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Peanut allergy diagnosis: A 2020 practice parameter update, systematic review, and GRADE analysis

2020; Elsevier BV; Volume: 146; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2020.07.031

1097-6825

Matthew Greenhawt, Marcus Shaker, Julie Wang, John Oppenheimer, Scott H. Sicherer, Corinne Keet, Keri Swaggart, Matthew A. Rank, Jay M. Portnoy, Jonathan A. Bernstein, Derek K. Chu, Chitra Dinakar, David B.K. Golden, Carolyn Horner, David M. Lang, Eddy Lang, David A. Khan, Phil Lieberman, David R. Stukus, Dana Wallace,

Eosinophilic Esophagitis

Given the burden of disease and the consequences of a diagnosis of peanut allergy, it is important that peanut allergy be accurately diagnosed so that an appropriate treatment plan can be developed. However, a test that indicates there is peanut sensitization present (eg, a “positive” test) is not always associated with clinical reactivity. This practice parameter addresses the diagnosis of IgE-mediated peanut allergy, both in children and adults, as pertaining to 3 fundamental questions, and based on the systematic reviews and meta-analyses, makes recommendations for the clinician who is evaluating a patient for peanut allergy. These questions relate to when diagnostic tests should be completed, which diagnostic tests to utilize, and the utility (or lack thereof) of diagnostic testing to predict the severity of a future allergic reaction to peanut. Given the burden of disease and the consequences of a diagnosis of peanut allergy, it is important that peanut allergy be accurately diagnosed so that an appropriate treatment plan can be developed. However, a test that indicates there is peanut sensitization present (eg, a “positive” test) is not always associated with clinical reactivity. This practice parameter addresses the diagnosis of IgE-mediated peanut allergy, both in children and adults, as pertaining to 3 fundamental questions, and based on the systematic reviews and meta-analyses, makes recommendations for the clinician who is evaluating a patient for peanut allergy. These questions relate to when diagnostic tests should be completed, which diagnostic tests to utilize, and the utility (or lack thereof) of diagnostic testing to predict the severity of a future allergic reaction to peanut. IgE-mediated peanut allergy has an estimated prevalence of between 0.2% and 4.5%, depending on geographic area of the world and the methodology used for assessment. While the prevalence in the United States appears to have tripled in a recent 10-year period, in the United Kingdom, the prevalence seems to have plateaued over a similar period, denoting regional heterogeneity in such trends. Peanut allergy is associated with substantial economic and psychologic burden on families that is associated with poor quality of life and high anxiety related to the potential consequences of their child having a severe allergic reaction. Peanut allergy is often a severe and usually a lifelong allergy that is a leading cause of food-related anaphylaxis. One peanut allergy treatment has been approved by the US Food and Drug Administration, and several other emerging treatments are approaching consideration for US Food and Drug Administration approval. However, presently peanut allergy is managed through peanut avoidance and by carrying emergency medication such as autoinjectable epinephrine to treat symptoms that may arise from unintended ingestion. Given this burden of disease and the consequences of diagnosis, it is important that peanut allergy be accurately diagnosed so that an appropriate treatment plan can be developed. However, a positive peanut test result is not always associated with clinical reactivity. This practice parameter addresses the diagnosis of IgE-mediated peanut allergy, both in children and adults, as pertaining to 3 fundamental questions (see Box 1). This parameter exclusively discusses IgE-mediated peanut allergy and all references herein pertain to IgE-mediated food allergy to peanut only and not to peanut as a potential trigger in eosinophilic esophagitis or non-IgE-mediated food allergy such as food protein induced enterocolitis syndrome (FPIES). Similarly, emerging technologies such as basophil activation testing were also not included in this analysis.Box 1GRADE questions evaluated in this practice parameterPICO questions: GRADE analysis of diagnostic testing in the diagnosis of peanut allergy1.Should diagnostic testing for peanut allergy be performed in adults and children with a history of suspected peanut allergy who are requesting evaluation for peanut allergy?2,A. In the patient presenting for evaluation of suspected peanut allergy, which of the 3 tests—SPT, sIgE to whole peanut, or Ara h 2—would provide the highest diagnostic accuracy as determined by the more optimal positive/negative likelihood ratio?2,B. In a patient presenting for evaluation of suspected peanut allergy, does testing for peanut components in addition to either SPT or sIgE to whole peanut increase the diagnostic accuracy?3.In the patient presenting for evaluation of suspected peanut allergy, can the results of a diagnostic test be used to predict the severity of a future allergic reaction? PICO questions: GRADE analysis of diagnostic testing in the diagnosis of