Sublingual immunotherapy for allergy to crustaceans: the nine-year clinical experience of a Midwest Allergy-Immunology practice.

doi:10.21203/rs.3.rs-3238203/v1

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Research Article

Sublingual immunotherapy for allergy to crustaceans: the nine-year clinical experience of a Midwest Allergy-Immunology practice.

https://doi.org/10.21203/rs.3.rs-3238203/v1

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published 11 May, 2024

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Background

Diet restrictions and fear of adverse reactions put a significant burden on the nutrition, growth and life styles of children and adults with food allergies. Desensitization to crustaceans by means of sublingual immunotherapy was assessed for efficacy and safety with a view of validating it as a disease-modifying modality. Allergy to crustaceans was chosen as a working model because of its well-defined immunological and clinical features.

Methods

Results

Sixty-six patients were identified who had been treated by sublingual immunotherapy for either systemic or localized reactions to crustaceans. Demographics and relevant comorbidities were consistent with those of the atopic population. Sublingual immunotherapy with serially diluted mixtures was initiated at 6.4 - 160 ng/dose and was gradually escalated over a period of 5 – 48 months to 0.5 mg/dose three times a day. The sublingual immunotherapy course ranged from 5 to 72 months (average: 51 months), following which, eighteen patients underwent shrimp oral challenge. No systemic reactions occurred upon challenge; no patient required epinephrine. Tolerance of target dose equal to or exceeding 42 g shrimp was achieved in 11 patients (61%), seven of whom had originally presented with systemic reactions to crustaceans. Seven patients (38%) developed one or more of the following localized reactions: oral itching, nasal symptoms, localized perioral hives, localized hives at pressure points, nausea, vomiting, abdominal pain upon exposure to a cumulative dose of 39.2-148.2 g of shrimp during the 4 hours of the challenge. Five of these patients had originally presented with systemic reactions to crustaceans. Five of the 7 patients who developed localized symptoms during the challenge were subsequently placed on routine exposure to 12-20 g shrimp every other day. Two patients continued sublingual immunotherapy but declined routine exposure to shrimp every other day because they had no intention to incorporate crustaceans to their routine diet. On repeat challenge 6-9 months after original challenge, all five patients who had routine exposure to 12-20 g shrimp every other day tolerated the procedure to target dose without any symptoms.

Conclusions

Desensitization to crustaceans by sublingual immunotherapy appears to be safe and effective. Whether the immune modification induced by sublingual immunotherapy is permanent resulting in sustained tolerance, or the achieved degree of desensitization depends on regular exposure is not known; therefore, following challenge, regular consumption three-four times per week was recommended.

IgE-mediated food allergies affect 4–10% of children and 2–3% of adults.¹ After early childhood, permanent IgE-mediated food allergies are unlikely to spontaneously resolve, and their systemic manifestations upon exposure lead to life-threatening events. Food allergies of systemic nature become a cause of anxiety for patients and their family affecting all aspects of their lives that pertain to food consumption.² Regarding shellfish, and shrimp in particular, anxiety is further heightened by the common catering practice to include shrimps as hors d’oeuvres and appetizers in social events where food is served, thus increasing the risk for contamination of all other foods offered. Furthermore, shrimp, a food with no carbohydrates and no unsaturated fats is a preferred source of protein in most health-conscious diets.

There is no treatment that would eradicate a permanent allergy, and guidelines focus on prevention and management of accidental exposures with epinephrine, antihistamines, steroids, and other means to control systemic manifestations of acute mast cell activation and degranulation.² The clinical and pathological manifestations of the allergy status however can be altered by effective manipulation of immune responses to induce a level of tolerance.³ In the past, such desensitization was attempted by means of subcutaneous immunotherapy with disappointing results.⁴ It is for this reason that desensitization with subsequent continuous exposure to food allergen is now focusing on protocols of sublingual and oral administration.^5,6 While a remarkable level of understanding and clinical applications has been attained in the induction of peanut tolerance, this is not the case with other foods.^3,5,6 Regarding allergy to crustaceans and desensitization treatment, practical approaches remain quite limited in spite of the fact that incidence of shellfish allergy is one of the most rapidly increasing food allergies, especially in the East Asian and Pacific populations.^7,8 More advanced basic research as well as wide-scale clinical trials are needed to delineate the nature of shellfish allergy and assess the sustainability of tolerance induced by immunotherapy. While such priorities are yet to be satisfied, the demand for effective desensitization at clinical-practice level remains undiminished. As a result of this pressure, many allergists have introduced to their practices desensitization protocols based on unpublished previous experience. So far, no case reports of successful desensitization to crustaceans have been published following an immunotherapy protocol specific for crustaceans. There is, however, a case report of clinical improvement of symptoms upon exposure in a patient with shrimp allergy treated with sublingual immunotherapy tablets for house dust mite allergy. This is not unexpected given the cross-reactivity between shrimp and dust mite.⁹ Herewith, desensitization to crustaceans by means of sublingual immunotherapy is assessed for efficacy and safety with a view of validating it as a disease-modifying modality.

