after treatment.
have suggested the opposite(21-23).
Female n (%)
16 (72.7)
10 (58.8)
14
19 (90.5)
14
16 (53.3)
1130
A recent study by Magen et al.(15) demonstrated
that CU patients were resistant to antihistamines.
Those authors reported HP positivity of 63.0% based
on 13C-UBT and a 27.8% succession rate with HP
eradication. In our study, 86.4% of patients with
CSU were HP positive. Signs of urticaria resolved
completely after eradication treatment for HP in
15.8% of patients.
Idiopathic pruritus refers to conditions that cannot be explained in terms of dermatological or systemic diseases, and that generally cause no skin damage or that exhibit lower levels of secondary itching
lesions. IGP constitutes nearly 30.0% of all itchiness.
It is observed in both sexes, although the level is
slightly higher in females(24). Previous reports have
identified an association between HP and other dermatological diseases, including chronic pruritus,
prurigo nodularis, and prurigo pigmentosa(9, 25, 26).
Sakurane M. et al.(27) demonstrated that eradication
therapy was effective in several intractable skin diseases (such as CU, pruritus cutaneous, nummular
dermatitis and prurigo chronica multiformis (PCM))
in patients exhibiting HP positivity through gastroscopic examination. That study suggested that chronic HP infection may perpetuate eruptions and result
in disease deterioration as well as in the manifestation and persistence of skin diseases(27). Akashi et al.(8)
observed HP positivity in patients with CU (30.5%)
and in patients with PCM (58.8%), and administered
eradication treatment. That study further confirmed
HP as an important pathogenic factor and underlined
the use of eradication therapy for the treatment of
intractable skin diseases, including PCM(8). We determined HP positivity in 76.5% of patients with IGP.
Following eradication treatment for HP, we observed
complete recovery from itching in 23.1% of patients.
Rosacea is a chronic inflammatory dermatosis
characterized by papules and pustules over an erythematous and a telangiectasic base in the mid face
area. Both rosacea and peptic ulcer exhibit seasonal
variation, and some antibiotics used in the treatment of HP cause remission of symptoms of
patients with rosacea. An association between HP
and rosacea has therefore been posited. Various
mechanisms have been proposed to explain the contribution of HP to rosacea development. Nitric
oxide production is induced by HP, and increased
concentrations of nitric oxide in patient serum and
tissues result in vasodilation, inflammation, and
immunomodulation. This condition is thought to be
responsible for the flushing and erythema observed
in patients with rosacea(28-30).
Emine Colgecen, Seyhan Karacavus et Al
In addition to research observing HP positivity
in patients with rosacea, some studies have also
reported significant remission in rosacea symptoms
following eradication treatment for HP (6, 31-35) .
However, other studies have reported no relation
between HP and rosacea(36, 37). The prevalence of HP
in patients with rosacea in this study was 76.2%.
This is comparable to the rate reported in a recent
study involving Egyptian patients(6). In addition, we
observed that HP was present at a very high level in
patients with PPR (83.3%), higher than that in
patients with ETR (66.7%). We therefore think there
may be a relation between subtypes of rosacea and
HP infection, which is consistent with the previous
research reported by Diaz et al.(33). HP eradication
significantly improved PPR lesions and reduced
relapse rates in our study, but did not affect ETR
lesions in the rosacea patient group. Boixeda et al.(34)
reported higher rates of improvement in PPR lesions
(83.3%) after eradication of the microorganism compared to ETR lesions (36.5%). We suggest that these
results represent evidence for a positive cause and
effect relationship between inflammatory rosacea
and HP infection, especially in cases with gastritis
and dyspeptic symptoms.
There are a number of limitations to our study.
Most importantly, the patient cohort was small.
Additionally we did not employ histological examination and the urease test, although these are of
greater diagnostic value for the detection of HP, due
to their invasive nature(1, 4, 5, 11). The specificity and
sensitivity of UBT for the detection of HP infection
are close to 100%(11). In addition, this study did not
investigate the potential underlying mechanisms of
HP eradication in the pathophysiology of CSU, IGP,
and rosacea.
Conclusion
CSU, IGP, and rosacea are important dermatological diseases that adversely affect patients’ quality
of life. HP may be involved in the etiopathogenesis
of these diseases. In selected cases, HP eradication
may have beneficial effects on the course of the disease. Whether these treatment programs have any
effect on remission rates in these patients should now
be clarified with further prospective studies involving larger patient series.
