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Corticosteroid-dependent idiopathic anaphylaxis: A report of five cases
Corticosteroid-dependent idiopathic anaphylaxis: A report of five cases Carol A. Wiggins, Chicugo,
MD, Mark S. Dykewicz,
MD, and Roy Patterson,
MD
Ill.
idiopathic anaphylaxis (IA) is a life-threatening disease that is being increasingly recognized. in patients with frequent episodes of anaphylaxis. prednisone controls the events and then either rnduces remission or suppresses the manifestations of the disease until a spontaneous remission occurs. We report jve patients with IA uaho have recurrent episodes whenever prednisone is tapered below a threshold dose, ranging from I5 to 65 mg every other day. These patients demonstrate the concept of a threshold dose oj’ prednisone that may exist in a subset of patients with IA, and they provide further evidence qf the previously reported .eficacy qf corticosteroids ,n the treatment of IA. We use the term corticosteroid-dependent IA to refer to the serious problem qf chronic IA requiring maintenance prednisone therap!. (J ALLERGYCLIN I~MWOI. 1989;84:3/1-15.)
Recurrent, unexplained. or IA is a phenomenon that is being recognized with increasing frequency.” ’ Events may be life threatening and lead to airway obstruction, cardiovascular collapse, and death. Although most patients have infrequent episodes, require no long-term treatment, and eventually go into spontaneous remission, other patients have frequently recurring episodes and are at higher risk.‘, ’ Our experience at Northwestern University has demonstrated that in patients with frequent episodes of IA, longterm pre’dnisone therapy controls IA by prevention of episodes of anaphylaxis.‘. 3,4 In most patients with frequent episodes of anaphylaxis, the prednisone may be gradually tapered and stopped without recurrent IA; these patients are considered to be in remission.’ The current series of IA at Northwestern University totals 143 patients. Most of these patients are controlled with cautiously decreasing doses of prednisone, had their prednisone tapered, and are in remission or have infrequent episodes of anaphylaxis for which long-term corticosteroid therapy is not indicated. However, we describe in this article the case From the Sectionof Allergy-Immunology, Departmentof Medicine, Northwestern University Medical School, Chicago, III. Supported >y the Ernest S. Bazley grant and National Institutes of Health Asthma and Allergic DiseasesCenter Grant AI 11403. Received for publication July IS, 1988. Revised March 1, 1989. Accepted i%r publication March 10, 1989. Reprint requests:Mark S. Dykewicz, MD, 303 E. Chicago Ave.. Chicago, IL 60611. l/1/13166
Abbreviations used IA: Idiopathic anaphylaxis
q.o.d.: Every other day t.i.d.:
Three times a day
I
1
histories of five patients who have recurrent episodes of anaphylaxis whenever prednisone is tapered below a threshold dose. PATIENTS AND CASE HISTORIES Patient evaluation All patients received an evaluation intended to exclude forms of anaphylaxis caused by identifiable precipitants (e.g., foods, physical factors, medications, and insect stings) or other differential considerations, such as carcinoid syndrome, systemic mastocytosis. or hereditary angioedema. No patients were receiving B-blockers. All patients had a history and physical examination performed by at least two Northwestern University physicians. A general laboratory evaluation of blood and urine and skin testing for inhalants (to define atopic status) and foods were also performed in all patients (Table 1). When this evaluation identified the possibility of a specific diagnosis other than IA, additional tests were performed (Table II). The patients, whose case histories follow. are summarized in Table III.
Case 1 A 35.year-old woman was referred for management after 2 years of recurrent anaphylaxis consisting of urticaria, laryngeal edema, and angioedema of the tongue, face, and feet. She had been treated with periodic injections of tri311
312 Wiggins et al. TABLE I. Tests performed during patient evaluation*
J. ALLERGY
on all patients
Skin testing Patient
No.
Aeroallergens
Foods
+ (PoWt + (peanut, pea, peach)? *General laboratory evaluation of blood and urine, complete blood count with differential, erythrocyte sedimentationrate, SMA-20, urinalysis, and complements (C3, C4, CH,); no significant abnormalities in any patient. tPatients were able to eat these foods without adversereaction.
amcinolone acetonide (Kenalog; E.R. Squibb, Princeton, NJ.), but episodes would recur several weeks after injections. After evaluation by our service failed to identify an etiology for her episodes, she was diagnosed as having IA. She began a regimen of prednisone, 30 mg daily, for 1 week and then 30 mg q.o.d., along with hydroxyzine, 25 mg, and ephedrine, 25 mg t.i.d. While she was receiving the above regimen, she developed recurrent laryngeal edema and eventually required as much as 50 mg of prednisone q.o.d. to suppress episodes of anaphylaxis. Cautious but repeated attempts to reduce her prednisone dosage were made during an &year period. Recurrent episodes of anaphylaxis consisting of urticaria, laryngeal edema, and angioedema of the face and extremities have occurred whenever her prednisone is tapered <35 mg q.o.d.
