Q:

8/15/2013
A 37yo woman with debilitating rhinitis during the Mt. Cedar, spring grass and fall mold season has receive SCIT three times in the past 20 years. The last time she developed joint pain and swelling and SCIT was discontinued early in the course. Because of the severity of her symptoms, she wanted to try it again. Epicutaneous skin testing showed reactions about equal to the histamine control, 9mm, HSA saline 0mm, for several relevant allergens and smaller reactions to a few other pollens and molds and to dust mites. I formulated a pollen extract and a dust mite/mold extract and initiated treatment using a Rush protocol. She tolerated Rush without a reaction but, over the next few days, had a severe migraine that she feels was triggered by intensely painful occipital lymph node swelling. She was unable to function until she received a course of high dose steroids. She developed pain in the small joints of her hands and swelling of the PIP joints of both thumbs.

I believe this was an IgG mediated reaction. Would it be reasonable to measure IgG antibodies to the antigens in her extract and reformulate the extract excluding the antigens that test positive for IgG antibody? I have never ordered IgG testing of aeroallergens. Do you have any other suggestion on how to help this patient?

A:

Thank you for your inquiry.

The issue that your patient presents is one which we have dealt with previously on our website, namely whether or not immunotherapy can produce an immune complex/vasculitic reaction. For your convenience, I have copied below our response to a similar inquiry which presents the results of a literature search to discern the potential relationship between vasculitis and allergen immunotherapy.

As you can see from our reply to this previous inquiry, there are reports in the literature of vasculitic reactions attributed to allergen immunotherapy. They are rare, and attribution of cause and effect can always be questioned in such anecdotal reports, but they do give some credence to the fact that serum sickness-like illnesses can occur during allergy injection treatment.

Your patient’s history is certainly suggestive of a serum sickness-like reaction in terms of the joint involvement and perhaps the lymph node swelling as well. However, there are other features which mitigate against such a reaction; namely, you did not mention that she had any local reactions during the treatment, and lymph node swelling would normally be expected to occur at the lymph node sites draining the injection area (axillary lymph nodes). Nonetheless, the chronological relationship between her symptoms and the administration of the vaccine, and the previous history of joint pain after her latest course, all are suggestive of an immune complex-like reaction to treatment. The question then becomes, how does one verify this diagnosis.

Your suggestion of obtaining IgG anti-aeroallergen is reasonable, but it would be very unusual for her not to have IgG against the treatment antigens since exposure itself should produce the classical immune response to immunotherapy with production of IgG “blocking antibody.” If she did not have that antibody, it would be highly unusual, and its presence would not in any way tell you that this antibody was operative in the production of her disease. Finding antibody alone would be much like finding a positive skin test. It simply implies exposure, but does not necessarily indicate a cause and effect relationship between the symptoms and the presence of the antibody.

I think it would be much more productive, especially if results were negative, to look for more classic findings of the presence of an immune serum sickness-like reaction including tests such as: CH50 and C3, sed rate, rheumatoid factor; and perhaps even a test for immune complexes.

It would be helpful of course if I was incorrect and you did find that some, but not all, of the aeroallergens with which you treated had stimulated an IgG production. But, I think that would be highly unlikely, in view of the fact that, as noted, such IgG responses occur routinely during immunotherapy.

In summary, serum sickness-like responses to immunotherapy are extremely rare, but there are reports in the literature of such reactions. Therefore, even though a cause and effect relationship between her present symptoms and her immunotherapy may not exist, there is enough evidence in the literature to make it impossible to deny such a relationship.

In my opinion, the best way to evaluate her at this point in time would be to perform a classical immune complex/autoimmune/vasculitic workup. I do not think that ordering IgG anti-aeroallergens would be helpful because of the reasons noted above, but provided these tests were accurate, the lack of such response might be useful in ruling out the possibility that an immune complex reaction occurred because of the immunotherapy. Other than for that, finding the antibodies present would offer very little since they would simply indicate exposure and not establish a cause and effect relationship between these antibodies and her symptoms.