Helicobacter pylori infection in multiple forms of dermatosis
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
16)
17)
Tüzün Y, Keskin S, Kote E. The role of Helicobacter
pylori infection in skin diseases: facts and controversies. Clin Dermatol 2010; 28: 478-82.
Ozkan Z, Aksoy N, Yazar FM, Bozkurt M, Şahin A, et
al. An analysis of the relationship between gastric
Helicobacter pylori colonization and salivary cortisol.
Acta Medica Mediterranea 2015; 31: 579-83.
Erfan G, Mete R, Oran M, Yanık ME, Güneş H, et al.
Gaga Strain of Helicobacter pylori in recurrent aphtous stomatitis patients without dyspeptic symptoms:
response to eradication therapy. Acta Medica
Mediterranea 2014; 30: 285-9.
Hernando-Harder AC, Booken N, Goerdt S, Singer
MV, Harder H. Helicobacter pylori infection and dermatologic diseases. Eur J Dermatol 2009; 19: 431-44.
Kutlubay Z, Zara T, Engin B, Serdaroğlu S, Tüzün Y, et
al. Helicobacter pylori infection and skin disorders.
Hong Kong Med J 2014; 20: 317-24.
El-Khalawany M, Mahmoud A, Mosbeh AS, A B D
Alsalam F, Ghonaim N, et al. Role of Helicobacter
pylori in common rosacea subtypes: a genotypic comparative study of Egyptian patients. J Dermatol 2012;
39: 989-95.
Shakouri A, Compalati E, Lang DM, Khan DA.
Effectiveness of Helicobacter pylori eradication in
chronic urticaria: evidence-based analysis using the
Grading of Recommendations Assessment,
Development, and Evaluation system. Curr Opin
Allergy Clin Immunol 2010; 10: 362-9.
Akashi R, Ishiguro N, Shimizu S, Kawashima M.
Clinical study of the relationship between Helicobacter
pylori and chronic urticaria and prurigo chronica multiformis: effectiveness of eradication therapy for
Helicobacter pylori. J Dermatol 2011; 38: 761-6.
Kandyil R, Satya NS, Swerlick RA. Chronic pruritus
associated with Helicobacter pylori. J Cutan Med Surg
2002; 6: 103-8.
Lehours P, Yilmaz O. Epidemiology of Helicobacter
pylori infection. Helicobacter 2007; 12: 1-3.
Di Rienzo TA, D'Angelo G, Ojetti V, Campanale MC,
Tortora A, et al. 13C-Urea breath test for the diagnosis
of Helicobacter pylori infection. Eur Rev Med
Pharmacol Sci 2013; 17: 51-8.
Kaplan AP. Urticaria and angioedema. In: Wolff K,
Goldsmith LA, Katz SI, Gilchrest BA, Paller AS,
Leffell DJ, eds. Fitzpatrick’s Dermatology in General
Medicine. 7th ed. New York: Mc Graw Hill 2008: 33043.
Yadav MK, Rishi JP, Nijawan S. Chronic urticaria and
Helicobacter pylori. Indian J Med Sci 2008; 62: 15762.
Galadari IH, Sheriff MO. The role of Helicobacter
pylori in urticaria and atopic dermatitis. Skinmed
2006; 5: 172-6.
Magen E, Mishal J. Possible benefit from treatment of
Helicobacter pylori in antihistamine-resistant chronic
urticaria. Clin Exp Dermatol 2013; 38: 7-12.
Campanati A, Gesuita R, Giannoni M, Piraccini F,
Sandroni L, et al. Role of small intestinal bacterial
overgrowth and Helicobacter pylori infection in chronic spontaneous urticaria: a prospective analysis. Acta
Derm Venereol 2013; 93: 161-4.
Yoshimasu T, Furukawa F. Eradication therapy for
urticaria with high titers of anti H. pylori IgG antibody.
1131
18)
19)
20)
21)
22)
23)
24)
25)
26)
27)
28)
29)
30)
31)
32)
33)
34)
35)
Allergol Int 2014; 63: 37-40.
Liutu M, Kalimo K, Uksila J, Savolainen J. Extraction
of IgE-binding components of Helicobacter pylori by
immunoblotting analysis in chronic urticaria patients.
