Challenges remain in anaphylaxis diagnosis despite consensus criteria

Key takeaways:

• The definition of anaphylaxis is based on consensus.
• Definitions matter for treatment, public health and research.
• There are discrepancies between diagnosis guidelines from major organizations.

BOSTON — Consensus criteria for anaphylaxis diagnosis are moving toward more objective assessments of symptoms, according to a presentation at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.

“We all know what anaphylaxis is. We deal with it every single day,” Julia Upton, MD, MPH, associate professor, division of immunology and allergy, Hospital for Sick Children, University of Toronto, said during her presentation.

“But then, really, when you look more into it, this is a very, very important issue,” she continued. “We really don’t know as much as we think.”

The role of consensus

Upton cited the definition of anaphylaxis from the 2023 joint task force practice parameters.

“Anaphylaxis is a serious, systemic hypersensitivity reaction that is usually rapid in onset and may cause death,” she quoted.

“Severe anaphylaxis is characterized by potentially life-threatening compromise in respiration and/or the circulation, and it may occur without typical skin features, circulatory shock or compromised breathing being present,” she continued.

The definition of anaphylaxis matters because it helps patients decide when to use epinephrine and go to the ED, she said.

The definition also matters in epidemiology, treatment, public health and research, she continued.

“Imagine I’m developing a new drug, and I want to know the rate of anaphylaxis to that drug,” she proposed. “If I don’t know how to define anaphylaxis, I’m going to be pressed to define how often it happens.”

Definitions of anaphylaxis are based on consensus predominantly related to its signs and symptoms, Upton said.

“I don’t have a magic wand that can tell me whether somebody is undergoing anaphylaxis,” she said.

Supportive tests such as elevated tryptase may help in diagnosis, she said, along with multiple criteria developed through consensus that are frequently revised. Consensus is necessary because data must be interpreted, she added.

“Sometimes things are an easy yes. Sometimes things are an easy no. But often there’s a maybe that needs to be clarified,” Upton said.

Criteria for anaphylaxis have evolved to objectively measure the subjective symptoms, she continued. For example, patients may say that they are itchy, which is subjective. But if the patient is scratching for 2 minutes continuously, that would be an objective measure.

“It’s a neat thing that we can turn a subjective symptom into an objective symptom, so long as we agree,” Upton said. “So, there’s lots of things that we have to agree on.”

Upton also asked how physicians should classify swollen lips.

“Are lips [gastrointestinal (GI)]? Are lips part of the respiratory system? Are lips part of the skin?” she asked. “We resolve it by consensus, and the definitions pretty much agree that lips are part of the skin system.”

Anaphylaxis also occurs at the cellular level, Upton continued. Degranulation of the mast cells occurs within the first seconds of the reaction. Eicosanoids are released within minutes, and cytokines, chemokines and growth factors follow within hours.

“Some of the biomarkers and mediators are more related to certain features than others,” Upton continued.

For example, cysteinyl leukotrienes impact the respiratory, cardiovascular and skin systems. Platelet-activating factors affect the cardiovascular and skin systems. Anaphylatoxins impact the skin.

“As time goes on, we may have more and more tools to be even more objective, even more tests, being able to look at these pathways, being able to better quantify these mediators,” she said. “We will continue to evolve, which means that we have to continue to revisit the definitions of anaphylaxis.”

A hypothetical case

For now, physicians can use criteria from the National Institute of Allergy and Infectious Diseases (NIAID) and from the World Allergy Organization (WAO) for diagnosing and treating anaphylaxis, Upton said. She then suggested a hypothetical case of an infant, aged 6 months, who began scratching his trunk and acting fussy while vomiting once after getting a round of vaccines.

“Would you call this anaphylaxis?” she asked.

The NIAID guidelines say that anaphylaxis is highly likely when there is the rapid development of itch or flush in addition to persistent GI symptoms after exposure to a likely allergen.

“Well, he only vomited once. So maybe not,” Upton said.

The WAO guidelines also say that anaphylaxis is highly likely when there is acute onset of an illness involving the skin, mucosal tissue or both as well as severe gastrointestinal symptoms such as severe crampy abdominal pain or repetitive vomiting, particularly after non-food allergen exposure.

“He vomited once, but he’s very, very fussy. Maybe that’s because he has abdominal pain,” Upton suggested.

Generally, Upton said, the NIAID and WAO guidelines differ based on organ system involvement, whether the allergen exposure is known or likely, and specific symptoms.

“So shouldn’t I use the Brighton criteria?” Upton asked.

The 2007 Brighton criteria for identifying reactions caused by vaccines were updated in 2023 because researchers believed the earlier guidelines were being used to grossly over-diagnose anaphylaxis following COVID-19 vaccination.

“This new revision tried to produce the subjective criteria and shift them as much as possible to objective criteria,” Upton said.

According to the Brighton criteria, anaphylaxis involves the rapid progression of signs and symptoms in two or more systems from the onset, such as the skin and gastrointestinal systems.

“Maybe I would call this a definitive case,” Upton said. “It’s not that easy.”

The criteria then ask if the case meets one or more major skin or mucosal criteria such as generalized or widespread erythema with itch.

“I actually didn’t have that,” Upton said.

When there is no major skin or mucosal criteria, Brighton asks if there are two or more other symptoms with a major criterion present.

“The major gastrointestinal criteria required new onset vomiting, which doesn’t apply if only an oral vaccine is given,” Upton said. “I don’t know if this child had anaphylaxis or not, and you can probably go either way, depending on how you interpret the guidelines.”

Additionally, Upton said, the lack of specific consensus criteria for infants makes diagnosis difficult, especially since some symptoms overlap with normal infant behavior. Tryptase levels above the normal value as defined by the laboratory may indicate anaphylaxis.

“But many cases of anaphylaxis may not be associated with a tryptase above that,” Upton said. “Then you would need a follow-up to see if you actually have an increase.”

What’s next

“Another consensus is coming,” Upton said.

Knowledge gaps exist in diagnosis, she continued.

The 2023 joint task force practice parameter for anaphylaxis noted knowledge gaps in diagnosis, Upton said, including isolated acute allergic oropharyngeal and laryngeal angioedema and what constitutes “severe” gastrointestinal symptoms.

The 2023 updates also called for consensus about discrepancies between the NIAID and WAO guidelines and further validation of acute and basal serum tryptaselevels informed by TPSAB1 copy number variations.

“There’s also how we can use these mechanistic understandings that we’ve had in the last few years,” Upton said.

Rethinking these definitions and updating them based on available data is valuable, Upton said.

“The definition can really affect the incidence and prevalence of one of our most important diseases,” she said. “We have to know what we’re talking about. We probably won’t always agree, though I doubt we’ll ever find something that 100% of us agree with.”

Upton added that although getting doctors to agree is like “herding cats,” these definitions are important for treatment advice, public health and research.

“And more and more, we are prioritizing objective criteria in the consensus definitions and continuing to refine them over time,” she said. “And I think we all hope that continued advances in the labs and therapeutic responses will help clarify these different pathways and endotypes of anaphylaxis and contribute to the definition.”