PEDIATRICS Vol. 102 No. 1 July 1998, p. e13

ELECTRONIC ARTICLE:
Desensitization to Pancreatic Enzyme Intolerance in a Child With Cystic Fibrosis

Latha M. Chamarthy^*, L. Julio Reinstein, Bruce Schnapf^§, Robert A. Good^*, and Sami L. Bahna^*

From the Divisions of ^* Allergy/Immunology,  Gastroenterology/Nutrition, and ^§ Pulmonary Medicine, Department of Pediatrics, University of South Florida, Tampa, Florida, and ^*  All Children's Hospital, St Petersburg, Florida.

	ABSTRACT

Top Abstract Introduction Materials & Methods Discussion Conclusion References

Objective.  Pancreatic enzyme is essential in the treatment of cystic fibrosis (CF), but intolerance to it occasionally occurs. We encountered a child who was intolerant to multiple commercially available preparations of pancreatic enzymes and, hence, desensitization was attempted, with success.

Case Presentation.  A 33-month-old girl was diagnosed with CF at 6 months of age. Initially, she was started on Pancrease MT 16, which was subsequently discontinued because fecal fat studies were normal and she seemed to do well on Nutramigen and vitamin supplements. At 29 months of age, she developed diarrhea with bulky stools and weight loss. A fecal fat 72-hour study revealed a coefficient of absorption of 50%. She was treated with Pancrease MT 16, but had consistent vomiting 1 to 2 hours after administration of enzymes. The vomiting occurred on switching to different pancreatic enzymes preparations, ie, Creon 10, Viokase, and Pancrease MT 16. Vomiting occurred even with small doses of enzymes disguised in food. She had no history suggestive of gastroesophageal reflux, peptic ulcer, or pork allergy, and no vomiting on days when enzymes were not given. This was suggestive of type I hypersensitivity reaction. Pancreatic enzymes were discontinued, and she was given a low-fat, high-carbohydrate diet with satisfactory weight gain.

Methods.  Double-blind, placebo-controlled titrated oral challenges with pancreatic enzymes resulted in definite vomiting within 1 to 1.5 hours after challenges with Viokase and Pancrease MT 16, but not with placebo. Rush oral desensitization with Viokase solution was attempted, starting with 5 mg, and the dose was doubled every 20 minutes, aiming to reach a cumulative dose of 700 mg. However, the child vomited when a cumulative dose of 315 mg was reached. Another trial of slower desensitization was done using Pancrease MT 16 (1 capsule: 16 000 U of lipase, 48 000 U of amylase, and 48 000 U of protease), starting with 1/4 capsule per day, with increments of 1/4 capsule every 3 days, until an entire capsule was reached by day 10, then increased by ~1/2 capsule every 4 days until reaching the therapeutic dose of 1 capsule with each meal by day 25.

Results.  The patient tolerated this fairly well and has been on this treatment and regular diet for >1 year, without any adverse reaction. This illustrates a rare case of gastrointestinal adverse reaction to pancreatic enzymes that was treated successfully with desensitization.

Conclusion.  Pancreatic enzyme intolerance, although rare, would be a major problem in the management of patients with CF. Hence, desensitization would be essential and may be accomplished successfully using the protocol described in this report.

	INTRODUCTION

Top Abstract Introduction Materials & Methods Discussion Conclusion References

Pancreatic enzyme replacement is the basis of treatment for cystic fibrosis (CF). Although they are foreign proteins, pancreatic enzyme preparations seem to cause adverse reactions only rarely and are usually limited to one preparation. We encountered a child who was intolerant to multiple commercially available preparations of pancreatic enzymes and, hence, desensitization was attempted, with success.

	MATERIAL AND METHODS

Top Abstract Introduction Materials & Methods Discussion Conclusion References

Case Report

A 33-month-old girl was diagnosed with CF at 6 months of age. Initial evaluation revealed a sweat chloride of 130 mEq/L, a gene mutation study heterozygous for Delta F508, and low serum albumin and vitamin E levels. She initially was treated with Pancrease MT 16, awaiting the result of a 72-hour fecal fat study. The latter showed a coefficient of absorption of 96% and, therefore, Pancrease MT 16 was subsequently discontinued after a 1-week duration. She was given a casein hydrolysate formula (Nutramigen, Mead Johnson Nutritionals, Evansville, IN) and vitamin supplements with good weight gain.

At 29 months of age, the patient presented with failure to thrive and had five to six stools per day, which were bulky and malodorous. A 72-hour fecal fat study revealed a coefficient of absorption of ~50%, which prompted resumption of pancreatic enzymes. Ultrase (Scandipharm, Birmingham, AL) was first tried, but the child vomited consistently 1 to 2 hours after administration of the enzymes. The same reaction occurred on switching to three other preparations: Creon 10 (Solvay Pharmaceuticals, Marietta, GA); Viokase (Robins Co, Richmond, VA); and Pancrease MT 16 (McNeil Pharmaceutical, Raritan, NJ). No vomiting occurred on the days when enzymes were not administered or with the oral intake of other medications. Vomiting occurred even when small doses of enzymes were disguised in food. An empiric trial of metoclopramide and aluminum hydroxide/magnesium hydroxide suspension (Maalox, Ciba Self-Medication, Woodbridge, NJ) did not reduce the vomiting. There was no history of symptoms suggestive of gastroesophageal reflux, peptic ulcer, or allergy to pork (the source of such pancreatic enzymes). Because of the vomiting, pancreatic enzymes were discontinued, and the patient was given a low-fat, high-carbohydrate diet with satisfactory weight gain. An allergy/immunology consultation was then requested.