Case 2 A 33-year-old woman with a long history of asthma and allergic rhinitis was observed after 9 months of recurrent anaphylaxis. Life-threatening episodes were occurring monthly and consisted of u&aria and flushing along with stridor, wheezing, and dizziness. Snycope occurred on two occasions. Our evaluation failed to reveal any explanation for episodes other than IA. She was initially managed with prednisone, 40 mg per day for 1 week, followed by 40 mg q.o.d., along with hydroxyzine, 25 mg t.i.d. The following month she experienced an episode of anaphylaxis necessitating an increase in her prednisone dosage to 60 mg per day for 1 week, followed by 60 mg q.o.d. During the next few months, she did well and was free of episodes while her prednisone dosage was tapered to 35 mg q.o.d. One year after our evaluation, she moved to another state and was managed elsewhere. Six months later, she developed an inflammatory neuropathy resulting in paralysis for which she was treated with high-dose steroids. She had no episodes of anaphylaxis during the next 18 months while her prednisone was tapered to 15 mg q.o.d.
CLIN. IMMUNOL. SEPTEMBER 1989
Two years after our intial evaluation, she returned to our care, having several episodes of anaphylaxis per month while she was receiving 15 mg of prednisone q.o.d. Her prednisone was increased, and multiple subsequent attempts to taper to a lower dose during a l-year period have resulted in recurrent episodes of anaphylaxis whenever she receives <20 mg of prednisone q.o.d.
Case 3 A 29-year-old woman with a history of mild asthma was observed after a 7-month history of episodes of anaphylaxis recurring every 1 to 2 months and manifested by u&aria and angioedema, wheezing, and hypotension. She had previously been treated for episodes with rapidly tapering courses of prednisone, and episodes recurred shortly after prednisone was stopped. Evaluation by our service did not reveal any etiology for her episodes, and the diagnosis was made of IA. She was treated with prednisone, 40 mg per day, for 1 week, and then 60 mg q.o.d., and hydroxyzine, 25 mg t.i.d. Cautious repeated attempts to reduce her prednisone dosage during an IS-month period have led to six recurrent episodes of anaphylaxis whenever prednisone is tapered <45 mg q.o.d.
Case 4 A 74-year-old woman was observed after a lifethreatening episode of laryngeal edema complicated by a ventricular arrhythmia. She had a 40-year history of occasional episodes (three to four per year) of edema of the throat and tongue, and for 1 week before her most serious episode, she had been experiencing recurrent facial and perineal edema. Evaluation by our service failed to reveal any etiology for her episodes other than IA. She was treated with intravenous methylprednisolone and antihistamines for the acute episode, followed by prednisone, 40 mg daily, for 1 week, and then 40 mg q.o.d., and hydroxyzine, 10 mg t.i.d. Subsequent attempts to taper her prednisone during an 18-month period have led to three episodes of recurrent laryngeal edema whenever prednisone is tapered <15 mg q.o.d.
Case 5 A 33-year-old man with a long history of allergic rhinitis was observed after a 3-month history of weekly episodes of generalized pruritus, flushing, angioedema, stridor, abdominal pain, and diarrhea. Documented hypotension and loss of consciousness had occurred on two occasions. Evaluation failed to reveal any etiology for these episodes other than IA. He was treated with prednisone, 30 mg per day, for 1 week, and then 40 mg q.o.d., ephedrine, 25 mg t.i.d., and hydroxyzine, a total of 100 mgiday in divided doses. He continued to have episodes receiving this dosage and ultimately required as much as 60 mg of prednisone daily to prevent recurrent episodes. Cimetidine, 300 mg four times a day, was added, but he continued to have hypotensive episodes, even after the addition of the H, antihistamine. He was ultimately stabilized on dosage of 100 mg of pred-
VOLUME NUMBER
Corticosteroid-dependent
84 3
TABLE II. Tests performed -Patient
in individual
patients
for specific
(all normal
Considerations
History
No.
considerations
idiopathic anaphylaxis
313
results) --
Tests Performed
7. 5
Some episodes of flushing and/or GI symptoms
Carcinoid syndrome, 5) stcmic mastocykhli
5
Hypertension
Pheochromocytoma
2. 5
Several episodes within several hours after eating in restaurants
Metabisulfite sensitivity
Upper and lower GI serie\. urine 5-HIAA. chest w-.ray. hone scan, hone marrow biopsy. and (No. 5 only) upper endoscopy with smali bowel biopsy Urine VMA and metanephrines. abdominal CT scan Metabisultite challenge
GI. Gastrointestinal: VMA, vanillylmandelic acid; Cr, computed tomography.
