Successful treatment with erythromycin for idiopathic thrombocytopenic purpura.

Abstract

Macrolides have both immunomodulatory and antibacterial effects. We report 3 cases of primary immune thrombocytopenia (ITP) patients who were successfully treated with macrolides, irrespective of Helicobacter pylori (H. pylori) infection status. Case 1, an 88-year-old woman who was an H. pylori-positive ITP patient, was treated with clarithromycin (CAM). CAM was effective temporarily. As an alternative to CAM, she was successfully treated with erythromycin (EM) for more than 7 months. Case 2, a 61-year-old man who was an H. pylori-negative ITP patient, was unsuccessfully treated with CAM but successfully treated with EM. Case 3, a 75-year-old woman who was a H. pylori-negative ITP patient, was treated with CAM. CAM was effective temporarily. After approximately 6 months, she was treated with EM for a common cold, and her platelet count increased rapidly. Based on these findings, macrolide treatment was effective for ITP. The effectiveness of macrolides might suggest immunomodulatory effects as well as antibacterial effects for H. pylori.

Full text

Page 1

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
V O LU M E 46ㆍ N U M BER 2ㆍ June 2011
THE KOREAN JOURNAL OF HEMATOLOGY
C A S E R E P O R T
Successful treatment with erythromycin for idiopathic
thrombocytopenic purpura
Masashi Ohe1, Satoshi Hashino2
1Department of General Medicine, Hokkaido Social Insurance Hospital, 2Department of Gastroenterology and Hematology, Hokkaido
University Graduate School of Medicine, Sapporo, Japan
p-ISSN 1738-7949 / e-ISSN 2092-9129
DOI: 10.5045/kjh.2011.46.2.139
Korean J Hematol 2011;46:139-42.Korean J Hematol 2011;46:139-42.
Received on May 22, 2011
Revised on June 14, 2011
Accepted on June 14, 2011
Macrolides have both immunomodulatory and antibacterial effects. We report 3 cases
of primary immune thrombocytopenia (ITP) patients who were successfully treated with
macrolides, irrespective of Helicobacter pylori (H. pylori) infection status. Case 1, an
88-year-old woman who was an H. pylori-positive ITP patient, was treated with clari-
thromycin (CAM). CAM was effective temporarily. As an alternative to CAM, she was suc-
cessfully treated with erythromycin (EM) for more than 7 months. Case 2, a 61-year-old
man who was an H. pylori-negative ITP patient, was unsuccessfully treated with CAM
but successfully treated with EM. Case 3, a 75-year-old woman who was a H. pylori-neg-
ative ITP patient, was treated with CAM. CAM was effective temporarily. After approx-
imately 6 months, she was treated with EM for a common cold, and her platelet count
increased rapidly. Based on these findings, macrolide treatment was effective for ITP. The
effectiveness of macrolides might suggest immunomodulatory effects as well as anti-
bacterial effects for H. pylori.
Key Words
Idiopathic thrombocytopenic purpura, Erythromycin, Macrolide
Correspondence to
Masashi Ohe, M.D., Ph.D.
Department of General Medicine,
Hokkaido Social Insurance Hospital,
1-8-3-18 Nakanoshima, Toyohira-ku,
Sapporo 062-8618, Japan
Tel: ＋81-11-831-5151
Fax: ＋81-11-821-3851
E-mail: masshi@isis.ocn.ne.jp
Ⓒ2011 Korean Society of Hematology
INTRODUCTION
Macrolides have both immunomodulatory effects and anti-
bacterial effects against organisms such as Helicobacter pylori
(H. pylori) [1-3]. We have already reported 3 cases of idio-
pathic thrombocytic purpura (ITP), also known as primary
immune thrombocytopenia, which show increased platelet
counts following clarithromycin (CAM) treatment, irre-
spective of H. pylori infection status [4]. ITP is an auto-
immune disease induced by autoantibodies against platelets.
In our previous report, the fact that platelet count normalized
following CAM treatment suggested immunomodulatory
effects of macrolides. Erythromycin (EM) was the first mac-
rolide to be developed and showed poor activity against
bacteria compared with new macrolides such as CAM, which
has been developed to supersede EM［3]. We report 3 cases
of ITP that were successfully treated with macrolides. In
these cases, EM was considered more effective than CAM.
CASE REPORT
1. Case 1
　An 88-year-old woman who had been suffering from ITP
for several years was admitted for resection of a small tumor
of the tongue. Platelet count remained at a level of around
20×109/L. Initial laboratory data showed reduced platelet
counts (24×109/L). The patient was referred to our depart-
ment for management of platelet count, which needed to
be increased to about 50×109/L before tumor resection.
Although a positive result was obtained for anti-H. pylori
IgG antibodies, the patient could not be treated by eradication
therapy because of an allergy to penicillins. As the patient
was suffering from osteoporosis and refused platelet trans-
fusion, she was treated using CAM without prednisolone
(PSL). The clinical course is shown in Fig. 1. CAM was
given at 400 mg/day. Platelet count had increased to 42×109/L
by 5 days after CAM treatment and then resection was safely
performed. Little bleeding was seen during and after resec-
tion. After resection, the platelet count had decreased to
28×109/L despite CAM treatment. The patient was treated
with EM at a dose of 600 mg/day as an alternative to CAM.