Verification of Pancreatic Enzyme Intolerance

To verify the existence of pancreatic enzyme intolerance, double-blind, placebo-controlled titrated oral challenge tests were conducted with two pancreatic enzyme preparations.¹ Informed consent was obtained from the mother. One challenge was carried out per clinic visit. The nature of the challenge substance was hidden from the child, mother, and observers in the clinic until all challenges were completed. Definite vomiting occurred within 60 to 90 minutes after challenges with Pancrease MT 16 and Viokase, but not with the placebo. Because of the necessity of daily enzyme therapy, a special protocol for oral desensitization was designed.

Desensitization With Pancreatic Enzyme

An initial attempt of desensitization was patterned after protocols published previously for rapid drug desensitization.^2,3 The mother gave informed consent for the procedure. Viokase solution (10 mg/mL, ~230 U of lipase per milliliter) was prepared. The starting dose was 5 mg with doubling every 20 minutes, aiming to reach a total cumulative dose of 700 mg. The patient tolerated a cumulative dose of 315 mg (7200 units). When the next dose was administered, severe vomiting occurred that required treatment with promethazine suppositories.

When rapid desensitization could not be completed, a slower desensitization procedure was performed, a modification that often is done in drug desensitization.^2,3 An arbitrary protocol was designed (Table 1), using Pancrease MT 16. The mother was instructed on how to administer the enzyme mixed with food. The starting dose was 1/4 capsule (4000 U), and the therapeutic dose was attained in 25 days without any adverse reaction. The child has continued to do well and has been without vomiting on a regular diet with the intake of one capsule three times daily for >1 year.

	DISCUSSION

Top Abstract Introduction Materials & Methods Discussion Conclusion References

This patient illustrates a rare instance of well-documented intolerance to multiple preparations of pancreatic enzymes. To the best of our knowledge, no similar case has been reported. The fact that vomiting occurred regardless of the brand or form of enzyme suggests that the enzymes indeed were responsible. Because those pancreatic enzymes were from porcine origin, pork allergy could be a possibility. However, this patient was eating pork meat frequently without any adverse reactions. Because vomiting always occurred within 1 to 2 hours after ingestion of the enzymes, type I hypersensitivity reaction mediated by IgE seemed to be most likely. However, we could not confirm this because of the unavailability of standardized material for skin testing or for measuring specific IgE antibodies in the serum. Repeated attempts to bring the child back for skin testing with pancreatic enzyme preparations failed.

Because the type of hypersensitivity reaction in this patient could not be determined, we can only postulate on the mechanism(s) of the induced tolerance. In IgE-mediated reactions, it is believed that desensitization results from gradual binding of the specific antibodies to the antigen introduced and subsequent removal and degradation by the reticuloendothelial system. After desensitization, subsequent regular administration of the antigen seems to induce protective (blocking) IgG antibodies rather than IgE antibodies.⁴ However, if the antigen is discontinued for more than a few days, sensitization often recurs. In case of T cell-dependent antigens, oral tolerance can be induced via mucous membranes and results in limiting the immune reactivity to a subclinical level.⁵ It is not clear whether such tolerance is a result of deletion of sensitized T cells, induction of anergy, or generation of specific T suppressor cells.^6,7

	CONCLUSION

Top Abstract Introduction Materials & Methods Discussion Conclusion References

Pancreatic enzyme intolerance, although rare, would be a major problem in the management of patients with CF. Hence, desensitization would be essential and may be accomplished successfully using the protocol described in this report.

	FOOTNOTES

Received for publication Jan 5, 1998; accepted Mar 13, 1998.

This work was presented in part at the Annual Meeting of the American College of Allergy, Asthma and Immunology, November 7-12, 1997, San Diego, CA.

Reprint requests to (S.L.B.) Division of Allergy/Immunology, All Children's Hospital, 801 Sixth St S, Box 6990, St Petersburg, FL 33701.

	ABBREVIATIONS

CF, cystic fibrosis.

	REFERENCES

Top Abstract Introduction Materials & Methods Discussion Conclusion References

1. Bahna SL Food challenge procedures in research and in clinical practice. Pediatr Allergy Immunol. 1995; 6(suppl 8):49-53 [Medline]
2. Moreno JN, Poblete RB, Maggio C, Gagnon S, Fischl MA Rapid oral desensitization for sulfonamides in patients with acquired immunodeficiency syndrome. Ann Allergy Asthma Immunol 1995; 74:140-146 [Medline]
3. Patterson R, DeSwarte RD. Drug Allergy and Protocols for Management of Drug Allergies. 2nd ed. Providence, RI: Oceanside Publications; 1995
4. Sullivan TJ Antigen-specific desensitization of patients allergic to penicillin. J Allergy Clin Immunol. 1982; 69:500-509 [Medline]
5. Husby S, Mestecky J, Moldoveanu Z, Holland S, Elson CO Oral tolerance in humans, T-cell but not B-cell tolerance after antigen feeding. J Immunol. 1994; 152:4663-4674 [Abstract]
6. Hanson LÅ, Lundin S, Karlsson M, Dahlmen-Höglund A, Dahlgren U, Telemo E. Regulation of the immune response to oral administration of antigens in food allergic experimental animals. Nutr Res. 1998. In press
7. Weiner HL Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today. 1997; 18:335-343 [Medline]