TABLE 1111. Summary
Case IYo.
of cases of corticosteroid-dependent
Age 04
Sex
35 33 29 14 33
F F F F M
IA
Duration of episodes before treatment with prednisone
2 yr 9 mo 7 mo * 3 mo
Duration of control with prednisone
8 yr 4’/z yr 18 mo 18 mo 2 yr
Minimum dose of alternate-day prednisone (mg)
1s ‘0 1s I5 65
*This patient was managed with long-term treatment with prednisone after her first life-threatening episode of anaphylax!s
nisone daily. in addition to H, and Hz antihistamines and ephedrine. During the next 2 years, his prednisone was cautiously tapered; however, it was established that 65 mg q.o,d., was a threshold dose of prednisone, below which he would have recurrent episodes of anaphylaxis. This dosage of 65 mg q.o.d. has been maintained to prevent fatal IA.
DISCUSSION Recurrent IA is a life-threatening illness that constitutes a major risk for patients and is a serious man-
agement problem for their physicians. Although the etiology is unknown and no clear precipitants can be identified in patients with IA, a plan of management can be offered to prevent mortality and morbidity from episodes of anaphylaxis.3 In most patients with frequent episodes of IA, prednisone will either induce remission or suppress the manifestation of the disease until a spontaneous remission occurs. However, in the cases discussed in this article, although episodes are suppressed by prednisone, remission has not occurred,
and episodes recur whenever prednisone is tapered below a threshold dosage (Table III). We believe that these patients in particular demonstrate the usefulness of prednisone in IA. In a recent study of our series of 123 patients with IA, 5 1 patients presented with frequent episodes (more than six per year or two or more within a 2-month period). Of these 51 patients, 43 were available for follow-up and were treated with courses of prednisone in addition to continuous antihistamines; if oral adrenergic agents were tolerated,’ these agents were added. Of these 43 patients, 17 had their prednisone tapered and stopped, and 21 were receiving tapering dosage regimens without recurrent episodes. The remaining five patients, whose cases are summarized in this article, have recurrent episodes of anaphylaxis whenever prednisone is tapered below a threshold dosage ranging from 15 to 65 mg q .o.d. Compared to other patients with frequent episodes of IA,j the patients in this article have similar disease manifestations
314
Wiggins
et al.
and did not differ in their initial presentation. Similar to other patients with IA in our series,3 these five patients with corticosteroid-dependent IA are predominantly female (4/5 versus 69% of total series), and most patients had their first episode of IA between ages 20 to 40 years (4/5 versus 55% total series). These patients also have a high frequency of other allergic diseases and atopy (2/5 have allergic rhinitis versus 37% of total series; 2/5 have asthma versus 20% of total series; 2/5 had urticaria or angioedema before the onset of IA versus 46% of total series; 2/5 have positive immediate cutaneous reactivity to aeroallergens versus 54% of other patients with IA, and 2/5 have positive immediate cutaneous reactivity to foods versus 45% of other patients with IA tested). The dramatic effect of prednisone therapy on two patients with IA who do not have threshold prednisone doses has also been reported, demonstrating a marked reduction in the frequency of hospitalizations, emergency room visits, and anaphylactic episodes.4 Our experience at Northwestern University clearly demonstrates the efficacy of prednisone in the treatment of IA. Although the use of maintenance doses of prednisone, as described in these cases, may pose some risk of side effects, the alternative of a fatal episode of IA clearly justifies this therapy. Classically, anaphylaxis after antigen exposure in previously sensitized individuals is mediated by antigen-specific IgE that is cell bound to mast cells and basophils. On antigen exposure, cross-linking of cell-bound IgE causes activation of mast cells and basophils, resulting in release of histamine and numerous other mediators of inflammation, including chemotactic factors and arachidonic acid metabolites.5 The clinical manifestations of IgE-mediated anaphylaxis are the result of mediator-induced increased vascular permeability, vasodilation, smooth muscle contraction, and increased mucus secretion. It is well recognized that clinical manifestations observed in IgE-mediated anaphylaxis may occur in the absence of specific IgE antibody, as in the case of so-called anaphylactoid reactions triggered by aspirin and other nonsteroidal anti-inflammatory agents, opiates, exercise, and radiographic contrast media.6, ’ In IA, no specific trigger of episodes can be identified, although clinical manifestations are the same as anaphylaxis caused by identifiable triggers. Presumably, acute episodes of IA result from episodic release of histamine or other vasoactive substances from mast cells or basophils activated by unknown mechanisms.j Consequently, corticosteroid effects on cellular production and release of mediators may be relevant to the mechanism by which prednisone suppresses episodes of IA.