Page 2

Korean J Hematol 2011;46:139-42.
140 Masashi Ohe and Satoshi Hashino
Fig. 1. Change of platelet counts following clarithromycin (CAM) and
erythromycin (EM) treatments.
Fig. 2. Change of platelet counts following prednisolone (PSL), methyl-
prednisolone (mPSL), CAM, and EM treatments.
Fig. 3. Change of platelet counts following CAM and EM treatments.
The platelet count had increased to 35×109/L by 7 days after
starting EM treatment. After the patient was discharged,
the platelet count remained at about 34-39×109/L. We tried
stopping EM prescriptions for 1 month, but the platelet count
decreased to 26×109/L. Re-treatment with CAM did not im-
prove the platelet count, so she was re-treated using EM
at a dose of 800 mg/day instead of CAM. After 1 week,
platelet count increased from 21×109/L to 31×109/L. The dose
of EM was therefore reduced to 600 mg/day. By the end
of the observation period, platelet count had increased to
44×109/L.
2. Case 2
　A 61-year-old man was referred with purpura, which had
appeared several months before. Initial laboratory data
showed a reduced platelet count (14×109/L), so he was admit-
ted for further investigation. Anti-nuclear antibody was pos-
itive (titer 1：640, speckled). Testing for anti-dsDNA anti-
body, anti-SSA antibody, anti-RNP antibody, anti-Sm anti-
body, and anti-Topo I antibody all yielded negative results,
as did testing for anti-H. pylori IgG antibody. A bone marrow
specimen revealed hyperplasia of normal megakaryocytes.
Neither articular swelling nor skin rash suggestive of collagen
disease was present. Based on clinical and laboratory findings,
ITP was diagnosed. The clinical course is shown in Fig.
2. PSL was given at 60 mg/day for 4 days, but the platelet
count still decreased to 6×109/L. Methylprednisolone pulse
therapy was therefore performed and PSL reduced to 30
mg/day because of hyperglycemia. By 1 week after pulse
therapy, platelet count had only increased to 20×109/L. The
patient was treated with CAM at a dose of 400 mg/day
after obtaining informed consent. About 4 weeks after treat-
ment for ITP, platelet count did not increase and remained
at 17×109/L. The patient was therefore administered EM
at 600 mg/day as an alternative to CAM. After 2 weeks,
platelet count increased to 77×109/L and oral PSL could be
gradually tapered. By the end of the observation period,
platelet count increased to 208×109/L.
3. Case 3
　A 75-year-old woman suffering from ITP was admitted
with a gradual decrease in platelet count. Prior to admission,
platelet count had remained at a level of around 40×109/L.
Laboratory data on admission showed reduced platelet counts
(18×109/L). Anti-H. pylori IgG antibody and urea breath

Page 3

Korean J Hematol 2011;46:139-42.
Treatment with erythromycin for ITP141
tests were negative. The clinical course is shown in Fig.
3. CAM was given at 800 mg/day after informed consent
was obtained. Platelet count had rapidly increased to
131×109/L by 7 days after CAM treatment. However, after
1 month, platelet count had decreased to 40×109/L despite
CAM treatment. Because liver dysfunction occurred, we
stopped prescribing CAM. After the patient was discharged,
the platelet count remained at about 35-50×109/L without
medication. The patient was treated with EM at a dose of
600 mg/day for a common cold. After 1 week, platelet count
had increased from 43×109/L to 97×109/L. Because the patient
recovered from the cold, EM prescription was stopped. After
1 month, the platelet count had decreased to 41×109/L. By
the end of the observation period, platelet count had re-
mained at a level of around 40×109/L without medication.
DISCUSSION
　In Case 1, CAM treatment appeared to be effective tempo-
rarily. Re-treatment with CAM proved ineffective. Although
the platelet count remained at only about 31-44×109/L with
EM treatment, including re-treatment, EM was considered
more effective than CAM.
　ITP is an autoimmune disease induced by autoantibodies
against platelets. Recent studies have suggested that ITP pa-
tients infected with H. pylori can be successfully treated
by eradication (proton pump inhibitors, amoxicillin, and
CAM) [5, 6]. In Case 1, platelet counts might have increased
as a result of the antibacterial effects of macrolides against
H. pylori. However, the higher effectiveness of EM compared
with CAM could not be explained, as CAM generally shows
superior activity against H. pylori compared with EM [4].
This effectiveness might suggest the superiority of EM to
CAM with regard to immunomodulatory effects independent
of infection. Possibly this decrease in platelet count, despite
CAM treatment, might suggest side effects of CAM.
　In general, platelet count increases within 4 weeks of
starting PSL treatment. Similarly, platelet count increases
3-5 days after starting methylprednisolone pulse therapy.
Steroid therapy in Case 2 thus appeared largely ineffective.
　As CAM treatment only maintained platelet count, CAM
was not considered sufficiently effective in Case 2. However,
EM was clearly effective, as could be seen by gradual im-
provements in platelet counts.
　In Case 2, EM treatment was effective for an H. pylori-neg-
ative ITP patient. The pathogenesis of H. pylori-negative
ITP is thought to involve autoimmunity derived from
EM-sensitive bacteria other than H. pylori, or immunological
dysregulation independent of infection.
　In Case 3, CAM treatment appeared to be effective
temporarily. The cause of the decrease in platelet count,
despite CAM treatment, might suggest that CAM has side
effects, as in Case 1.
The fact that EM treatment for a common cold increased
the platelet count also suggests the effectiveness of EM for
ITP.
　In our previous report and in this report, the fact that
platelet count increased following macrolide treatment sug-
gests immunomodulatory effects of macrolides.
　Immunomodulatory effects from macrolide antibiotics
might be obtained by the eradication of bacteria or by modu-
lation of the immune system involving the mucosa on which
commensal bacteria reside [7]. Alternatively, these effects
might be pharmacological functions of the macrolide itself,
independent of antibiotic effects.
　Apart from antibacterial effects, macrolides have effects
on neutrophil function (decreased oxidant production, apop-
tosis) and on the production of cytokines involved in the
inflammation cascade (decreased production of IL-1, IL-6,
IL-8, and TNF and increased production of IL-10 and, possi-
bly, IL-4) [1]. With regard to T lymphocytes, EM and its
derivatives inhibit T lymphocyte proliferation and induce
T lymphocyte apoptosis [2].
　Apart from these immunomodulatory effects, macrolides
have steroid-sparing effects via their influence on cortico-
steroid metabolism [8]. In Case 2, steroid-sparing effects
might increase the platelet count.
　EM was the first macrolide to be developed. New macro-
lides such as CAM and azithromycin have since been devel-
oped to supersede EM. CAM is a semisynthetic macrolide
antibiotic, chemically identified as 6-0-methylerythromycin
A [9]. A close analogy exists between CAM and EM. However,
in the present report, although only 3 cases were studied,
macrolides proved effective for ITP, as in our previous report,
and EM was considered more effective than CAM.
　As a slight structural change is thought to be advantageous
to CAM in terms of antibacterial effects, similarly, a slight
change may be advantageous to EM for providing immuno-
modulatory effects.
　For the purpose of clarifying which macrolide is more
effective, crossover tests between EM and CAM are needed
in the future.
REFERENCES
1. Labro MT. Anti-inflammatory activity of macrolides: a new ther-
apeutic potential? J Antimicrob Chemother 1998;41(Suppl B):
37-46.
2. Wu L, Zhang W, Tian L, Bao K, Li P, Lin J. Immunomodulatory
effects of erythromycin and its derivatives on human T-lympho-
cyte in vitro. Immunopharmacol Immunotoxicol 2007;29:587-
96.
3. Blondeau JM, DeCarolis E, Metzler KL, Hansen GT. The
macrolides. Expert Opin Investig Drugs 2002;11:189-215.
4. Ohe M, Kohno M. Three cases of idiopathic thrombocytopenic
purpura showing an increase in the platelet count following clari-
thromycin treatment. Rinsho Ketsueki 2003;44:1044-6.
5. Gasbarrini A, Franceschi F, Tartaglione R, Landolfi R, Pola P,
Gasbarrini G. Regression of autoimmune thrombocytopenia after
eiradication of Helicobacter pylori. Lancet 1998;352:878.
6. Hashino S, Mori A, Suzuki S, et al. Platelet recovery in patients
with idiopathic thrombocytopenic purpura after eradication of

Page 4

Korean J Hematol 2011;46:139-42.
142 Masashi Ohe and Satoshi Hashino
Helicobacter pylori. Int J Hematol 2003;77:188-91.
7. Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, et al. Com-
mensal bacteria (normal microflora), mucosal immunity and
chronic inflammatory and autoimmune diseases. Immunol Lett
2004;93:97-108.
8. Rubin BK, Henke MO. Immunomodulatory activity and effec-
tiveness of macrolides in chronic airway disease. Chest 2004;
125(Suppl 2):S70-85.
9. Iwasaki H, Sugawara Y, Adachi T, Morimoto S, Watanabe Y.
Structure of 6-0-methylerythromycin A (clarithromycin). Acta
Cryst 1993;C49:1227-30.