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Does Helicobater pylori initiate or perpetuate immune
thrombocytopenic purpura?
Marc Michel, Nichola Cooper, Christelle Jean, Christine Frissora,
and James B. Bussel
From the Department of Pediatrics, Division of Hematology/Oncology,
and Department of Medicine, Division of Gastroenterology, Weill
Medical College of Cornell University, New York–Presbyterian
Hospital, New York, NY.
To determine the prevalence of Helicobacter pylori (H pylori)
infection in North American patients with immune thrombocytopenic
purpura (ITP) and the effect of H pylori eradication on the platelet
count, a prospective study was performed. Seventy-four patients aged
10 years and older (mean age of 41 years) with chronic ITP and a
platelet count below 60 x 109/L were enrolled. H pylori infection
was found in 22% of patients by means of a breath test and could not
be predicted by gastrointestinal symptoms. H pylori–positive
patients (52.5 years of age) were older than H pylori–negative
patients (38.5 years of age; P = .0035). Fifteen of the 16 H
pylori–positive patients were treated and the bacteria was
eradicated in 14 (93%). After 3 months, a significant response
(platelet count > 50 x 109/L and doubling the initial count) was
observed in only one patient. After a median follow-up of 11.5
months, none of the 14 patients had responded. Ten H pylori–negative
patients treated with the same regimen also did not increase their
platelet counts. In conclusion, unlike several previous reports,
this study does not implicate H pylori in the pathogenesis of ITP
since the prevalence of H pylori infection was low and eradication
of H pylori did not positively influence the course of the ITP.
Helicobacter pylori (H pylori), a ubiquitous Gram-positive
bacterium, was initially discovered in 1982 as an infectious cause
of peptic ulcers. Following discovery of its causative role in
gastritis and peptic ulcer disease, subsequent studies implicated H
pylori in the pathogenesis of gastric adenocarcinoma and
mucosa-associated lymphoid tissue (MALT) lymphoma. More recently, H
pylori has been suspected to be involved in various autoimmune
disorders including pernicious anemia and immune thrombocytopenic
purpura (ITP).1-8
In 1998, Gasbarrini et al2 reported a substantial increase in the
platelet count in all 8 H pylori–positive adults with immune
thrombocytopenic purpura (ITP) in whom H pylori was eradicated.
Subsequent uncontrolled studies from Italy3-5 and Japan6-8 all
showed an apparently higher-than-expected prevalence of H pylori9,10
in patients with ITP. Furthermore, 38%7 to 73%4 of H pylori–positive
patients with ITP achieved a partial or complete platelet recovery
after H pylori eradication. On the other hand, additional studies
have not supported a role for H pylori in ITP. The prevalence of H
pylori infection was not increased in French patients with ITP when
compared with age-matched controls,11 and while the prevalence of H
pylori was high, no significant improvement of the platelet count
was observed after H pylori eradication in a report from Spain.12
We therefore conducted a prospective study to assess the prevalence
of H pylori infection in North American patients with ITP and the
efficacy of H pylori eradication on the platelet count. If
eradication of H pylori was not achieved with the initial regimen,
treatment was pursued with alternative regimens. To determine if the
H pylori eradication regimen could have nonspecific effects on the
platelet count, 10 ITP patients whose H pylori test was negative
were also treated with the same eradication regimen. In addition, a
short questionnaire was completed by the patients at the time of
testing to see if H pylori–infected patients with ITP could be
identified by symptoms referable to their gastrointestinal (GI)
tract.
Patients
All patients with ITP, defined according to the criteria set forth
in the American Society of Hematology (ASH) Guidelines,13 who
attended the Weill-Cornell center over the 12 month study period
were eligible to enroll in this study if they fulfilled the
following inclusion criteria: age of 10 years and older, a platelet
count of less than 60 x 109/L within 2 weeks of H pylori testing,
and no knowledge of a positive HIV test. Patients who were treated
by immunosuppressive treatments or other drugs for their ITP at the
time of inclusion were eligible if the doses of the ongoing
medications were stable for at least 4 weeks before inclusion. After
inclusion, both intravenous immunoglobulins (IVIg's) and intravenous
anti-D (IV anti-D) were allowed as a rescue therapy if clinically
required (ie, very low platelet count, grade III or IV bleeding
symptoms, or scheduled invasive procedures). Patients were not
eligible for the study if they had been treated for H pylori within
2 years or if they had been treated with either an antibiotic,
lansoprazole (or another proton pump inhibitor), or bismuth within
the past 4 weeks.
