Consensus report defines anaphylaxis, provides clinical support tool

Key takeaways:

• The consensus aims to rectify discrepancies between prior statements.
• The report was drafted to be understood by broad audiences.
• The goal is to improve identification of anaphylaxis and use of epinephrine.

The Global Allergy and Asthma Excellence Network has published a consensus report on anaphylaxis — including an updated definition, overview and clinical support tool — in The Journal of Allergy & Clinical Immunology.

“This consensus document came to fruition because there were inconsistent anaphylaxis clinical criteria used in clinical care and research,” Timothy E. Dribin, MD, associate professor, division of emergency medicine, Cincinnati Children’s Hospital Medical Center, told Healio.

In 2006, the National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network (FAAN) published consensus criteria for diagnosing anaphylaxis.

“That was a landmark study that was endorsed by numerous stakeholder organizations,” Dribin said. “Those criteria have been used now for over a decade in clinical care and for research.”

The World Allergy Organization (WAO) proposed modified clinical criteria in 2020, which were very similar overall to the NIAID/FAAN criteria but with some significant departures that led to confusion for clinicians and researchers, Dribin said.

“You’re not comparing apples to apples,” he said. “The impetus for this study is to resolve these differences to develop one set of clinical criteria that can be widely agreed upon, both for clinical care and research purposes.”

Definition and overview

Using input from 31 medical stakeholder organizations and 15 patient advocacy organizations, the 46 members of the Global Allergy and Asthma Excellence Network (GA²LEN) Anaphylaxis Study team crafted a new definition of anaphylaxis, as well as an overview of anaphylaxis and a clinical support tool.

“It’s far too easy in research to have a small group of experts come together and say, ‘This is what we think should be done.’ Our goal was to make sure these criteria were uniformly adopted into both clinical care and research,” Dribin said.

Contributors included the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; the American Academy of Pediatrics; the Society of Critical Care and Medicine.

The NIH, FDA and European Medicines Agency also participated in the study, along with the Australasian Society for Allergy and Clinical Immunology, British Society for Allergy & Clinical Immunology, and European Society of Anaesthesiology and Intensive Care.

“We had to have the input of a wide group of experts globally to ensure that we’re listening to as many people as possible,” Dribin continued. “We didn’t want it to be just for researchers, and we didn’t want it to be just for allergists.”

In fact, the authors said that the consensus was designed to be generalizable for providers in a variety of specialties, including anesthesia, emergency medicine, hospital medicine, intensive care and primary care in addition to allergy.

The authors also said that they had consensus when they reached 80% agreement or higher during a modified Delphi process.

“We had a consensus of over 90% for all three of the study outputs, which was pretty impressive, given, as you can imagine, 46 experts weighing in,” Dribin said. “Those experts have a lot of different opinions, so we were very happy at the end of it that we had widespread support for the different study outputs.”

With 93.5% agreement, the team defined anaphylaxis as “a serious allergic (hypersensitivity) reaction that can progress rapidly and may cause death.”

The definition also says the skin/mucosa, respiratory, cardiovascular and gastrointestinal systems may be involved, with potential for fatal outcomes with respiratory and/or cardiovascular involvement, with or without skin/mucosa involvement.

This definition was drafted to be easily understandable by health care professionals and laypersons alike, GA²LEN said.

With 97.8% consensus, the overview includes information about anaphylaxis, including presentations, findings specific to infants, common allergens, courses, outcomes, pathogenesis, diagnosis and management. The authors said that it is not a systematic review, nor is it a practice parameter.

Clinical support tool

Patients who met one of three criteria in NIAID/FAAN or one of two criteria in WAO likely had anaphylaxis, Dribin said. NIAID/FAAN and WAO criteria also differed in allergen identification and the number of organ systems involved.

In its consensus clinical support tool, GA²LEN said anaphylaxis is likely when one of three criteria are fulfilled, based on the agreement of 93.5% of the 46 experts on the team.

“We wanted to make sure that it was really obvious to the user with each criterion whether the allergen exposure was a no known allergen exposure, likely, or a known allergen exposure,” Dribin said, adding that these criteria were drafted to be easier to use for people who are not familiar with them.

The first criterion applies when there is no known allergen exposure but there is sudden onset of illness, defined as minutes to several hours, involving skin/mucosal symptoms and either respiratory or cardiovascular involvement.

“This criteria is probably most commonly used in an emergency department or acute care setting , where patients come in with a constellation of findings and there is no clear trigger of what causes the symptoms,” Dribin said. “The only time you should use it is if there is no known allergy exposure.”

The second applies when the allergen exposure is likely or known and two or more systems are suddenly involved, including skin/mucosal symptoms, respiratory or cardiovascular involvement, or severe gastrointestinal involvement.

“A likely allergen exposure would be if someone’s eating out at a restaurant and they’re known to be food allergic, and all of a sudden, they eat a food and they start having hives and vomiting and trouble breathing,” Dribin said. “Even if they’re not exactly sure what the food culprit was, it’s probably likely that they were exposed.”

The third applies when the allergen is known and there is a sudden onset of either respiratory involvement following exposure to an allergen that has not been inhaled or cardiovascular involvement.

“Let’s say someone you know is allergic to peanuts, and they’re at school or at a birthday party, and they didn’t realize that there was peanut in the food that they were eating,” Dribin said. “That’s a known allergen exposure.”

The inclusion of isolated respiratory involvement with non-inhaled allergens in this criterion has an impact on the care that should be provided, Dribin said.

