85 yo wm with tongue angioedema Dec 2010; autoimmune labs WNL. Thought to be due to ACEI, which was discontinued. Asymptomatic until 4 episodes within the past month; 1st after eating peanuts, second after a pecan bar; doesn't recall circumstances of the third, and the most recent was unrelated to food. Seen today; sent off autoimmune and C1 esterase labs today. He insisted on being tested to nuts; PSTs negative at 20 min, with a 5mm wheal to histamine. Left the office and met his wife for coffee; returned 2 hours after his visit complaining of pruritus and wheals at the site of the PSTs. Flare was approx 3-4mm wider than the wheals; had a 1cm wheal to histamine; 7mm wheals to almond, Brazil nut, hazelnut and pecan; 5mm to cashew, 2mm to walnut. Coconut, pistachio and diluent control remained negative. This was clearly NOT the type of induration sometimes seen 24 hours after PSTs to molds. Any significance to the apparently delayed Type I response to nuts in an 85 year old gentleman with no previous reactions to any nuts? Thanks!


Thank you for your inquiry.

Your patient has developed what has been termed an “isolated late phase response” to allergy testing. This phenomenon was perhaps first described by Jerry Dolovich, and has been recognized for a number of years. However, unfortunately, the clinical significance of such responses is unknown. But I have not been able to find any instance where they have been documented to indicate clinical sensitivity to the allergen involved.

Below you will see three references on this topic. One is an isolated case report from Dr. Dolovich; the other is an investigation designed to determine the incidence and possible significance of the isolated late phase response in children; and the third is a quote taken from our Parameters on diagnostic testing.

The one common thread between these references is that, as noted above, the clinical significance of the isolated late phase response is unknown.

With these observations in mind, my personal opinion is that your patient has idiopathic angioedema and that the late phase responses you have noted are of no clinical significance. You could, if the patient wanted confirmation of this, order in vitro tests for specific IgE to the foods to which he showed a positive response. It is of course plausible that these late phase responses could be IgE-mediated (since the pathogenesis is unknown and there is such a thing as a late phase IgE-mediated response) which might confuse the issue, but more than likely the serum-specific IgE tests will be negative.

Thank you again for your inquiry and we hope this response is helpful to you.

J Allergy Clin Immunol. 1988 Oct;82(4):676-9.
Isolated late cutaneous skin test response to ampicillin: a distinct entity.
Dolovich J, Ruhno J, Sauder DN, Ahlstedt S, Hargreave FE.
Department of Pediatrics, McMaster University Medical Center, Hamilton, Ontario, Canada.
A case presentation describes a young woman with a history of two reactions to ampicillin therapy and a reproducible skin test reaction of intermediate timing that disappeared within 48 hours. The skin test response was to ampicillin only and not to other penicillin-related skin test reagents. Tests for serum IgE and IgG antibody to ampicillin were negative. The histology was that of a mononuclear and neutrophilic cellular infiltrate with neutrophil margination in the vessels. There was no immunoglobulin, complement, or fibrin deposition. The skin test reaction began and ended earlier than would be expected for a classic delayed hypersensitivity reaction. It is considered to be an isolated late cutaneous response but cannot yet be designated a late cutaneous allergic response. Reactants characteristic of an Arthus reaction were not present, and no alternative immunologic basis was confirmed.

Less frequently, the late-phase cutaneous response may occur in the absence of an immediate skin test response and may be confused with cell-mediated, delayed hypersensitivity.

Ann Allergy Asthma Immunol. 2000 Mar;84(3):294-8.
Isolated late cutaneous reactions to allergen skin testing in children.
Lierl MB.
Allergy/Immunology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Background: Occasionally parents report a reaction developing at the site of an allergen skin test several hours after application of the test, despite there having been no immediate reaction. The medical literature contains little information regarding isolated late reactions (ILRs) to allergen skin testing.
Objective: The goal of this project was to determine the incidence of ILRs in children undergoing allergen skin testing.
Methods: Prick and intradermal (ID) skin testing was performed for routine clinical indications in an allergy clinic. Children with a positive histamine control, and at least one negative immediate reaction to allergen skin testing were enrolled in the study. The parents were given detailed instructions to examine the skin test sites 6 hours later, and to record the size of any erythematous indurated sites. Circles of various diameters were included on the report form to assist the parents' size estimates.
Results:  Fifty-seven children enrolled in the study and 50 returned the forms. No patients reported ILRs to prick skin tests. Eighteen of the 50 respondents reported 40 ILRs to ID tests, of > or = 5 mm diameter; 7 of these were > or = 10 mm. The most common allergen causing ILR was cockroach, accounting for 20% of the ILRs. Each of the other allergens also caused ILRs. The clinical history did not show a definite correlation of symptoms with exposure to the allergens causing ILRs, although all 14 patients with ILRs to indoor allergens had year-round symptoms. There was no correlation between the incidence of ILRs and age, gender, or diagnosis of asthma.
Conclusion: ILRs to allergen skin testing occurred in 36% of pediatric allergy clinic patients. The clinical significance of such reactions is unknown.

Quote from Parameters:
“Isolated late cutaneous reactions were observed in approximately 36% of children undergoing skin tests for suspected allergies. Most of these isolated late-phase cutaneous responses were due to inhalant allergens, such as cockroach and various mold spores. The clinical significance of this is as yet unknown.”  SOURCE: Allergy diagnostic testing: an updated practice parameter (2008).

Phil Lieberman, M.D.

Close-up of pine tree branches in Winter Close-up of pine tree branches in Winter