J. ALLERGY
CLIN. IMMUNOL. SEPTEMBER 1989
In animal studies, it is well established that corticosteroids inhibit the synthesis and release of prostaglandins in a variety of tissues, including rat lung and kidney homogenates”, 9 and rat peritoneal mast cells. ‘” Corticosteroids have also been demonstrated to inhibit IgE-mediated histamine release from isolated mouse mast cells. I’ Suppression of release of rat mast cell protease II into blood and intestinal secretions and depletion of mucosal mast cells from rat jejunum by glucocorticosteroids has also been well demonstrated. I2 In humans, corticosteroids have been demonstrated to suppress histamine release from basophils.‘3 The effects of corticosteroids on human mast cells are less clear. Corticosteroids fail to inhibit IgE-mediated release of mediators from human lung mast cells in vitro. I4 However, studies of mast cells in the human nasal mucosa have demonstrated reduction in the release of inflammatory mediators during the late, but not immediate, response after antigen challenge after systemic glucocorticosteroid treatment,15 and a decrease in mast cell histamine content after topical application of steroids during the birch-pollen season. I6 REFERENCES 1. Boxer MB, Greenberger PA, Patterson R. Clinical course and summary of idiopathic anaphylaxis in 73 patients. Arch Intern Med 1987;147:269. 2. Wolf B, Lieberman P. Retrospective review of 89 patients with anaphylaxis [Abstract]. J ALLERGYCLIN IMMUNOL1988; 81:238. 3. Wiggins CA, Dykewicz MS, Patterson R. Idiopathic anaphylaxis: classification, evaluation, and treatment of 123 patients. J ALLERGYC~nvIMMUNOL1988;82:849. 4. Boxer MB, Greenberger PA, Patterson R. The impact of prednisone in life-threatening idiopathic anaphylaxis: reduction in acute episodes and medical costs. Ann Allergy 1989;62:201. 5. Wasserman SI. Mediators of immediate hypersensitivity [CME article]. J ALLERGYCLIN IMMUNOL1983;72:101. 6. Kaliner MA. Anaphylaxis. NER Allergy Proc 1984;5:324. 7. Sheffer AL. Anaphylaxis [CME article]. J ALLERGYCLIN IM-
MUNOL1988;75:227. 8. Flower RJ, Blackwell GJ. Anti-inflammatory steroids induce biosynthesis of a phosphohpase A, inhibitor which prevents prostaglandin generation. Nature 1979;278:456. 9. Danon A, Assouline G. Inhibition of prostaglandin biosynthesis by corticosteroids requires RNA and protein synthesis. Nature 1978;273:552. 10. Heiman AS, Crews FT. Hydrocortisone selectively inhibits IgE-dependent arachidonic acid release from rat peritoneal mast cells. Prostaglandins 1984;27(3):335. 11. Da&on M, Sterk AR, Hirata F, Ishizaka T. Biochemical analysis of glucocorticosteroid-inhibition of IgE-mediated histamine release from mouse mast cells. J Immunol 1982;129(3):121. 12. King SJ, Miller HRP, Newlands GFJ, Woodbury RG. Depletion of mucosal mast cell protease by corticosteroids: effect on intestinal anaphylaxis in the rat. Proc Nat1 Acad Sci USA 1985;82:1214. 13. Schleimer RP, MacGlashan DW, Gillespie E, Lichtenstein LM.
VOLUME NUMBER
Corticosteroid-dependent
84 3
Inhibition of basophil histamine release by anti-inflammatory steroids in studies of the mechanism of action. J lmmunol 1982;129(41:1632. 14. Schleimer RP, Schulman ES, MacGlashan DW Jr. Peters SP.
Adams GK III, Lichtenstein LM, Adkinson NF. Effects on dcxamethasone on mediator release from human lung fragments and purified human lung mast cells. J Clin Invest 19x3:71:1830.
Bound volumes
available
idiopathic
anaphylaxis
315
15. Pipkom LJ. Proud D, Lichtenstein LM. Schleimcr RP. Peters SP, Adkinson NF. Kagey-Sobotka A. Norman PS. Naclerio RM. Effect of short-term systemic glucocorticosteroid treatment on human nasal mediator release after antigen challenge. J Clin Invest 1987;80:956. 16. Pipkorn I.!. Ennerbdck L. Nasal muco~ mast cells and histamine in hay fever: effect of topical glucocorticosteroid treatment. fnt Arch Allergy Appl Immunoi 1987:X4 i23
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Bound volumes of THEJOURNALOFALLEKGYANDCI.INICALIMMUNOLOGY are available to subscribers (only) for the 1989 issues from the Publisher, at a cost of $43.00 ($54.50 international) for Vol. 83 (January-June) and Vol. 84 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C.V. Mosby Co., Circulation Department, 11830 Westline Industrial Dr., St. Louis. MO 63146-3318: phone (800) 3254177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.