Based upon the history, the only therapy that would be effective is steroids, and I would “treat to need” acutely, but if symptoms persist, I think it would even further prompt the need for an “immunologic evaluation.”

The last question to be answered is whether or not a further attempt at immunotherapy could be considered. There is no definitive answer to that, but since has had two such reactions, I would probably not proceed any further with an attempt to control her symptoms with allergy injections. The only exception to this would be, as noted, if you did find a lack of an IgG response to a clinically pertinent allergen which has been responsible for her symptoms. I think you could then assume that the reaction was not IgG-mediated. This would imply, however, that these tests were highly sensitive and that a “false-negative” did not occur.

Thank you again for your inquiry and we hope this response is helpful to you. Also, if you have any further questions, we would be happy to try to expand this response as well.

Allergen immunotherapy as a potential cause of vasculitis
Question posted on 6/6/2013:
65 year-old women reaching maintenance on immunotherapy developed a localized vasculitic rash treated by dermatology with steroids. She was also on Singular and Flonase. Both drugs were discontinued and the rash resolved with steroid treatment. She is only taking Flonase at this time. No other medical conditions are present at this time. Are the experts aware of Immunotherapy causing vasculitis?

Response:
Thank you for your inquiry.

Yes, vasculitis has rarely been attribted to immunotherapy. There have been a smattering of case reports of vasculitis occurring during allergen immunotherapy (see references and abstracts below). Because of this, and for other reasons, there have been systematic searches for the presence of immune complexes (presumably the mechanism underlying the vasculitides reported) occurring during immunotherapy. The results of these efforts have been variable, and at times contradictory (see abstracts and references below).

There is no consensus on this topic expressed in our most recent Allergen Immunotherapy Parameters by Cox, et al., but there is a reference to the use of immunotherapy in patients with “autoimmune diseases.” This of course indirectly speaks to your question. I have copied below the quote from the Immunotherapy Parameters.

If one takes all of these sources, no definitive conclusion can be drawn as to whether or not there is a documented cause and effect relationship between allergen immunotherapy and the induction of vasculitis. If there is a cause and effect relationship, the incidence must be extremely rare, but based on these case reports, one cannot completely rule out immunotherapy as a potential cause for vasculitis. But, based upon the rarity of these events, the inability to consistently detect the presence of immune complexes during immunotherapy, and the expected relative frequency of these two entities occurring together by chance, it is my opinion that it is more likely that coincidence rather than cause and effect has accounted for the majority of these reports. If indeed there is a cause and effect relationship, however, as noted, the occurrence of vasculitis due to immunotherapy is extremely rare.

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

Allergol Immunopathol (Madr). 2005 Nov-Dec;33(6):333-4.
Vasculitis during immunotherapy treatment in a patient with allergy to Cupressus arizonica.
Sánchez-Morillas L, Reaño Martos M, Iglesias Cadarso A, Pérez Pimiento A, Rodríguez Mosquera M, Domínguez Lázaro AR.
Source
Allergology Department, Clínica Puerta de Hierro, Madrid, Spain.
Abstract
Allergen immunotherapy dates back to 1911 and has been used successfully to treat large numbers of patients throughout the last century.
Case Report: a 66 year-old woman presented with symptoms of allergic rhinitis and asthma due to sensitization to Cupressus arizonica. Specific immunotherapy was prescribed as a continuous 2-year treatment with a depot preparation of standarized and characterized allergen extracts of Cupressus arizonica pollen. Forty-eight hours after one maintenance dose of 0.8 cc, the patient presented palpable violaceous purpuric lesions and pruritus on both legs. We performed skin prick and intradermal tests with Cupressus arizonica. Twenty-four hours later, the 1/1 dilution intradermal skin test was positive. Biopsy showed leukocytoclastic vasculitis.
Conclusions: A middle-aged woman experienced cutaneous non-necrotizing vasculitis after 2 years of maintenance immunotherapy. The interval between injections and the first appearance of cutaneous lesions suggests a type III hypersensitivity immune reaction. Skin biopsy of the positive intradermal test also supports this hypothesis.