In order to see if the status of H pylori could be predicted by
gastrointestinal symptoms or past medical history, all patients were
asked to complete a short standardized questionnaire at the time of
the breath test (Table 1).
View this table:
Table 1.. Results of questionnaire in H pylori–positive and H
pylori–negative patients
Approval for this study was obtained from the Institutional Review
Board of the New York Hospital–Cornell Medical Center and informed
consent was provided by all subjects or their parents according to
the Declaration of Helsinki. Patients 10 to 18 years of age provided
their assent.
H pylori infection testing
All enrolled patients underwent at time of inclusion a BreathTek
Urea breath test commercially available from Prometheus (San Diego,
CA). In H pylori–positive patients, eradication was assessed by
another urea breath test performed 1 to 2 months after completion of
treatment. Patients not responding to eradication treatment had a
third test performed after a subsequent treatment regimen was
completed. The breath test initially required a 4-hour fast before
it could be performed. This led several otherwise eligible patients
to decline to participate.
H pylori eradication regimen
Patients infected with H pylori were treated according to a standard
H pylori treatment protocol currently in use in the United States
(referred to as the Prevpac, TAP Pharmaceutical Products, Lake
Forest, IL). For patients older than 12 years of age, this consisted
of lansoprazole 30 mg, clarithromycin 500 mg, and amoxicillin 1000
mg taken together twice a day for 2 weeks. Children 10 to 12 years
of age received lansoprazole 30-mg capsules, clarithromycin tablets
at a dose of 15 mg/kg/day to a maximum dose of 500 mg/day, and
amoxicillin 500-mg tablets at a dose of 45 mg/kg/day to a maximum
dose of 1000 mg/day. The penicillin-allergic patients were not given
amoxicillin. If H pylori was not eradicated after initial treatment,
the patient was referred to the study gastroenterologist (C.F.) to
determine an alternative therapy.
Control groups
To see if there was an effect on the platelet count after the
Prevpac administration, all of the initial patients enrolled began
treatment "blindly" at the time of the breath test screening before
the results had returned. After 10 patients whose H pylori test was
subsequently found to be negative had been treated (ITP treatment
control group), only patients whose breath test was positive
received the Prevpac. Nine of the 10 control patients received the
Prevpac; 1 was penicillin allergic. In order to compare the
prevalence of H pylori infection in our population of ITP patients
to the prevalence in healthy individuals, recent epidemiologic data
available in a North American population14,15 was used.
Monitoring
As a minimum, platelet counts were performed at the time of testing,
within 2 weeks of breath screening, once every 2 weeks for the first
8 weeks, and every 4 weeks for the next 4 months.
Response criteria
A complete response (CR) was defined as the achievement of a
platelet count of at least 150 000/µL within 3 months (13 weeks)
after completion of H pylori eradication therapy. Partial response
(PR) was defined as a platelet count above 50 x 109/L and at least a
doubling of the initial count. Patients considered at bleeding risk
during the study period who required active treatment (higher doses
of steroids, IVIg or IV anti-D) more than 8 weeks after the
eradication treatment were considered as nonresponders.
Analysis
Data were expressed as mean ± standard deviation (SD) or as median
(range). A chi-square or Fischer exact test were used for analysis
of categoric data; the t test was used to compare groups in which
the data involved continuous variables. A 2-tailed P value of less
than .05 was considered significant; probabilities of .05 to .10
were considered a trend.
Patient characteristics
Seventy-four consecutive consenting patients, including 50 women
(67.5%) and 24 men, with a mean age of 41 years (SD ± 18.3)
fulfilling the inclusion criteria were enrolled and tested for the
presence of H pylori. Sixty-three of the 74 patients (85%) were
white, 7 (9.5%) were Hispanic, 3 (4%) were Asian, and 1 patient was
African American.
Sixty-four (90%) of the enrolled patients had chronic ITP (ie,
duration > 6 months) and 21 (28%) had previously undergone
splenectomy.
Prevalence of H pylori infection
Sixteen of the 74 patients (21.6%) had a positive breath test. This
rate of infection was lower than the prevalence of 32.5% assessed in
7465 healthy adults in the US population by means of serology14 (P =
.04).
H pylori–positive patient characteristics
As expected, increased age was associated with a higher likelihood
of H Pylori infection in both the healthy controls14 and the ITP
patients (Figure 1). The mean age of the H pylori–positive patients
(52.5 years, SD ± 15.9) was higher than the mean age of the H
pylori–negative patients (38.5 years, SD ± 18.3; P = .0035).
Although there was a trend for a longer duration of ITP in H
pylori–positive patients (10.2 years versus 6.4 years in H
pylori–negative patients; P = .07), only the mean age was
significantly different when H pylori–positive and –negative
patients were compared (Table 2).