Charts of a Midwest Allergy-Immunology practice from the period January 2014 – June 2023 were reviewed to identify patients with allergy to crustaceans treated with sublingual immunotherapy and to retrospectively evaluate their responses to oral challenge. Patients with a presenting history of systemic or localized reactions to crustaceans were included based on history, positive IgEs to crustaceans and positive skin tests to crustaceans. Patients with food allergies other than to crustaceans were all included in the study if they had a history of systemic reactions to crustaceans. Patients who were not compliant with the immunotherapy protocol for at least 65% of doses, averaged per year of immunotherapy, were excluded.

Sublingual immunotherapy with five-fold serially diluted mixtures was initiated at 6.4 - 160 ng/dose. Initiating doses were empirically inversely titrated against IgE levels with the 6.4 ng dose assigned to patients who presented with shrimp IgE > 100 kU/L and the 160 ng dose for patients who presented with IgE < 10 kU/L. Depending on availability and patients’ circumstances, doses were escalated gradually on variable intervals which ranged from weekly to quarterly, with an intention to reach maintenance dosing over a period of 6 – 48 months. Target dose was 0.5 mg/dose three times a day. Within six months of reaching target dose and while immunotherapy at this level was still going on, patients were to undergo shrimp oral challenge. Challenges were performed while patients were still receiving target-dose immunotherapy at 0.5 mg/dose.

Oral challenges by administration of gradually increasing doses were performed at the Allergy Associates of La Crosse – Challenges and Biologics Unit under continuous supervision by qualified personnel. Escalation of administered doses was every 20 minutes. Administration of each dose was preceded by vital signs, pulse oximetry and physical examination of eyes, ear-nose-throat, skin, respiratory and cardiovascular systems. Baseline spirometry was performed at the beginning of the challenge.

The initiating oral-challenge dose was 2 mg shrimp protein. This amount was administered in the form of 0.5 ml of 0.4% w/v shrimp-protein extract, which was diluted in glycerin/water solution to make up a volume of 10 ml. This step was followed by increasing doses of fresh, lightly boiled shrimp with a starting dose of 0.425 g. Weight was expressed as the weight of peeled (shelled), deveined and lightly boiled shrimp (as opposed to shrimp protein, which is approximately 25% of a shrimp’s weight). Target dose was 42 g shrimp weight – approximately 4 medium-size shrimps. Cumulative amount at target dosing was 81.2 g of shrimp weight.

Reactions to increasing doses were classified as localized versus systemic. Localized Reaction was defined as:

one of any of the following: oral/peri-oral itching/numbness, peri-oral hives, hives limited to pressure points, nasal symptoms (congestion/runny nose/repetitive sneezing); or
two symptoms if any one of the above was present and the second symptom was: malaise, dizziness, abdominal cramps, nausea/vomiting, anxiety, palpitations, provided that no hypotension or hypoxia were observed and no worsening of objective clinical signs occurred with advancement to the next- higher challenge dose.
Isolated malaise, dizziness, abdominal cramps, nausea/vomiting, and signs of anxiety were recorded as localized reactions.

Systemic Reaction was defined as:

sudden drop in systolic blood pressure as a single symptom; or
generalized hives/flushing, angioedema, throat, lower respiratory, cardiovascular, gastrointestinal symptoms consistent with mast cell degranulation and involving at least two different systems, as commonly defined.¹⁰

No systemic reactions occurred during or after challenges; no patient required epinephrine. Tolerance of target dose of 42 g or more was achieved in 11 patients (61%), with cumulative amount of 81.2 g for 5 patients, and cumulative amount varying from 106.2-148.2 g for six. Seven of these patients had originally presented with systemic reactions to crustaceans. Patients who passed the oral challenge were advised to consume shrimp and other crustaceans on a regular basis, one-two servings two-three times per week.