Allergy. 1998 Jan;53(1):102-3.
Distal digital vasculitis induced by specific immunotherapy.
Branco-Ferreira M, Clode MH, Palma-Carlos AG.
Source
Immunoallergology Unit, Hospital de Santa Maria, Lisbon, Portugal.

J Rheumatol. 1993 Nov;20(11):1970-2.
Digital vasculitis following allergic desensitization treatment.
Cabrera GE, Citera G, Gutiérrez M, Scopelitis E, Espinoza LR.
Source
Department of Medicine, Louisiana State University School of Medicine, New Orleans.
Abstract
Systemic necrotizing vasculitis or a polyarteritis nodosa-like clinical presentation, is an unusual complication of immunotherapy (hyposensitization therapy). We describe a patient who developed features of vasculitis several years after beginning hyposensitization treatment for allergic rhinitis. In the 7 months preceding the onset of the vasculitis he experienced 4 episodes of anaphylaxis immediately after receiving desensitization injections. The vasculitis was characterized by the abrupt onset of pain and discoloration of the middle 3 digits of his right hand. Cyanosis and small areas of frank necrosis of these digits were present. Erythrocyte sedimentation rate and C-reactive protein were elevated and total serum complement was decreased. The development of digital vasculitis following hyposensitization is clearly illustrated in this patient.

Am J Med. 1980 Apr;68(4):479-85.
Onset of polyarteritis nodosa during allergic hyposensitization treatment.
Phanuphak P, Kohler PF.
Abstract
In six of 20 consecutive patients with polyarteritis nodosa, the onset of vasculitic symptoms coincided with hyposensitization therapy for presumptive atopic (immunoglobulin E-mediated) respiratory disease. Atopic symptoms had been present for less than three months in half of the patients and over 10 years in the remainder. Active vasculitis persisted in all patients despite immediate cessation of the hyposensitization treatment. Three patients died within eight months. When compared with the 14 other patients with polyarteritis nodosa, those undergoing hyposensitization had significantly greater skin involvement and peripheral blood eosinophilia (p = less than 0.05). Evidence for circulating immune complexes with decreased hemolytic complement, increased cryoglobulins or increased Clq binding was present in both groups. No single allergen was used in all patients, no antiallergen precipitating antibodies were detected and less than 16 mg of allerginic protein had been injected in five of the patients.

"Although concern about the safety of allergen immunotherapy in patients with autoimmune disorders has been raised in the past, there is no substantive evidence that such treatment is harmful in patients with these diseases. Therefore the benefits and risks of allergen immunotherapy in patients with HIV infection, other immunodeficiencies, or autoimmune disorders must be assessed on an individual basis"

SOURCE: COX L et al Allergen immunotherapy: A practice parameter third update The Journal of Allergy and Clinical Immunology, Volume 127, Issue 1, Supplement , Pages S1-S55, January 2011.

Asian Pac J Allergy Immunol. 1989 Jun;7(1):15-21.
A preliminary study of circulating immune complexes during allergen immunotherapy in Thai patients.
Bunnag C, Dhorranintra B.
Source
Department of Otolaryngology Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Abstract
Circulating immune complexes are suspected as a potentially serious adverse effect after prolonged allergen immunotherapy. This study was undertaken to determine whether there were any significant immunological differences between 32 subjects with allergic rhinitis/asthma treated with immunotherapy of various durations and 13 subjects with similar diagnosis who had never been treated by immunotherapy. All patients were carefully examined for symptoms and signs of immune-complex diseases with negative results. The presence of circulating immune complexes was evaluated by the modified 125I-C1q binding test, the solid phase conglutinin (K) binding test and determination of C3, C4 and C3d levels. In addition, urinalysis, and quantitative determination of serum IgG, IgA, IgM and IgE were also performed. The overall results suggested that prolonged allergen immunotherapy did not result in an increase of circulating immune complexes or other adverse immunological consequences.