MD, Mark S. Dykewicz,
MD, and Roy Patterson,
MD
Ill.
idiopathic anaphylaxis (IA) is a life-threatening disease that is being increasingly recognized. in patients with frequent episodes of anaphylaxis. prednisone controls the events and then either rnduces remission or suppresses the manifestations of the disease until a spontaneous remission occurs. We report jve patients with IA uaho have recurrent episodes whenever prednisone is tapered below a threshold dose, ranging from I5 to 65 mg every other day. These patients demonstrate the concept of a threshold dose oj’ prednisone that may exist in a subset of patients with IA, and they provide further evidence qf the previously reported .eficacy qf corticosteroids ,n the treatment of IA. We use the term corticosteroid-dependent IA to refer to the serious problem qf chronic IA requiring maintenance prednisone therap!. (J ALLERGYCLIN I~MWOI. 1989;84:3/1-15.)
Recurrent, unexplained. or IA is a phenomenon that is being recognized with increasing frequency.” ’ Events may be life threatening and lead to airway obstruction, cardiovascular collapse, and death. Although most patients have infrequent episodes, require no long-term treatment, and eventually go into spontaneous remission, other patients have frequently recurring episodes and are at higher risk.‘, ’ Our experience at Northwestern University has demonstrated that in patients with frequent episodes of IA, longterm pre’dnisone therapy controls IA by prevention of episodes of anaphylaxis.‘. 3,4 In most patients with frequent episodes of anaphylaxis, the prednisone may be gradually tapered and stopped without recurrent IA; these patients are considered to be in remission.’ The current series of IA at Northwestern University totals 143 patients. Most of these patients are controlled with cautiously decreasing doses of prednisone, had their prednisone tapered, and are in remission or have infrequent episodes of anaphylaxis for which long-term corticosteroid therapy is not indicated. However, we describe in this article the case From the Sectionof Allergy-Immunology, Departmentof Medicine, Northwestern University Medical School, Chicago, III. Supported >y the Ernest S. Bazley grant and National Institutes of Health Asthma and Allergic DiseasesCenter Grant AI 11403. Received for publication July IS, 1988. Revised March 1, 1989. Accepted i%r publication March 10, 1989. Reprint requests:Mark S. Dykewicz, MD, 303 E. Chicago Ave.. Chicago, IL 60611. l/1/13166
Abbreviations used IA: Idiopathic anaphylaxis
q.o.d.: Every other day t.i.d.:
Three times a day
I
1
histories of five patients who have recurrent episodes of anaphylaxis whenever prednisone is tapered below a threshold dose. PATIENTS AND CASE HISTORIES Patient evaluation All patients received an evaluation intended to exclude forms of anaphylaxis caused by identifiable precipitants (e.g., foods, physical factors, medications, and insect stings) or other differential considerations, such as carcinoid syndrome, systemic mastocytosis. or hereditary angioedema. No patients were receiving B-blockers. All patients had a history and physical examination performed by at least two Northwestern University physicians. A general laboratory evaluation of blood and urine and skin testing for inhalants (to define atopic status) and foods were also performed in all patients (Table 1). When this evaluation identified the possibility of a specific diagnosis other than IA, additional tests were performed (Table II). The patients, whose case histories follow. are summarized in Table III.
Case 1 A 35.year-old woman was referred for management after 2 years of recurrent anaphylaxis consisting of urticaria, laryngeal edema, and angioedema of the tongue, face, and feet. She had been treated with periodic injections of tri311
312 Wiggins et al. TABLE I. Tests performed during patient evaluation*
J. ALLERGY
on all patients
Skin testing Patient
No.
Aeroallergens
Foods
+ (PoWt + (peanut, pea, peach)? *General laboratory evaluation of blood and urine, complete blood count with differential, erythrocyte sedimentationrate, SMA-20, urinalysis, and complements (C3, C4, CH,); no significant abnormalities in any patient. tPatients were able to eat these foods without adversereaction.
amcinolone acetonide (Kenalog; E.R. Squibb, Princeton, NJ.), but episodes would recur several weeks after injections. After evaluation by our service failed to identify an etiology for her episodes, she was diagnosed as having IA. She began a regimen of prednisone, 30 mg daily, for 1 week and then 30 mg q.o.d., along with hydroxyzine, 25 mg, and ephedrine, 25 mg t.i.d. While she was receiving the above regimen, she developed recurrent laryngeal edema and eventually required as much as 50 mg of prednisone q.o.d. to suppress episodes of anaphylaxis. Cautious but repeated attempts to reduce her prednisone dosage were made during an &year period. Recurrent episodes of anaphylaxis consisting of urticaria, laryngeal edema, and angioedema of the face and extremities have occurred whenever her prednisone is tapered <35 mg q.o.d.
Case 2 A 33-year-old woman with a long history of asthma and allergic rhinitis was observed after 9 months of recurrent anaphylaxis. Life-threatening episodes were occurring monthly and consisted of u&aria and flushing along with stridor, wheezing, and dizziness. Snycope occurred on two occasions. Our evaluation failed to reveal any explanation for episodes other than IA. She was initially managed with prednisone, 40 mg per day for 1 week, followed by 40 mg q.o.d., along with hydroxyzine, 25 mg t.i.d. The following month she experienced an episode of anaphylaxis necessitating an increase in her prednisone dosage to 60 mg per day for 1 week, followed by 60 mg q.o.d. During the next few months, she did well and was free of episodes while her prednisone dosage was tapered to 35 mg q.o.d. One year after our evaluation, she moved to another state and was managed elsewhere. Six months later, she developed an inflammatory neuropathy resulting in paralysis for which she was treated with high-dose steroids. She had no episodes of anaphylaxis during the next 18 months while her prednisone was tapered to 15 mg q.o.d.
CLIN. IMMUNOL. SEPTEMBER 1989
Two years after our intial evaluation, she returned to our care, having several episodes of anaphylaxis per month while she was receiving 15 mg of prednisone q.o.d. Her prednisone was increased, and multiple subsequent attempts to taper to a lower dose during a l-year period have resulted in recurrent episodes of anaphylaxis whenever she receives <20 mg of prednisone q.o.d.
Case 3 A 29-year-old woman with a history of mild asthma was observed after a 7-month history of episodes of anaphylaxis recurring every 1 to 2 months and manifested by u&aria and angioedema, wheezing, and hypotension. She had previously been treated for episodes with rapidly tapering courses of prednisone, and episodes recurred shortly after prednisone was stopped. Evaluation by our service did not reveal any etiology for her episodes, and the diagnosis was made of IA. She was treated with prednisone, 40 mg per day, for 1 week, and then 60 mg q.o.d., and hydroxyzine, 25 mg t.i.d. Cautious repeated attempts to reduce her prednisone dosage during an IS-month period have led to six recurrent episodes of anaphylaxis whenever prednisone is tapered <45 mg q.o.d.
Case 4 A 74-year-old woman was observed after a lifethreatening episode of laryngeal edema complicated by a ventricular arrhythmia. She had a 40-year history of occasional episodes (three to four per year) of edema of the throat and tongue, and for 1 week before her most serious episode, she had been experiencing recurrent facial and perineal edema. Evaluation by our service failed to reveal any etiology for her episodes other than IA. She was treated with intravenous methylprednisolone and antihistamines for the acute episode, followed by prednisone, 40 mg daily, for 1 week, and then 40 mg q.o.d., and hydroxyzine, 10 mg t.i.d. Subsequent attempts to taper her prednisone during an 18-month period have led to three episodes of recurrent laryngeal edema whenever prednisone is tapered <15 mg q.o.d.
Case 5 A 33-year-old man with a long history of allergic rhinitis was observed after a 3-month history of weekly episodes of generalized pruritus, flushing, angioedema, stridor, abdominal pain, and diarrhea. Documented hypotension and loss of consciousness had occurred on two occasions. Evaluation failed to reveal any etiology for these episodes other than IA. He was treated with prednisone, 30 mg per day, for 1 week, and then 40 mg q.o.d., ephedrine, 25 mg t.i.d., and hydroxyzine, a total of 100 mgiday in divided doses. He continued to have episodes receiving this dosage and ultimately required as much as 60 mg of prednisone daily to prevent recurrent episodes. Cimetidine, 300 mg four times a day, was added, but he continued to have hypotensive episodes, even after the addition of the H, antihistamine. He was ultimately stabilized on dosage of 100 mg of pred-
VOLUME NUMBER
Corticosteroid-dependent
84 3
TABLE II. Tests performed -Patient
in individual
patients
for specific
(all normal
Considerations
History
No.
considerations
idiopathic anaphylaxis
313
results) --
Tests Performed
7. 5
Some episodes of flushing and/or GI symptoms
Carcinoid syndrome, 5) stcmic mastocykhli
5
Hypertension
Pheochromocytoma
2. 5
Several episodes within several hours after eating in restaurants
Metabisulfite sensitivity
Upper and lower GI serie\. urine 5-HIAA. chest w-.ray. hone scan, hone marrow biopsy. and (No. 5 only) upper endoscopy with smali bowel biopsy Urine VMA and metanephrines. abdominal CT scan Metabisultite challenge
GI. Gastrointestinal: VMA, vanillylmandelic acid; Cr, computed tomography.