“If someone inhales an allergen and they’re having wheezing, that patient would be managed the same as someone with an asthma exacerbation. They would be given inhaled bronchodilators, potentially systemic steroids. They would not be given epinephrine,” he said.

“However, if someone eats a peanut and they develop wheezing, that patient would be likely to have anaphylaxis, and they should receive intramuscular epinephrine,” Dribin said.

Also, the NIAID/FAAN and WAO did not link their criteria with indications for administering epinephrine, although they did advise the use of epinephrine when anaphylaxis was suspected.

“We wanted to make sure that the users understood that the criteria should help inform whether someone is likely to have anaphylaxis, but the use of epinephrine should be independent of that,” Dribin said.

The GA²LEN clinical support tool advises providers to administer epinephrine immediately when anaphylaxis is suspected, even when patients do not fulfill these criteria, based on clinical judgment.

“The clinician sees them, and they look very sick. It would be prudent to give epinephrine in those situations,” Dribin said. “It’s up to the clinician.”

Epinephrine via manual injectors or autoinjectors should be administered in the middle third of the anterolateral thigh with additional doses every 5 to 15 minutes when the reaction does not respond to the initial epinephrine dose, the clinical support tool says.

Further, Dribin said that the NIAID/FAAN and WAO statements included specific system symptoms in their criteria for identifying anaphylaxis.

“We thought that actually muddled the criteria and made them harder to interpret,” Dribin said.

GA²LEN moved examples of the most common serious symptoms listed by organ system to the bottom of the clinical support tool to make it easier for users to recognize them, Dribin said.

Specifically, the clinical support tool identifies anaphylaxis involvement in the skin via urticaria, flushing, erythema and facial swelling, adding that infants also may experience mottling.

Mucosal involvement includes the lip, tongue or oropharyngeal swelling, along with severe tightness in the throat and difficulties swallowing. Infants may demonstrate repeated lip licking.

Symptoms in the respiratory system include wheeze, labored breathing, hypoxemia, cough and dyspnea, with stridor or voice change also possible. Infants may sound hoarse when they cry as well.

Cardiovascular involvement includes hypotension, syncope, dizziness or a change in mental status that is unexplained. Infants may experience persistent tachycardia that is not explained.

In the gastrointestinal system, abdominal pain may be severe and crampy, with repetitive vomiting and diarrhea. Dribin noted that this is a change from NIAID/FAAN, which indicated persistent involvement instead of severe.

“How do you define what’s severe and what’s not severe? There’s still some subjectivity,” he said. “It’s not enough to say someone has a little bit of nausea. They threw up once and they’re feeling better. The gastrointestinal involvement needs to be more significant.”

Further, Dribin noted that unlike the NIAID/FAAN and WAO statements, the GA²LEN consensus includes findings that are distinct in infants and young children, which is important because they may be nonverbal.

“They may present with some findings that overlap with normal infant behavior,” Dribin said. “They’re crying. They’re irritable. It may be because they missed their nap. But it also may be because they’re having an allergic reaction.”

Pre-hospital providers such as EMS personnel may be less comfortable in recognizing anaphylaxis in these age groups, Dribin said.

“The hope of this is to improve the recognition and management of anaphylaxis in that age group,” he said. “We think this is going to be really helpful in those settings that aren’t used to caring for many kids, especially in your general emergency departments and rural areas.”

Improving outcomes

The goal of the consensus is to improve anaphylaxis recognition and epinephrine use, Dribin said, which would reduce the odds for hospitalizations, serious illnesses and even death.

“There’s been a lot of data showing there’s significant epinephrine underuse for anaphylaxis. In adults, it’s 7%. In children, it’s around 21% of patients who should get epinephrine receive it. So that’s a pretty glaring deficit,” he said.

“If patients receive timely epinephrine, and they get repeat dosing when their symptoms don’t respond to the initial dose, we hope that it can reduce the risk of fatalities and improve patient outcomes,” he continued.

The authors drafted the consensus to be adaptable too, Dribin said.

“Right now, it’s only in English,” he said. “When we were developing the consensus definition of what anaphylaxis was, we were really cognizant that some terms do not translate well to non-English languages. So, I think translating it to other languages will be key.”

Dribin also noted that “we live in a digital age,” where technology is playing a growing role in supporting decision-making, adding that the clinical support tool could be embedded in electronic health records or even in mobile apps.

“That clinical support tool would walk the user through how to use it,” he said. “Was there a known allergen exposure? Was there a likely allergen exposure?”

Prompts would then guide users through assessing the involvement of the four organ systems included in the criteria before providing feedback on the likelihood of anaphylaxis and whether epinephrine should be administered.

“That would be very helpful in the pre-hospital setting and in places that have less resources, where providers are forced to rely on their own knowledge or have to look things up to figure out how to dose someone,” Dribin said.

With last year’s approval of ARS Pharma’s neffy epinephrine nasal spray, and other alternatives to injectable epinephrine on the way, Dribin said that the clinical support tool can be updated in real time to incorporate these devices and provide easy-to-use and up-to-date information.

“We expect that there should be other non-injectable epinephrine devices that are approved that we hope will improve the rate of epinephrine in the community, because we know that people are afraid to use needles,” he said.

Overall, Dribin was optimistic that this consensus document will have a positive impact on care as its authors propose using it to replace previous definitions and clinical criteria.

“These new criteria, when the next practice parameter comes out, will probably be what most experts say should be adopted into clinical care and for research purposes,” Dribin said.

For more information:

Timothy E. Dribin, MD, can be reached at timothy.dribin@cchmc.org.