Allergy. 1989 Feb;44(2):123-31.
Circulating immune complexes during immunotherapy in allergy to dog.
Valovirta E, Viander M, Koivikko A, Vanto T, Lindström P, Wager O, Pekkola-Heino K, Ingeman L, Kekomäki R.
Source
Department of Pediatrics, University of Turku, Finland.
Abstract
Circulating immune complexes (CIC) were determined from dog-allergic asthmatic children (n = 35) receiving immunotherapy with dog dander and hair extract. The results from CIC are expressed in SDU (standard deviation units) and presented as follows: pretreatment results (n = 20), rush results (n = 11), mid-schedule results (n = 20), maintenance results (n = 15) and the results of the placebo-treated group (n = 12). The results of the placebo-treated group (n = 12) and those of the untreated atopic (n = 12) and non-atopic (n = 14) were controls. CIC levels were analysed by means of KgB-ELISA (conglutinin binding enzyme linked immunosorbent assay), C1qB-ELISA (C1q-binding enzyme linked immunososrbent assay), RFb-ELISA (rheumatoid factor binding enzyme linked immunosorbent assay) and by PIPA (platelet 125J-labelled staphylococcal protein-A test). The CIC level determined by KgB-ELISA in dog-allergic asthmatic children was higher than that of the atopic controls (P less than 0.05) already before the onset of the hyposensitization. During conventional hyposensitization with dog dander and hair the CIC level remained the same as before treatment. On day 5 of rush hyposensitization the mean level of CIC showed no increase when compared with the pretreatment values. A statistically significant correlation (P less than 0.01) was observed between the dog dander and hair-specific IgG antibodies and the CIC level measured by KgB-ELISA during the maintenance period of conventional immunotherapy. The samples of sera to measure this correlation were collected before the injection of allergen and after 2 weeks of injection during maintenance treatment.

Wiad Lek. 2004;57(3-4):123-30.
[Allergen specific-IgG4 in circulating immune complexes in patients with inhalant allergy undergoing specific immunotherapy].
[Article in Polish]
Rogala B, Jarzab J, Rymarczyk B, Tłuczykont B.
Source
Z Katedry i Kliniki Chorób Wewnetrznych, Alergologii i Immunologii Klinicznej w Zabrzu Slaskiej Akademii Medycznej w Katowicach.
Abstract
The mechanism of action of specific immunotherapy (SIT) is still not definitely clear. The problem of the presence of allergen specific-IgG4 in circulating immune complexes (CIC) of patients with inhalant allergy is being discussed. The aim of the study was to determine the allergen specific-IgG4 serum levels and concentration in CIC in patients with inhalant allergy who underwent specific immunotherapy with relevance to its clinical benefits. The trial was carried out on 57 patients with seasonal allergic rhinitis (SAR) and 55 with perennial allergic rhinitis (PAR). Each of them underwent 3-year specific immunotherapy with Allergovit (Nexter-Allergopharma) or Novo Helisen Depot (Nexter-Allergopharma). 56 patients with pharmacologically treated allergic rhinitis served as a control group. Serum levels of allergen specific-IgG4 (as-IgG4), IgE, as-IgE and as-IgG4 concentration in CIC were measured in each patient and correlated with the clinical score of the disease activity. Nonparametric tests (the U Mann-Whitney test, Kruskall-Wallis test and Spearman's correlation rang test) were used. Serum levels of as-IgG4 and bound in CIC were statistically higher in the SIT group than in the control group and differed significantly between SAR and PAR groups. Immunotherapy caused significantly higher concentrations of as-IgG4 in CIC in PAR group than in SAR patients. No significant associations were found between studied immunological indices and clinical effects of SIT. Specific immunotherapy of allergic rhinitis is connected with the increase of as-IgG4 serum level and its concentration in circulating immune complexes.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology