Pediatr Blood Cancer 2006;47:742745

Splenectomy in Children With Chronic ITP: Long-Term Efcacy and Relation Between its Outcome and Responses to Previous Treatments
Ugo Ramenghi, MD,1* Giovanni Amendola,2 Loredana Farinasso,1 Paola Giordano,3 Giuseppe Loffredo,4 Bruno Nobili,5 Silverio Perrotta,5 Giovanna Russo,6 and Marco Zecca7
This retrospective study was conducted to determine whether the response to splenectomy is related to the response to previous treatments. We examined the records of 90 children splenectomized for chronic ITP. Platelet counts were constantly >50 109/L in 68 patients (75%). An improvement in the quality of life was observed in 79 (85%). The success of splenectomy was strongly correlated with a good response to previous treatment. A negative response to any of the prior treatments had no predictive value. This nding is relevant when elective splenectomy is considered as a treatment option. Pediatr Blood Cancer 2006;47:742745.
2006 Wiley-Liss, Inc.

Key words:

immunoglobulins; splenectomy; thrombocytopenic purpura

INTRODUCTION Immune thrombocytopenic purpura (ITP) in children is an autoimmune disorder characterized by low platelet count and mucocutaneous bleeding that resolves spontaneously within 618 months in 8090% of cases. Chronic ITP is dened as thrombocytopenia persisting for more than 6 months [1,2]. Several medical treatments are available for children with low platelet counts and mucocutaneous bleeding [2,3]. If thrombocytopenia persists for more than 12 months and requires repeated treatment, elective splenectomy should be considered [2]. A remission rate in the range of 70% may be expected [4,5]. A platelet response to intravenous immunoglobulin (IVIG) has been reported to predict the response to splenectomy [6], though this has not been corroborated and few pediatric patients have been considered [715]. We therefore carried out a retrospective analysis of 90 children splenectomized for ITP to assess the long-term effect of splenectomy and look for correlations between its outcome and the response to pre-splenectomy treatments. METHODS We examined the records of all children splenectomized for chronic ITP in 11 Italian pediatric centers and previously treated with several treatments including IVIG. Chronic ITP was dened as severe thrombocytopenia (platelet count <50 109/L) persisting for a minimum of 6 months. Patients with positive serological markers for HIV, HCV, HBV, or EBV were excluded. There was no clinical or laboratory evidence of non-idiopathic thrombocytopenia. Ninety patients (54 M, 36 F) were eligible. Their mean age at diagnosis was 8 3.9 (range 1.317.8) and at the time of splenectomy was 11.3 4.2 years (range 2.423.4). The mean time between diagnosis and splenectomy was 2.4 years (range 0.519.5). The mean follow-up after splenectomy was 47 months (range 5180).
2006 Wiley-Liss, Inc. DOI 10.1002/pbc.20978

Each patient received at least one IVIG course at a total dose of 2 g/Kg of body weight; 45 received one or more courses of 0.4 g/Kg/day for 5 days; 22 one or more course of 0.81 g/Kg/day for 2 days; and 23 several courses of both doses. The response to i.v. IG was determined from the highest platelet count measured 3 to 7 days after the rst dose. Twenty-nine children were treated with anti-D IG (15 mg/Kg/ day for 3 days). Oral prednisone (12 mg/Kg/day) or i.v. methylprednisone (>5 mg/Kg/day) were given to 81 children. Forty received prednisone only, twelve received methylprednisone only, and twenty-nine both schedules. Twenty-nine children were treated with dexamethasone (24 /day for 4 days). Response to treatment was dened as mg/m negative (NR) if the platelet count did not rise above 50 109/L, positive (PR) if it did, and good (GR) if it exceeded 150 109/L. Splenectomy was performed when thrombocytopenia persisted for more than 6 months after diagnosis and associated to the following: bleeding, transiently successful treatment and/or substantial side-effects such as headache and vomiting after IVIG, hypertension and/or Cushings syndrome after steroids, and hemolysis after anti-D IG. When an elective splenectomy was planned, a pre-operative prophylaxis (including IVIG, parental steroids and anti-D
1
2

Department of Pediatrics, University of Torino, Torino, Italy; Department of Pediatrics, Umberto I Hospital, Nocera Inferiore, Italy; 3Department of Pediatrics, University of Bari, Bari, Italy; 4 Department of Pediatrics, Pausilipon Hospital, Napoli, Italy; 5 Department of Pediatrics, Second University of Napoli, Napoli, Italy; 6Department of Pediatrics, University of Catania, Catania, Italy; 7 Department of Pediatrics, San Matteo Hospital, Pavia, Italy Grant sponsor: Banca del Piemonte. *Correspondence to: Ugo Ramenghi, Divisione di Ematologia, Dipartimento di Scienze Pediatriche, piazza Polonia 94, 10126 Torino, Italy. E-mail: ugo.ramenghi@unito.it Received 20 June 2006; Accepted 20 June 2006

Splenectomy in Children With ITP

743

IG) to reduce the risk of intraoperative and postoperative bleeding was performed. The response to splenectomy was considered positive if the platelet count remained stable at >50 109/L throughout the follow-up. Patients were divided into responders and non-responders to splenectomy and correlations were sought for their responses (NR, PR, and GR) to pre-splenectomy treatments. After splenectomy, parents and physicians were asked to complete a simple form to assess whether school attendance, social events, and sports activities had improved. Eighty-seven children (97%) were vaccinated against pneumococcus, forty-seven (52%) against hemophilus inuenza type B and thirty-four (38%) against meningococcus. After splenectomy, 83 patients (92%) received a continuous antibiotic prophylaxis (benzatilpenicillin in 37 cases, penicillin in 34, amoxicillin in 6, azithromycin in 5, cefotaxime in 1), even if the usefulness of antibiotics has not been demonstrated [16,17]. Statistical Analysis Data were analyzed as of December 31, 2002 with the SAS package (SAS Institute, Cary, NC) and NCSS (Number Cruncher Statistical System, Kaysville, Utah). Results were expressed as median and range or as absolute number and percentage, as appropriate, or as otherwise stated. Normal distribution of values was evaluated with the Shapiro-Wilks W test. Differences in the percentages of responders to splenectomy in function of their pre-splenectomy treatment were evaluated with Fishers exact test or the chi-square test, as appropriate. The relative risk and 95% condence limit (95% CI) of response to splenectomy for patients who responded to pre-splenectomy therapy versus those who did not were also calculated. All P values are two-tailed. Value <0.05 were considered signicant and expressed in detail; values from 0.05 to 0.1 are also shown in detail, where values >0.1 are expressed as NS. RESULTS Response to Pre-Splenectomy Management A PR was observed in 21/45 patients treated with IVIG 0.4 g/Kg/day for 5 days, in 8/22 treated with 0.81 g and 12/29 who received both doses: a GR was observed in 35 of these two groups of IVIG. A PR was observed in 25/40 treated with oral prednisone, in 9/12 treated with i.v. methylprednisolone and in 12/23 who received both oral and i.v. treatment. A GR was displayed by 10/25 patients who responded to oral prednisone. A PR was observed in 18/29 treated with high-dose dexamethasone and in 5/25 treated with anti-D IG. The responses to steroid treatment were too small to allow separate assessment of GR. Response to Splenectomy Sixty-eight children (75%) displayed a positive response to splenectomy. The quality of life was regarded as improved
Pediatr Blood Cancer DOI 10.1002/pbc

after splenectomy by both parents and physicians in all responders, and also in 11/22 patients whose platelet levels were not constantly above 50 109/L during the follow-up. No signicant difference was observed between the response to splenectomy and the interval occurring from diagnosis and splenectomy. Table I summarizes the main patient characteristics. Relation Between Response to Splenectomy and Previous Treatment Table II shows the relationship between the response to prior treatment and the response to splenectomy. A distinction was drawn between a PR (>50, but <150 109/L) and a GR (>150 109/L). The pre-splenectomy responses to steroid treatment (PR and GR) and the GR to IVIG were positively correlated with the response to splenectomy. Infections There were 10 infectious episodes (0.028 patient/year) during the follow-up. One 10-year-old boy, splenectomized 6 years earlier, died 2 hr after admission for profound asthenia and fever of undetermined etiology. No difference in infection incidence was observed between patients who did or did not receive antibiotic prophylaxis. DISCUSSION We examined the records of 90 pediatric patients splenectomized for ITP. Since the main goal of splenectomy is to achieve and maintain a platelet level that prevents bleeding and allows a normal social life, we considered as responders all patients who achieved and stably maintained a platelet level >50 109/L. Sixty-eight (75%) patients maintained platelet count >50 109/L throughout the follow-up. Furthermore the quality of life (social and sport activities), was also improved in 11/22 who did not display a stable improvement in platelet count. Splenectomy was thus useful in 88% of this series. Evaluation of the relationship between the response to splenectomy and the response to all previous treatments showed a correlation between both the response to IVIG and oral steroid treatment and the response to splenectomy. A high correlation was observed between a GR to IVIG or steroid and a positive response to splenectomy. When the platelet increase was to >150 109/L after IVIG, the
TABLE I. Patient Characteristics Mean age at diagnosis (years) Mean age at splenectomy (years) Mean duration of follow-up (months) Number of subjects with platelet count constantly above 50 109/L after splenectomy Number of subjects with improvement of social and sport activity after splenectomy 8 3.9 11.3 4.2 47 36 68 (75%) 79 (88%)

