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Monday, March 8, 2010

Grading systemic reactions to immunotherapy

The potential for anaphylaxis in subcutaneous specific immunotherapy (SCIT) is obvious. Current practice standards for evaluating, grading, and treating systemic reactions are vague, and in some cases, too rigid to encompass the highly variable symptom presentation. On top of this, the judicious application of epinephrine in anaphylaxis evolution has not been evaluated in a systematic way.

Cox et al., representing the AAAAI/ACAAI Joint Task Force for Grading Systemic Reactions to Immunotherapy, in collaboration with the WAO, present a draft recommendation for SCIT systemic reaction (SR) grading system in this month’s issue. It is based on the Internet Immunotherapy Safety Survey, started in 2008, from which the task force hoped to learn the incidence rate of systemic reactions, especially fatal or near-fatal reactions, and how and when epinephrine was given. The goal: to develop a global, functional SR grading system that could be used to standardize intervention, especially epinephrine use, to minimize the risk of fatal or near-fatal reactions.

The Task Force proposes a grading system based on the organ system involved and severity. Organ systems are defined as: cutaneous, conjunctival, upper respiratory, lower respiratory, gastrointestinal, cardiovascular and other. A reaction from a single organ system such as cutaneous, conjunctival, upper respiratory, but not asthma, gastrointestinal or cardiovascular is classified as a Grade 1 Symptoms from more than one organ system or asthma, gastrointestinal, cardiovascular are classified as Grades 2 or 3. Grade 4 includes the conventional clinical indicators of a severe reaction, such as loss of consciousness, hypotension, and respiratory failure, while Grade 5 is death. Clinician judgment assesses the grade. The proposed system also includes time of onset, first symptom, and time when epinephrine was given, if at all.

The authors suggest additionally that this grading system allows flexibility to accommodate the clinical management details. The task force contends that a common grading approach that can be used by clinicians and researchers will make it easier to compare SRs and interventions between different SCITs from surveillance and clinical trial data.

Dr. Cox notes, “The WAO grading system for SR has been endorsed by the following WAO Regional and National Member Societies: AAAAI, Latin American Society of Allergy and Immunology (SLAAI), Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI), and the ACAAI.

The rostrum includes an Excel spreadsheet for documenting SR grade and treatment that can downloaded and used by clinicians and researchers to collect on SR frequency, severity and response to treatment.”

We asked Dr. Cox to comment on how the treatment thresholds mentioned in the paper are more discriminating than those used in the past, given that the authors note that using response to treatment to assess severity is misleading as both mild and severe reactions may or may not resolve after IM epinephrine. Dr. Cox responded as follows:

“The grading table [uses] response to treatment or drop in PEF as an example of… a Grade 2 or 3 reaction to provide the clinicians with some general guidelines. That is why it is prefaced as an e.g. and it is not a specific requirement/criteria for... that particular grade. We also stipulate that 'The grade is determined by the physician’s clinical judgment,' so it is up to the physician to decide whether the asthma reaction is Grade 2 or 3 and they may or may not decide to include response to treatment in determining the Grade…. These were added during the review process at the request of some reviewers who wanted more specific guidelines.”

We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.


  1. From the authors:
    This paper and the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System have been extensively reviewed by many individuals and several organizations. Comments from the invited reviewers and members of the Joint Task Force for Grading Systemic Reactions to Immunotherapy are posted below. The authors’ responses to the comments are also included.

  2. From Erkka Valovirta M.D. Ph.D.: I have been following this discussion and somehow I think that it would be much more beneficial to publish an organization statement endorsed by WAO, AAAAI, ACAAI, EAACI, Asian, Latin American and Japan All
    Society as well as by ARIA. This topic is one of the most important topics in allergen immunotherapy and that´s why I strongly suggest an organizational statement , which is then easy to implement in all countries.

    Authors' Response: The intent is to publish as a WAO organization paper and invite the other organizations to review and endorse the grading system. The organizations who have endorsed the
    grading system [are] recognized in the paper.

  3. From Sten Dreborg, MD, PhD: I understand I got the paper just for information, but couldn't resist commenting. There are two points I think are of importance 1. The exposure to all types of allergens,
    e.g. cat can induce symptoms/subclinical symptoms (in asthmatics inducing a slight decrease in FEV 1.0) that causes severe reactions in patients earlier tolerating the same dose. Not only pollens. Response
    2. A patient showing itching of the throat or palms within few minutes -and in my opinion is correctly treated -gets adrenaline and later perhaps beta 2 agonists and steroids, but never develops full
    anaphylaxis, should in my opinion be registered as anaphylaxis. This is difficult to describe in an ordered way.

    Authors' response: The authors agree that signs or symptoms from a single organ system after administration of a known allergen represent anaphylaxis and warrant prompt treatment with epinephrine-see excerpt from the paper below:
    “recommend that any signs or symptoms of anaphylaxis such as generalized pruritus, erythema, urticaria, and angioedema alone, and any other systemic symptom including those not involving vital organs, again, when associated with the administration of a known or suspected allergen or agent, should be treated immediately and, as necessary, with appropriate intramuscular (IM) doses of epinephrine.”

  4. From Moises Calderon: Thank you very much for all your hard work and for putting together this manuscript. These are my comments:
    It is my understanding that the proposal of a “Consensus on the Grading of Systemic Reactions due to SIT” was initially suggested to “unify” existing grading systems (e.g., Müller, Portnoy, EAACI)
    aiming to avoid the delay of treatment and therefore, to prevent fatalities. For this reason, a simplified table was originally proposed to facilitate the early recognition of symptoms, their severity
    and their evolution in time to assist the physician with the selection of the appropriate treatment (not only adrenaline). The idea was to provide a simple and practical table that can be used by the
    physician without hesitation or confusion. However, on page 23 it is stated that “the final grade will not be determined until the event is over.” This is inconsistent.

    Authors' response: Since the grade is dependent on the most severe symptom, the scoring cannot really be completed until the event is over. One goal of this grading system is facilitate collection and comparison of data so we can determine the appropriate treatment for SCIT SR. At the present, there is not agreement regarding when epinephrine should be administered.

  5. From Stephen Durham: The main focus of the classification is symptoms and symptom severity. The result for symptoms in my
    view is excellent. However, key issues raised in Warsaw concerning the need for the classification to take into account the timing of onset of symptoms (i.e., < or > than 15 mins) and whether or not adrenaline was administered have not been adequately addressed. They are discussed but not scored and are included in the table only as descriptive parameters. If numbers are not attached to these important parameters for the classification score of severity, then the classification will be of less value.

    Authors' response: We think the grade should reflect the severity of symptoms and timing is a predictor but not a measure of severity i.e., -respiratory failure with loss consciousness at 16 minutes should not be graded differently from the same symptoms occurring at 5 minutes.