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PEDIATRICS Vol. 111 No. 1 January 2003, pp. 87-90

Response to Intravenous Immunoglobulin Predicts Splenectomy Response in Children With Immune Thrombocytopenic Purpura

Derick Holt, BS^||, Justin Brown, MPH^,¶, Kelly Terrill, PharmD^*, Robert Goldsby, MD^*, Rebecka L. Meyers, MD, Jody Heximer, RN^*, Beth Nordfors, RN^* and William B. Slayton, MD^*

^* Department of Pediatrics, Divisions of Hematology/Oncology
Surgery
Department of Family and Preventive Medicine
^|| Department of Oncological Sciences, University of Utah School of Medicine
^¶ Thrasher Research Fund, Salt Lake City Utah

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	ABSTRACT

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Objective. Response to intravenous immunoglobulin (IVIG) has been shown to predict response to splenectomy in adults with immune thrombocytopenic purpura (ITP). However, reports in children have been inconsistent. We sought to determine whether response to IVIG is predictive of response to splenectomy in children.

Methods. Thirty-two assessable children were identified by a retrospective chart review. Response was graded according to previously published criteria as follows: "excellent" (platelets >150 000 within 1 week), "good" (platelets between 50 000 and 150 000), and "poor" (platelets <50 000). "Response" refers to both splenectomy and IVIG, and response to splenectomy was counted only when it was durable.

Results. Twenty-one of 23 patients who had a good or excellent response to IVIG also had an excellent response to splenectomy. Six of 9 patients who had a poor response to IVIG also had a poor response to splenectomy. Response to IVIG was a sensitive predictor of response to splenectomy in 88% of patients. Response to IVIG had a specificity of 75%, a positive predictive value of 91%, and a negative predictive value of 67%. Response to prednisone and length of time to splenectomy were not correlated with splenectomy response.

Conclusions. These results suggest that response to IVIG is predictive of response to splenectomy in children with chronic ITP. This correlation may be of value in deciding whether a splenectomy should be performed in children with chronic ITP.

Key Words: ITP • splenectomy • intravenous immunoglobulin

Abbreviations: ITP, immune thrombocytopenic purpura • IVIG, intravenous immunoglobulin • ANA, antinuclear antibodies • SLE, systemic lupus erythematosus

	INTRODUCTION

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Children with chronic immune thrombocytopenic purpura (ITP) often benefit from splenectomy.¹ However, approximately 25% of patients who undergo splenectomy fail to increase their baseline platelet count into a range that would prevent bleeding.^2,3 The decision of when and whether to perform a splenectomy is complex, especially because the majority of children with chronic ITP will spontaneously enter remission with expectant management.²

An ability to predict reliably the response to splenectomy could be helpful in making this decision. Numerous recent studies have focused on whether response to intravenous immunoglobulin (IVIG) is predictive of response to splenectomy in adults, and most of these have shown a correlation between IVIG response and splenectomy response.^4–8 However, the natural history of acute ITP in adults is different from that in children. Childhood ITP tends to result more often from immune complexes, whereas adult ITP is more often attributable to an underlying autoimmune disorder. Adult acute ITP tends to be more resistant to medical therapy, and these patients are more likely to develop chronic ITP. Chronic ITP in adults and children tend to be very similar. Because more adult patients with ITP have an underlying autoimmune cause for their acute ITP, the correlation between response to IVIG during the acute phase and response to splenectomy seen in adults might not be present in children. Hemmila et al⁹ asked this question and found a correlation between IVIG response and splenectomy response. However, a more recent study by Bussel et al,⁴ which focused on both adults and children, found no correlation. We sought to test the hypothesis that response to IVIG is predictive of splenectomy response in children with ITP.