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Ramenghi et al.
TABLE II. Response to Splenectomy According to the Response to Pre-Splenectomy Treatment Response to splenectomy Response to pre-splenectomy treatment Positive response to i.v. IG (Plt> 50 10 /L) No Yes Good response to i.v. IG (Plt > 150 109/L) No Yes Response to anti-D IG (Plt > 50 109/L) No Yes Positive response to PDN (Plt > 50 109/L) No Yes Good response to PDN (Plt > 150 109/L) No Yes
9

Negative 11 (34%) 11 (19%) 19 (35%) 3 (9%) 5 (25%) 0 (0%) 13 (41%) 4 (11%) 17 (29%) 0 (0%)

Positive 21 (66%) 47 (81%) 36 (65%) 32 (91%) 15 (75%) 5 (100%) 19 (59%) 33 (89%) 41 (71%) 11 (100%)

Relative risk (95% CI)

1.8

(0.84.0)

NS

4.0

(1.317) 0.005

1.5

(0.233)

NS

3.8

(1.313) 0.005

3.8

(1.134) 0.04

Relative risk and 95% condence interval (95% CI) express the relative probability of positive response to splenectomy of the patients who responded to pre-splenectomy treatment versus those who did not.

probability of a poor response to splenectomy was extremely low. In 1997 Law et al. [6] found a correlation between the response to splenectomy and the response to IVIG in 30 patients with chronic ITP, but this was not conrmed in subsequent studies. In particular Ruivard et al. [10] and Radaelli et al. [14] studying adult patients and Bussel et al. [12] studying adults and children did not conrm the correlation between the response to IVIG and the response to splenectomy. However, ITP has different behavior in adult and children, and we think that these two groups of patients should be studied separately. In a group of 23 children, Hemmila et al. [11] observed a positive relation between IVIG response and response to splenectomy; this observation was conrmed by Holt et al. [15] in 32 children. Our study was conducted on a larger case series, and this allowed us to distinct and analyze separately the PR and the GR, showing that a GR to either steroid or IVIG pre-splenectomy treatment is highly predictive of a positive response to splenectomy. We suggest that graduation of the response is important in prediction of the effect of splenectomy. Besides, the absence of a pre-splenectomy response is not predictive of a poor response to splenectomy: our 90 children with chronic ITP included 16 patients who had never responded to any treatment: 9 of them displayed a positive response to splenectomy. Recent data demonstrate the efcacy of rituximab in 1/3 of children with chronic refractory ITP [1820]; thus, rituximab should be given before splenectomy in chronic ITP, particularly in younger patients. In conclusion, our study conrms that splenectomy is a useful and relatively low-risk procedure for children with chronic symptomatic refractory ITP. The study demonstrates that a GR to pre-splenectomy treatment is highly predictive
Pediatr Blood Cancer DOI 10.1002/pbc

of successful splenectomy. In particular any increase in platelet count to >150 109/L after IVIG or steroid treatment is highly predictive of a positive response to splenectomy. ACKNOWLEDGMENT We wish to thank the Italian Association for Pediatric Hematology and Oncology (AIEOP) and in Particular Dr. Momcilo Jankovic, San Gerardo Hospital, Monza; Dr Angelo Claudio Molinari, Gaslini Hospital, Genova; Prof Domenico Del Principe, Pediatric Department, University of Roma; Prof Andrea Pession, Pediatric Department, University of Bologna and Prof Domenico De Mattia, Pediatric Department, University of Bari, Italy, for providing data concerning their patients who entered the study. This work was partially supported by Banca del Piemonte grant to UR. REFERENCES
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Splenectomy in Children With ITP

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Pediatr Blood Cancer DOI 10.1002/pbc