TABLE 1111. Summary
Case IYo.
of cases of corticosteroid-dependent
Age 04
Sex
35 33 29 14 33
F F F F M
IA
Duration of episodes before treatment with prednisone
2 yr 9 mo 7 mo * 3 mo
Duration of control with prednisone
8 yr 4’/z yr 18 mo 18 mo 2 yr
Minimum dose of alternate-day prednisone (mg)
1s ‘0 1s I5 65
*This patient was managed with long-term treatment with prednisone after her first life-threatening episode of anaphylax!s
nisone daily. in addition to H, and Hz antihistamines and ephedrine. During the next 2 years, his prednisone was cautiously tapered; however, it was established that 65 mg q.o,d., was a threshold dose of prednisone, below which he would have recurrent episodes of anaphylaxis. This dosage of 65 mg q.o.d. has been maintained to prevent fatal IA.
DISCUSSION Recurrent IA is a life-threatening illness that constitutes a major risk for patients and is a serious man-
agement problem for their physicians. Although the etiology is unknown and no clear precipitants can be identified in patients with IA, a plan of management can be offered to prevent mortality and morbidity from episodes of anaphylaxis.3 In most patients with frequent episodes of IA, prednisone will either induce remission or suppress the manifestation of the disease until a spontaneous remission occurs. However, in the cases discussed in this article, although episodes are suppressed by prednisone, remission has not occurred,
and episodes recur whenever prednisone is tapered below a threshold dosage (Table III). We believe that these patients in particular demonstrate the usefulness of prednisone in IA. In a recent study of our series of 123 patients with IA, 5 1 patients presented with frequent episodes (more than six per year or two or more within a 2-month period). Of these 51 patients, 43 were available for follow-up and were treated with courses of prednisone in addition to continuous antihistamines; if oral adrenergic agents were tolerated,’ these agents were added. Of these 43 patients, 17 had their prednisone tapered and stopped, and 21 were receiving tapering dosage regimens without recurrent episodes. The remaining five patients, whose cases are summarized in this article, have recurrent episodes of anaphylaxis whenever prednisone is tapered below a threshold dosage ranging from 15 to 65 mg q .o.d. Compared to other patients with frequent episodes of IA,j the patients in this article have similar disease manifestations
314
Wiggins
et al.
and did not differ in their initial presentation. Similar to other patients with IA in our series,3 these five patients with corticosteroid-dependent IA are predominantly female (4/5 versus 69% of total series), and most patients had their first episode of IA between ages 20 to 40 years (4/5 versus 55% total series). These patients also have a high frequency of other allergic diseases and atopy (2/5 have allergic rhinitis versus 37% of total series; 2/5 have asthma versus 20% of total series; 2/5 had urticaria or angioedema before the onset of IA versus 46% of total series; 2/5 have positive immediate cutaneous reactivity to aeroallergens versus 54% of other patients with IA, and 2/5 have positive immediate cutaneous reactivity to foods versus 45% of other patients with IA tested). The dramatic effect of prednisone therapy on two patients with IA who do not have threshold prednisone doses has also been reported, demonstrating a marked reduction in the frequency of hospitalizations, emergency room visits, and anaphylactic episodes.4 Our experience at Northwestern University clearly demonstrates the efficacy of prednisone in the treatment of IA. Although the use of maintenance doses of prednisone, as described in these cases, may pose some risk of side effects, the alternative of a fatal episode of IA clearly justifies this therapy. Classically, anaphylaxis after antigen exposure in previously sensitized individuals is mediated by antigen-specific IgE that is cell bound to mast cells and basophils. On antigen exposure, cross-linking of cell-bound IgE causes activation of mast cells and basophils, resulting in release of histamine and numerous other mediators of inflammation, including chemotactic factors and arachidonic acid metabolites.5 The clinical manifestations of IgE-mediated anaphylaxis are the result of mediator-induced increased vascular permeability, vasodilation, smooth muscle contraction, and increased mucus secretion. It is well recognized that clinical manifestations observed in IgE-mediated anaphylaxis may occur in the absence of specific IgE antibody, as in the case of so-called anaphylactoid reactions triggered by aspirin and other nonsteroidal anti-inflammatory agents, opiates, exercise, and radiographic contrast media.6, ’ In IA, no specific trigger of episodes can be identified, although clinical manifestations are the same as anaphylaxis caused by identifiable triggers. Presumably, acute episodes of IA result from episodic release of histamine or other vasoactive substances from mast cells or basophils activated by unknown mechanisms.j Consequently, corticosteroid effects on cellular production and release of mediators may be relevant to the mechanism by which prednisone suppresses episodes of IA.