Seven patients (38%) developed one or more of the following localized reactions: oral itching, nasal symptoms, localized perioral hives, localized hives at pressure points, nausea, vomiting, abdominal pain upon exposure to a cumulative amount of 39.2-148.2 g shrimp during the 4 hours of the challenge. Five of these patients had originally presented with systemic reactions to crustaceans.

Five of the seven patients who developed localized symptoms during the challenge were subsequently placed on routine exposure to 12–20 g of shrimp (two medium-size Gulf Shrimps or one Jumbo Shrimp) every other day. Two patients who experienced localized symptoms during challenge elected to continue sublingual immunotherapy but declined regular every-other-day intake of 12–20 g shrimp because at that time they decided against introduction of crustaceans to their routine diet; on follow up, they were satisfied with the outcome of the challenge and wished to continue immunotherapy without having to undergo a repeat challenge. Repeat challenges were performed at 6, 7 and 9 months of regular every-other-day consumption. On repeat challenge, all five patients who had followed regular every-other-day consumption of 12–20 g shrimp tolerated the procedure to target doses, which ranged from 42 and 67 g (cumulative amount 81.2 and 106.2 g respectively), without symptoms.

On routine follow-up, none of the patients who passed the original or the repeat challenge reported adverse reactions with regular intake of shrimp at the prescribed amounts or with larger amounts of crustaceans – lobster, crab, crayfish included – consumed with meals.

The diagnosis of an IgE-mediated permanent food allergy is a life-changing event for patients and their families. The risk of a systemic reaction upon exposure and the possibility of anaphylaxis makes a life-threatening event out of any accidental exposure even when minute amounts of protein are involved or, especially in the case of crustaceans, when aerosolized particles are likely to be inhaled. Furthermore, each systemic episode is an entirely independent event which may turn out more severe than previous ones.^1,2,11 Adding to the uncertainty of systemic reactions due to food allergies, there is no diagnostic modality that would predict severity of reaction: skin tests and immunological essays for IgE antibody levels only predict likelihood of reaction and not severity.¹² The unpredictability of each reaction and the possibility of a fatal outcome places a constant burden on affected people who live under the threat of a sudden systemic reaction on practically every encounter, no matter how trivial, with food. Further complicating things, information on ingredients lists of manufactured foods is often misleading or erratic, and personnel involved in the preparation and serving of meals may lack access to relevant information. In light of these facts, long-term continuous control of immune responses to food allergens is a pressing necessity. Allergen-specific immunotherapy is the only disease-modifying modality for food allergy. Its implementation in a feasible, efficient, cost-effective, and safe way is the mainstay of long-term management.¹³ With the present report, sublingual immunotherapy is presented, for the first time, as a useful modality in the long-term management of allergy to crustaceans. Administration of sublingual immunotherapy at home three times a day was tolerated by all patients and compliance remained satisfactory during the treatment period. During challenges, no systemic reactions were observed. Subsequent regular exposure to shrimp every other day was also tolerated without problems. Patients who remained asymptomatic during challenge, as well as patients who developed symptoms of localized nature with their first challenge and were placed on a limited-exposure protocol of 15–20 g every other day, have not developed symptoms with subsequent exposures to larger amounts of crustaceans. Consumption of crustaceans at standard-serving (3 oz.) was not associated with symptoms on follow-up in either group.

The mechanisms of tolerance induction through sublingual immunotherapy have been extensively studied for long, but several of its long-term aspects are yet to be delineated.¹⁴ Sublingual immunotherapy is user-friendly, inexpensive, free of significant complications, and is characterized by compliance levels superior to those of other forms of immunotherapy for allergens.¹⁵

Regarding the long-term sustained outcome of desensitization, little is known and is mostly derived from experience with other food desensitization protocols. Sublingual immunotherapy for peanut allergy has been shown to result in decreased peanut-specific basophil activation and skin prick reactivity, as well as other parameters of IgE-effected sensitivity.¹⁶ Upon discontinuation of sublingual immunotherapy, however, less than 11% of followed subjects had achieved sustained unresponsiveness.¹⁶ Since sustained-unresponsiveness studies cannot be pursued in a private-practice setting, this issue will have to be addressed by larger-scale research projects. The patients of this cohort have all been advised to continue exposure to shrimp indefinitely at a minimum dose of 20 grams every other day. As of the time of writing this report, no adverse events have been reported following regular intake of said amounts or with consumption of usual servings of crustaceans.