	METHODS

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This study was reviewed by the University of Utah Institutional Review Board and deemed exempt. We performed a retrospective chart review of patients identified by a cross-reference of a surgical database using the terms "ITP" and "splenectomy" between January 1980 and November 2001. A diagnosis of ITP was confirmed on the basis of a platelet count <20 000, a complete blood count showing no other cytopenias, and lack of organomegaly or significant lymphadenopathy on physical examination. Patients with other diagnoses were excluded from the analysis. Additional data collected included age at diagnosis, gender, treatment modalities, response to treatment, and laboratory testing, including result of bone marrow aspirate, direct antiglobulin test, and antinuclear antibodies (ANA). We calculated the interval between diagnosis and surgery. Data were analyzed, including patients with positive ANA and direct antiglobulin tests, but these data were also analyzed separately. For purposes of uniformity, we analyzed responses to the first course of IVIG. Response to both IVIG and splenectomy was graded as follows: excellent (platelets >150 000 within 1 week), good (platelets between 50 000 and 149 000), and poor (platelets <50 000). Patients with initial response to splenectomy but subsequent relapse were counted as poor.⁷ To calculate odds ratios, sensitivity, and specificity, we subsequently collapsed these categories into responders (platelets 50 000) and nonresponders (platelets <50 000).

Statistical Analysis
A Fisher exact test was used to measure the association between response to IVIG and splenectomy in our 3 x 3 table. After grouping "good" and "excellent" responses together we calculated the sensitivity, specificity, and positive and negative predictive values of a response to IVIG in predicting a response to splenectomy. A multivariate logistic regression was used to calculate an odds ratio for a positive response to IVIG, controlling for patient age, gender, and length of time between diagnosis and splenectomy. We compared the length of time between diagnosis and splenectomy between responders and nonresponders to splenectomy using a Wilcoxon rank-sum test.

Literature Review
A literature review was performed using the PubMed database cross-referencing key words "IVIG," "splenectomy response," and "ITP"; immunoglobulin, "splenectomy," "ITP," and "retrospective"; and "IVIG," "ITP," and "response to splenectomy"; and revealed 5 previous studies.

	RESULTS

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Demographics
A total of 43 patients were identified by cross-reference of the database. Seven were discarded because they did not have ITP, and 4 had incomplete data. There were a total of 32 assessable patients. Only 7 of these patients received subsequent doses of IVIG, so only the initial response was evaluated. The age at diagnosis ranged from 6 months to 17 years. There were 15 girls and 17 boys. Two patients had ANA and additional serologic evidence of systemic lupus erythematosus (SLE). Four patients had a positive direct antiglobulin test and evidence of hemolytic anemia, or Evans syndrome.¹⁰ Length of follow-up ranged from 1 month to 7 years, with a mean of 2.4 years (median: 2.25 years; standard deviation: 1.38 years).

Response to IVIG
Total doses of IVIG ranged from 0.5 g/kg to 3.0 g/kg administered over 1 to 5 days, with 3 patients receiving <1 g/kg. These 3 children (1 g/kg) all were responders to both IVIG and splenectomy. Nine patients (28%) had a poor response to IVIG, 15 patients (47%) had a good response, and 8 patients (25%) had an excellent response. Both of the patients who had missing dosing data were good responders to IVIG and splenectomy.

Eight patients (25%) had a poor response to splenectomy, no patients had a good response, and 24 (75%) patients had an excellent response. Of the 8 patients who had a poor response to splenectomy, 2 initially had good or excellent responses but subsequently relapsed at 4 and 12 months. Both of these patients had underlying autoimmune problems. One had a positive ANA and was lost to follow-up 3 months after ITP relapse. The other patient had refractory Evan’s syndrome and died 9 months after cord blood transplant from acute hepatic failure of unknown cause.¹¹

A Fisher exact test using the original 3-level grouping showed a highly significant association between response to IVIG and response to splenectomy (P = .004). Fourteen of 15 patients with a good response and 7 of 8 patients with an excellent response to IVIG had an excellent response to splenectomy (Table 1). On the basis of the homogeneity of splenectomy outcome for good and excellent responders to IVIG and in accordance with a previously published study, we grouped these good and excellent responders into 1 category.⁷ Characteristics of the patients by splenectomy response are shown in Table 2.

View this table: [in this window] [in a new window]   TABLE 1. Response to Splenectomy Graded by Response to IVIG

 

View this table: [in this window] [in a new window]   TABLE 2. Demographics by Response to Splenectomy

 
Twenty-one (95%) of 23 patients who were good or excellent responders to IVIG also responded to splenectomy, but only 3 (33%) of 9 poor responders to IVIG were responders to splenectomy. Response to IVIG was a sensitive predictor of response to splenectomy in 91% of patients, with a specificity of 66%, a positive predictive value of 87%, and a negative predictive value of 75%. In a multiple logistic regression model, response to IVIG remained significantly predictive of response to splenectomy after controlling for patient gender, age at diagnosis, and length of time between diagnosis and splenectomy (odds ratio: 36; P = .013). None of the covariates was significantly related to response to splenectomy (P .50 in each case).