Patients completed a questionnaire of GI symptoms to see if this
would predict which patients were infected. There was a trend for
patients with heartburn and gas or burping to be H pylori infected
(Table 1).
Eradication of H pylori
The 16 H pylori–positive patients all had chronic ITP and 15 had
been previously treated for their ITP by 1 to 6 therapies including
splenectomy in 5 (Table 3). Since 1 patient had her platelet count
return to normal prior to beginning treatment of H pylori, only 15
of the 16 H pylori–positive patients were treated. Fourteen patients
received the Prevpac, one patient who was allergic to penicillin was
first treated with clarithromycin and lansoprazole. Overall, H
pylori was successfully eradicated in 14 of the 15 patients (93%).
The H pylori was allowed to persist in a 74-year-old woman whose
platelet count was stably greater than 50 x 109/L; she did not
respond to the Prevpac and then developed diarrhea and vomiting
during alternative treatment with metronidazole and doxycyclin.
Platelet outcome in H pylori–positive patients
The median follow-up of infected patients was 11.5 months (range,
3-18 months; Table 3). Three months after the treatment, the time
point at which responses were seen in other studies, a significant
increase of platelet count was observed in only one patient (patient
no.12; Table 3). However, since the patient had a chronic relapsing
ITP, the role of the Prevpac was difficult to ascertain. Moreover,
after 7 months of follow-up, her platelet count was 53 x 109/L; a
breath test was not performed at time of relapse. In another case
(no. 13) in which no platelet change was seen at 3 months,
mycophenolate mofetil and cyclosporin were begun and at 6 months the
count was 100 000/µL. In total, 11 of the 15 patients (73%) required
changes in their baseline treatment within 6 months after receiving
the eradication regimen (Table 3).
Platelet outcome in H pylori–negative patients
After 3 months of follow-up, no significant increase in the platelet
count was observed in any of the 9 consecutive H pylori–negative
patients who were treated by the Prevpac or the one receiving an
alternative regimen (Table 4). The increase in the platelet count
observed in patient no. 5 was likely to be a consequence of the
administration of mycophenolate mofetil that was started a month
before for an underling systemic lupus erythematosus. After 6 months
of follow-up, a CR or a PR was achieved in 4 patients (nos. 3, 4, 5,
and 8) but in all cases after the initiation of new treatment (Table
4). Patient no. 10 was the only who did not require any change in
her baseline ITP treatment after receiving the H pylori eradication
regimen (Table 4).
Whether the investigation and eradication of H pylori infection
should be pursued in patients with ITP is a matter of debate.
Infectious agents such as HIV and hepatitis C virus (HCV) may
trigger an immune-mediated thrombocytopenia and/or cause it to
persist13 while other viruses resulting in chronic infections, such
as human T-cell lymphoma/leukemia virus 1 (HTLV-1), do not seem to
have this effect.16 Recent studies in primarily Italian and Japanese
populations2-8 have suggested that H pylori could initiate and
perpetuate ITP. Initiation would be suggested by an increased mutual
coincidence of H pylori and ITP over that observed in the general
population. Perpetuation would be suggested by amelioration of ITP
as a result of H pylori eradication. In the studies cited above,
although approximately half of the patients in whom H pylori was
eradicated did not change their platelet counts (Table 5),
perpetuation has been better demonstrated than initiation. If H
pylori perpetuated ITP in as few as 10% to 20% of patients, then an
appropriate strategy for management of ITP might involve testing for
H pylori and eradicating it in those patients who were infected.
Since the relationship between H pylori and ITP remains
controversial in adults11,12 and is far from being established in
children,17 this study was performed to investigate the prevalence
of H pylori infection in 74 North American patients with ITP aged 10
and older and to determine the effect of H pylori eradication. The
determination of active H pylori infection was assessed by a breath
test, a noninvasive, highly sensitive and specific method18 that has
been used in almost all of the previous studies (Table 5 includes a
literature review).
The prevalence of 21.6% of H pylori infection found in the 74
patients with ITP was surprisingly low compared with the prevalence
of 32.5% assessed by presence of serum IgG antibodies in 7465
healthy adults in the United States.14 The difference in the method
of H pylori detection and the ethnic distribution of our patient
population are unlikely to explain this low rate of infection.
Indeed, in a previous study, the prevalence of H pylori infection
among 239 healthy white Americans was 34% using a urea breath
test.19 While 25% of children 6 to 19 years old are infected in the
United States,15 none of the 11 patients aged of 19 or younger
included in the series reported here had a positive breath test.