A pertinent feature of the present study is the assessment of symptoms and their evaluation in regard to their characterization as systemic or not. The resulting decision to continue with the challenge versus halting it was of major importance for the outcome of the challenges. By consensus, the emergence of a second symptom from a different system calls for an obligatory definition of the reaction at hand as an immune response of systemic nature.^2,10,11 In view of the risk for anaphylaxis, such a development would have led to cessation of the challenge and its assessment as a failure. For certain symptoms, however, a departure from the literary application of these criteria practice may be necessary, if these symptoms can be safely attributed to non-immune events, especially anxiety-related responses. In our study, certain symptoms were characterized as localized events even if they occurred along with other localized symptoms from a different system. Specific criteria for such an assessment were applied. Symptoms were termed as localized if: i) they could be directly and unequivocally ascribed to anxiety, ii) their severity had no measurable equivalent in objective parameters, iii) increasing challenge doses led to no worsening of any other symptom and no escalation of the reaction was observed. The highly variable, subjective, and heterogenous nature of malaise, dizziness, nausea/vomiting, abdominal cramps, anxiety, tachycardia, and flushing is to be considered before the clinician in charge of the challenge arrives at the conclusion that mast cell degranulation of systemic magnitude has occurred. Without this modification and careful evaluation of symptoms within their context and timeliness, the rate of falsely-assessed failed food challenges is likely to be over-appreciated to the detriment of the patient’s interest.

Desensitization to crustaceans by sublingual immunotherapy over a period of 5–48 months is assessed as a safe and effective treatment modality in the chronic management of allergy to crustacean. Tolerance to exposure is achieved and maintained while regular administration of modest amounts of shrimp continues. Whether the immune modification induced by sublingual immunotherapy is permanent resulting in sustained tolerance, or the achieved degree of desensitization depends on regular exposure is not known; therefore, following oral challenge, regular consumption three-four times per week is recommended.

Ethics Approval and Consent to Participate

Consent to initiate immunotherapy and to proceed with immunotherapy and supervised oral challenges was obtained by all subjects or subjects’ parent(s). Ethical approval in accordance with the Declaration of Helsinki and Federal Policy for the Protection of Human Subjects was granted through the Institutional Review Board of Mayo Clinic.

Consent for Publication

Hereby, the authors L.M. Theodoropoulou and N.A. Cullen grant permission to the Editors of the Journal Allergy, Asthma and Clinical Immunology of the Canadian Society of Allergy and Clinical Immunology, to publish the present research paper with the title: Sublingual immunotherapy for allergy to crustaceans.

Competing Interests

Both authors declare that they have no conflict of interest or competing interests in relation to this study.

Funding

No funding was received for this study.

Authors’ Contributions

Lydia M. Theodoropoulou: Collection and analysis of data, writing of manuscript, presentation of abstract and incorporation of feedback.

Niamh A. Cullen: Design of study, supervision, editing of manuscript.

Acknowledgements

We thank Cheng Her, Allergy Associates of La Crosse, Wisconsin; and Anne Hendrickson and Beth Davidson, Allergy Choices, Inc., Onalaska, Wisconsin for their valuable technical support.

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Table is available in the Supplementary Files section

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Journal Publication

published 11 May, 2024

Read the published version in Allergy, Asthma & Clinical Immunology →

Reviewers agreed at journal
26 Nov, 2023
Reviewers invited by journal
10 Oct, 2023
Editor assigned by journal
20 Sep, 2023
First submitted to journal
16 Sep, 2023
Editorial decision: Major revision
05 Sep, 2023

You are reading this latest preprint version

Sublingual immunotherapy for allergy to crustaceans: the nine-year clinical experience of a Midwest Allergy-Immunology practice.

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Journal Publication

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Abstract

Introduction

Methods

Results

Discussion

Conclusions

Declarations

References

Table

Supplementary Files

Status:

Journal Publication

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