Debate Continues Over Multiallergen Subcutaneous Immunotherapy

Kate Johnson

November 30, 2021

A resolution is needed in the ongoing controversy between US and European allergists over the best approach to subcutaneous allergy immunotherapy (SCIT), "since it is likely that one or the other group of patients is receiving sub-optimal treatment," according to Harold S. Nelson, MD, an allergist and immunologist, and professor at National Jewish Health in Denver, Colorado.

While US guidelines recommend that polysensitized SCIT patients be treated with a mixture containing all the allergen extracts to which they have evident clinical sensitivity, European guidelines recommend using only one or sometimes two of the most clinically important allergens that a patient is sensitive to, Nelson explained in a review article.

"To me, this is suboptimal treatment, because the patient, despite the expense and inconvenience of undergoing SCIT, is still symptomatic much of the year," Nelson told Medscape Medical News. With multiallergen SCIT, "If a patient has a number of allergies that cause clinical symptoms — say they have allergic rhinitis in the spring due to trees, in June due to grasses, in August and September due to weeds, and perennially due to house dust mites — then all these symptom-causing allergies can be treated effectively with one injection. If you believe you should treat the patient for the one or two most important allergies, the others remain untreated and symptomatic."

US allergists seem satisfied with the multiallergen approach, "because empirically it appears to be working well," Nelson wrote in his review, claiming that the basis for the international disagreement rests mostly on four studies conducted in the United States in the 1950s and 1960s. "[T]hese studies are quite convincing," he explained. "However, this is not true for most European authors."

According to Nelson, most of the objections regarding multiallergen SCIT — such as dose dilution and degradation of allergens by proteolytic activity of other extracts — "are easily avoided." In terms of dilution, he said that "numerous" randomized, double-blind, placebo-controlled studies have been conducted to determine that more than 10 pollens or several environmentals can be combined in one vial without diluting any allergen below the established effective dose. Regarding degradation, because it is well recognized that fungi and cockroach extracts can degrade pollen, dander, and dust mite extracts, "a simple rule" is to avoid mixing them, he advised.

European experts reject much of the evidence supporting multiallergen mixtures because there is conflicting evidence and the supporting studies are old, small, and do not meet current regulatory standards, Nelson writes. However, he defended two studies from the 1960s as "the best" studies demonstrating efficacy of multiallergen mixtures delivered by SCIT: one by Lowell and Franklin from Massachusetts General Hospital in Boston, Massachusetts ( JAMA. 1967 Sep 18;201(12):915-917), and the other by Johnstone at Strong Memorial Hospital in Rochester, New York ( Pediatrics. 1968 Nov;42(5):793-802). Another study from the 1960s ( N Engl J Med. 1965 Sep 23;273(13):675-679) and a study of 18 subjects in the 1980s ( J Allergy Clin Immunol. 1986 Oct;78(4 Pt 1):590-600) form the backbone of evidence for multiallergen SCIT, he said.

Evidence weighing against the efficacy of multiallergen SCIT includes a study by Jean Bousquet, MD, PhD ( J. Allergy Clin Imunol. 1991;88:43-53), honorary professor of Pulmonary Medicine at the University of Montpellier, France.

Reached for comment on Nelson's review, Bousquet agreed that "This debate is not new, but started before the turn of the millennium, and we do not have an evidence-based conclusion yet," he told Medscape Medical News. "There is an urgent need to perform randomized controlled trials (possibly using a cluster approach) to confirm that mixed extracts are effective. Real world data using eHealth may also be of interest."

According to Bousquet, the multiallergen approach used by most US allergists "is not evidence-based, but opinion-based. There is no study in pollen or mite allergy using standardized extracts (criteria used for registration by FDA [US Food and Drug Administration] or EMA [European Medicines Agency]) in a sufficient sample size and/or appropriate statistical analysis showing that mixed allergen extracts are effective," he explained. "On the other hand, pivotal studies approved by FDA and EMA have shown that AIT [allergy immunotherapy] with single extracts was effective in patients with multiple allergenic sensitizations (polysensitization). The European approach is therefore evidence-based."

Similarly, Antonella Muraro, MD, PhD, past-president of the European Academy of Allergy and Clinical Immunology (EAACI), and chair of the EAACI's Allergen Immunotherapy guidelines, told Medscape Medical News that "an evidence-based guidance is intended to optimize benefits and reduce harms for the patient as well as to minimize controversies in practice and policies."

Curr Opin Allergy Clin Immunol. 2021.1;21(6):583-589. doi: 10.1097/ACI.0000000000000784. Review Article.

Nelson disclosed that he is a consultant to ALK; Bousquet left his position as a member of the board of Stallergenes 6 years ago; and Muraro disclosed no relevant financial relationships.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.

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