J. ALLERGY
CLIN. IMMUNOL. SEPTEMBER 1989
In animal studies, it is well established that corticosteroids inhibit the synthesis and release of prostaglandins in a variety of tissues, including rat lung and kidney homogenates”, 9 and rat peritoneal mast cells. ‘” Corticosteroids have also been demonstrated to inhibit IgE-mediated histamine release from isolated mouse mast cells. I’ Suppression of release of rat mast cell protease II into blood and intestinal secretions and depletion of mucosal mast cells from rat jejunum by glucocorticosteroids has also been well demonstrated. I2 In humans, corticosteroids have been demonstrated to suppress histamine release from basophils.‘3 The effects of corticosteroids on human mast cells are less clear. Corticosteroids fail to inhibit IgE-mediated release of mediators from human lung mast cells in vitro. I4 However, studies of mast cells in the human nasal mucosa have demonstrated reduction in the release of inflammatory mediators during the late, but not immediate, response after antigen challenge after systemic glucocorticosteroid treatment,15 and a decrease in mast cell histamine content after topical application of steroids during the birch-pollen season. I6 REFERENCES 1. Boxer MB, Greenberger PA, Patterson R. Clinical course and summary of idiopathic anaphylaxis in 73 patients. Arch Intern Med 1987;147:269. 2. Wolf B, Lieberman P. Retrospective review of 89 patients with anaphylaxis [Abstract]. J ALLERGYCLIN IMMUNOL1988; 81:238. 3. Wiggins CA, Dykewicz MS, Patterson R. Idiopathic anaphylaxis: classification, evaluation, and treatment of 123 patients. J ALLERGYC~nvIMMUNOL1988;82:849. 4. Boxer MB, Greenberger PA, Patterson R. The impact of prednisone in life-threatening idiopathic anaphylaxis: reduction in acute episodes and medical costs. Ann Allergy 1989;62:201. 5. Wasserman SI. Mediators of immediate hypersensitivity [CME article]. J ALLERGYCLIN IMMUNOL1983;72:101. 6. Kaliner MA. Anaphylaxis. NER Allergy Proc 1984;5:324. 7. Sheffer AL. Anaphylaxis [CME article]. J ALLERGYCLIN IM-
MUNOL1988;75:227. 8. Flower RJ, Blackwell GJ. Anti-inflammatory steroids induce biosynthesis of a phosphohpase A, inhibitor which prevents prostaglandin generation. Nature 1979;278:456. 9. Danon A, Assouline G. Inhibition of prostaglandin biosynthesis by corticosteroids requires RNA and protein synthesis. Nature 1978;273:552. 10. Heiman AS, Crews FT. Hydrocortisone selectively inhibits IgE-dependent arachidonic acid release from rat peritoneal mast cells. Prostaglandins 1984;27(3):335. 11. Da&on M, Sterk AR, Hirata F, Ishizaka T. Biochemical analysis of glucocorticosteroid-inhibition of IgE-mediated histamine release from mouse mast cells. J Immunol 1982;129(3):121. 12. King SJ, Miller HRP, Newlands GFJ, Woodbury RG. Depletion of mucosal mast cell protease by corticosteroids: effect on intestinal anaphylaxis in the rat. Proc Nat1 Acad Sci USA 1985;82:1214. 13. Schleimer RP, MacGlashan DW, Gillespie E, Lichtenstein LM.
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Inhibition of basophil histamine release by anti-inflammatory steroids in studies of the mechanism of action. J lmmunol 1982;129(41:1632. 14. Schleimer RP, Schulman ES, MacGlashan DW Jr. Peters SP.
Adams GK III, Lichtenstein LM, Adkinson NF. Effects on dcxamethasone on mediator release from human lung fragments and purified human lung mast cells. J Clin Invest 19x3:71:1830.
Bound volumes
available
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anaphylaxis
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15. Pipkom LJ. Proud D, Lichtenstein LM. Schleimcr RP. Peters SP, Adkinson NF. Kagey-Sobotka A. Norman PS. Naclerio RM. Effect of short-term systemic glucocorticosteroid treatment on human nasal mediator release after antigen challenge. J Clin Invest 1987;80:956. 16. Pipkorn I.!. Ennerbdck L. Nasal muco~ mast cells and histamine in hay fever: effect of topical glucocorticosteroid treatment. fnt Arch Allergy Appl Immunoi 1987:X4 i23
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