Other Diagnoses
One of the 9 IVIG nonresponders had a positive ANA and additional serologic evidence of SLE, and 3 IVIG nonresponders had Evans’ syndrome. One IVIG responder had Evans syndrome, and 2 had serologic evidence of lupus. Excluding these patients, 4 of 5 poor responders to IVIG were also poor responders to splenectomy, and 19 of 21 good or excellent responders to IVIG were excellent responders to splenectomy (P < .01).

Response to Prednisone
We investigated whether the response to prednisone predicted response to splenectomy. Twenty-four patients had assessable data regarding prednisone treatment. A Fisher exact test showed no significant association with response to splenectomy (P > .15), although the power was low because of a small sample size (0.22).

Length of Time to Splenectomy
We tested whether there was an association between the length of time between ITP diagnosis and splenectomy, and response to splenectomy. A Wilcoxon rank-sum test showed no association (P > .50), although because of small sample size, the power was low (<0.10). The mean length of time in years (±standard deviation) between diagnosis and splenectomy for the poor and the good/excellent responders was 1.38 (±1.37) and 1.67 (±1.80), respectively.

	DISCUSSION

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Although accepted as a treatment for chronic ITP, splenectomy can be risky. Risks of splenectomy include anesthesia complications, postoperative bleeding, and life-threatening infections. Recent splenectomy complications at our institution have included halothane-induced liver failure requiring liver transplant, a nicked inferior vena cava leading to life-threatening hemorrhage, and postsplenectomy septic shock requiring a prolonged intensive care unit stay. Although modern vaccines probably decrease the risk of life-threatening infections after splenectomy, the current risk of postsplenectomy sepsis is unknown. Parents of asplenic patients must be vigilant for signs of infection and seek medical attention when their child has a fever. After a failed splenectomy, families have to cope with 2 chronic medical problems. Factors that predict response to splenectomy could be helpful in determining which patients are most likely to benefit from this procedure.

The correlation between response to IVIG and splenectomy was first suggested by Law et al⁷ in a cohort of 30 patients, including 9 children. Nineteen of 21 patients who responded to IVIG responded to splenectomy. In addition, none of the patients who responded poorly to IVIG responded to splenectomy, resulting in a negative predictive value of 100%. In 2 separate letters to the editor, studies that focused solely on adults showed lack of correlation between IVIG and splenectomy responses. Both authors hypothesized that the discrepancy with Law’s study was attributable to the inclusion of children.^5,12 One additional adult study has supported Law’s observation,¹³ whereas 3 studies have shown no correlation.^4,8,14 A recent study by Hemmila et al⁹ focused on 23 children and found that 14 of 16 patients who responded to IVIG also responded to splenectomy. Subsequently, Bussel et al⁴ reported no correlation between IVIG response and response to splenectomy in a cohort of 26 pediatric patients. Our study provides additional evidence to suggest that response to IVIG is predictive of splenectomy response in children with ITP.

Problems remain in our ability to reach solid conclusions from this study. Typical of a retrospective study, drug dosing was variable. In some cases, length of follow-up was short. Nevertheless, this study supports previous work suggesting that IVIG response is predictive of response to splenectomy. Some IVIG nonresponders were splenectomy responders, and splenectomy still is a reasonable choice in an IVIG nonresponder who tends to bleed. A complicating diagnosis such as SLE or Evans syndrome should be sought in these patients. In conclusion, our data suggest that children who respond to IVIG will ultimately respond to splenectomy. A large, prospective study of the relationship between IVIG and splenectomy response in children would help to clarify this question.

	ACKNOWLEDGMENTS

 
This study was supported by grant HL-03962 and the LGC Winslow Research Fellowship from the National Childhood Cancer Foundation.

	FOOTNOTES

 
Received for publication Jan 4, 2002; Accepted May 9, 2002.

Reprint requests to (W.B.S.) University of Florida College of Medicine, UFHSC Box 100296, Gainesville, FL 32610. E-mail: slaytwb{at}peds.ufl.edu

	REFERENCES

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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics

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