Int Arch Allergy Immunol 2001; 126: 213-7.
Greaves MW. Pathology and classification of urticaria.
Immunol Allergy Clin North Am 2014; 34: 1-9.
Liutu M, Kalimo K, Uksila J, Kalimo H. Etiologic
aspects of chronic urticaria. Int J Dermatol 1998; 37:
515-9.
Magen E, Schlesinger M, Hadari I. Chronic urticaria
can be triggered by eradication of Helicobacter pylori.
Helicobacter 2013; 18: 83-7.
Shakouri A, Compalati E, Lang DM, Khan DA.
Effectiveness of Helicobacter pylori eradication in
chronic urticaria: evidence-based analysis using the
Grading of Recommendations Assessment,
Development, and Evaluation system. Curr Opin
Allergy Clin Immunol 2010; 10: 362-9.
Akashi R, Ishiguro N, Shimizu S, Kawashima M.
Clinical study of the relationship between Helicobacter
pylori and chronic urticaria and prurigo chronica multiformis: effectiveness of eradication therapy for
Helicobacter pylori. J Dermatol 2011; 38: 761-6.
T-J Goon A, Yosipovitch G, Chan YH, Goh CL.
Clinical characteristics of generalized idiopathic pruritus in patients from a tertiary referral center in
Singapore. Int J Dermatol 2007; 46: 1023-6.
Neri S, Ierna D, D'Amico RA, Giarratano G, Leotta C.
Helicobacter pylori and prurigo nodularis.
Hepatogastroenterology 1999; 46: 2269-72.
Erbagci Z. Prurigo pigmentosa in association with
Helicobacter pylori infection in a Caucasian Turkish
woman. Acta Derm Venereol 2002; 82: 302-3.
Sakurane M, Shiotani A, Furukawa F. Therapeutic
effects of antibacterial treatment for intractable skin
diseases in Helicobacter pylori-positive Japanese
patients. J Dermatol 2002; 29: 23-7.
Gürer MA, Erel A, Erbaş D, Cağlar K, Atahan C. The
seroprevalence of Helicobacter pylori and nitric oxide
in acne rosacea. Int J Dermatol 2002; 41: 768-70.
Sato D, Yanaka A, Shibahara T, Matsui H, Nakahara A,
et al. Peroxiredoxin I protects gastric mucosa from
oxidative injury induced by H. pylori infection. J
Gastroenterol Hepatol 2008; 23: 652-9.
Ding SZ, Minohara Y, Fan XJ, Wang J, Reyes VE, et al.
Helicobacter pylori infection induces oxidative stress
and programmed cell death in human gastric epithelial
cells. Infect Immun 2007; 75: 4030-9.
Szlachcic A. The link between Helicobacter pylori
infection and rosacea. J Eur Acad Dermatol Venereol
2002; 16: 328-33.
Zandi S, Shamsadini S, Zahedi MJ, Hyatbaksh M.
Helicobacter pylori and rosacea. East Mediterr Health
J 2003; 9: 167-71.
Diaz C, O’Callaghan CJ, Khan A, Ilchyshyn A.
Rosacea: a cutaneous marker of Helicobacter pylori
infection? Results of a pilot study. Acta Derm Venereol
2003; 83: 282-6.
Boixeda de Miquel D, Vázquez Romero M, Vázquez
Sequeiros E, Foruny Olcina JR, Boixeda de Miquel P,
et al. Effect of Helicobacter pylori eradication therapy
in rosacea patients. Rev Esp Enferm Dig 2006; 98:
501-9.
Abram K, Silm H, Maaroos HI, Oona M. Risk factors
associated with rosacea. J Eur Acad Dermatol Venereol
1132
36)
37)
Emine Colgecen, Seyhan Karacavus et Al
2010; 24: 565-71.
Bamford JT, Tilden RL, Blankush JL, Gangeness DE.
Effect of treatment of Helicobacter pylori infection on
rosacea. Arch Dermatol 1999; 135: 659-63.
Gedik GK, Karaduman A, Sivri B, Caner B. Has
Helicobacter pylori eradication therapy any effect on
severity of rosacea symptoms? J Eur Acad Dermatol
Venereol 2005; 19: 398-9.
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Corresponding author
EMINE COLGECEN, MD
Bozok University Medical Faculty
Department of Dermatology
TR-66000 Yozgat
(Turkey)