Even eliminating these adolescents, the prevalence of H pylori
infection only reached 25.3% in the adults (16/63). These data do
not support H pylori initiating ITP in our patient population.
Could H pylori infection be predicted? The questionnaire contained 2
variables that showed a trend toward identifying H pylori infection:
heartburn or gas burping. As with the healthy controls, increased
age was associated with a higher likelihood of H pylori infection.
Therefore, if one wished to test ITP patients, one approach would be
to test those older than 50 years of age and those younger than 50
years of age with heartburn or gas burping. In the series reported
here, this would have identified 15 of the 16 infected patients
while testing only 52 of the total of 74.
Can eradication of H pylori cure ITP? One limitation of previous
studies was that at most 25% of the H pylori–positive patients who
received the eradication regimen were those with chronic severe
thrombocytopenia (ie, platelet count < 30 x 109/L and/or previous
splenectomy4; Table 5). By comparison, among the 15 H
pylori–positive patients treated in this study, all had chronic ITP
with a platelet count less than 55 x 109/L (7 were < 30 x 109/L) and
all have been previously treated for their ITP by 2 to 6 different
treatments including splenectomy in 5 cases (33%). Therefore, these
patients had a very low likelihood of spontaneous improvement and
the effectiveness of H pylori eradication on ITP outcome was easier
to assess. The eradication rate was 93% since alternative treatment
was pursued when the initial regimen was ineffective. However,
despite this good rate of eradication and unlike previous
studies,2-8 only one of our H pylori–positive patients achieved a
significant response 3 months after eradication and this response
did not last.
In this study, 3 months was chosen as the time limit for seeing an
effect of H pylori eradication. If no response was seen at that
time, other therapies were initiated if necessary. Previous studies
that provided time frames all demonstrated platelet recovery within
60 days after H pylori eradication.2,6,8 In this study, extending
the time beyond 3 months following H pylori eradication did not seem
to affect the response since the only platelet changes observed were
in those patients who had initiated other therapies. To explain the
high rates of response reported by others (Table 5), a nonspecific
effect of the drugs used to eradicate the bacteria seems unlikely
since in this present study none of the 10 H pylori–negative
patients who received the Prevpac experienced a significant
improvement in their platelet count.
The striking discrepancies between this report and those from Italy
and Japan suggest several hypotheses. One hypothesis is that the
response to H pylori infection could be influenced by the host's
immunogenetic background.20,21 However, the contradictory findings
reported in patients of similar European origin (ie, Spain, France,
and Italy)2,3,4,11,12 (Table 5) do not support this hypothesis.
Another possibility is that different strains of H pylori, namely
those with different cag or vag (cytotoxicity/virulence-associated
genes) proteins,20 could exert different immunologic effects on the
host T and B cells and hence on ITP. A third hypothesis is that the
expression of various Lewis (Le) antigens by H pylori isolates22 and
the subsequent production of anti-Le antibodies could play a role in
ITP pathogenesis since platelets may adsorb Lewis antigens from the
serum.
The management of ITP in adults is complex and may require
immunosuppressive therapies and/or splenectomy. One of the
challenges for physicians caring for patients with ITP is to find
less toxic and more effective approaches. The expectation at the
beginning of this study was that a percentage of patients could be
"cured" by administration of the Prevpac for 2 weeks. Unexpectedly,
in this study there was not a greater prevalence of H pylori in ITP
patients. Furthermore, and unlike most of the previous studies, none
of the patients substantially improved their platelet count as a
result of H pylori eradication. Therefore, even if the success of
treatment of the H pylori–infected patients could be predicted by
age and questionnaire, it is not obvious from this study that one
would choose to test and eradicate infection in them. Future studies
performed in this setting should be randomized and controlled and
should include large numbers of patients requiring therapy. In
addition to tracking the platelet count, other parameters that might
be important determinants of response as suggested in the hypotheses
considered above should also be studied.
Footnotes
Submitted March 25, 2003; accepted July 28, 2003.
Prepublished online as Blood First Edition Paper, August 14, 2003;
DOI 10.1182/blood-2003-03-0900.
The publication costs of this article were defrayed in part by page
charge payment. Therefore, and solely to indicate this fact, this
article is hereby marked "advertisement" in accordance with 18 U.S.C.
section 1734.
Reprints: Marc Michel, New York Presbyterian Hospital, Department of
Pediatrics, Division of Pediatric Hematology/Oncology, Weill Medical
College of Cornell University, 525 East 68th St, New York, NY 10021;
e-mail: drmarcmichel@hotmail.com.
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