peanut allergy1.Should diagnostic testing for peanut allergy be performed in adults and children with a history of suspected peanut allergy who are requesting evaluation for peanut allergy?2,A. In the patient presenting for evaluation of suspected peanut allergy, which of the 3 tests—SPT, sIgE to whole peanut, or Ara h 2—would provide the highest diagnostic accuracy as determined by the more optimal positive/negative likelihood ratio?2,B. In a patient presenting for evaluation of suspected peanut allergy, does testing for peanut components in addition to either SPT or sIgE to whole peanut increase the diagnostic accuracy?3.In the patient presenting for evaluation of suspected peanut allergy, can the results of a diagnostic test be used to predict the severity of a future allergic reaction? Diagnostic testing for peanut allergy is used to help make a diagnosis where there is suspicion of a peanut allergy based on the clinical history. Failure to make a correct diagnosis can result in either unnecessary avoidance in a nonallergic person, or erroneous guidance that the patient can safely ingest peanut ad libitum when there is in fact an allergy—both of which are problematic situations. A correct diagnosis facilitates peanut avoidance and counseling when the patient is at risk of potential life-threatening complications of peanut allergy and therefore is advised to carry epinephrine for use in case of symptomatic accidental ingestion. Alternatively, exclusion of peanut allergy allows peanut to be incorporated into the diet without concern, eliminating the burden of precautions and fear. Changes in peanut sensitization levels over time, compared with baseline, may be associated with whether the individual with allergy is likely to be outgrowing their peanut allergy. Although previous research in patients with established peanut allergy reported clinical diagnostic cutoff points for >95% chance of reaction and for 1300 references searched), a meta-analysis of the evidence, and a GRADE (Grading of Recommendations, Assessment, Development and Evaluation) analysis (a well-established methodology for developing evidence-based guidelines) of the results (see Table I) made its recommendations. All the recommendations were conditional in strength, with low or very low certainty of evidence. Thresholds for detection of sensitization were at 3 mm for skin prick test (SPT), and 0.35 KUA/L (KUA = kilo allergen unit) for both whole peanut serum-specific IgE (sIgE) and component-specific peanut sIgE, based on the most widely reported levels evaluated in the literature. Additional cutoffs were considered, but their use would have posed a significant limitation to the analysis, given very limited study numbers reporting these values. Extensive sensitivity analysis was performed to confirm the results.Table IThe GRADE system of recommendations and evidence certaintyStrength of recommendationFor the patientFor the clinicianStrongMost individuals in this situation would prefer the recommended course of action and only a small proportion would not.The attending provider should strongly consider the recommended course of action as a first-line management. Formal decision aids may have less of a role to help individuals make decisions consistent with their values and preferences.ConditionalThe majority of individuals in this situation would prefer the suggested course of action, but many would not.Different choices may be appropriate for different patients. Decision aids may be useful in helping individuals in making decisions consistent with their values and preferences. Clinicians should expect to spend more time with patients when working toward a decision.Certainty in estimates of effect/quality rating both for outcome and for an entire evidence base as it pertains to a PICO questionHighThere is high confidence that the true effect lies close to that of the estimate of the effect.ModerateThere is moderate confidence in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.LowThere is limited confidence in the effect estimate. The true effect may be substantially different from the estimate of the effect.Very lowThere is very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effectAdditional information regarding GRADE methodology, including how recommendations are formulated and the evidence certainty is rated can be found in Shaker et al1Shaker M.S. Oppenheimer J. Wallace D.V. Golden D.B.K. Lang D.M. Joint Task Force for Allergy Practice PMaking the GRADE in anaphylaxis management: Toward recommendations integrating values, preferences, context, and shared decision making.Ann Allergy Asthma Immunol. 2020; 124: 526-535.e2Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar and on the Joint Task Force on Allergy Practice Parameters website (https://www.allergyparameters.org/resources-for-understanding-grade/). Open table in a new tab Additional information regarding GRADE methodology, including how recommendations are formulated and the evidence certainty is rated can be found in Shaker et al1Shaker M.S. Oppenheimer J. Wallace D.V. Golden D.B.K. Lang D.M. Joint Task Force for Allergy Practice PMaking the GRADE in anaphylaxis management: Toward recommendations integrating values, preferences, context, and shared decision making.Ann Allergy Asthma Immunol. 2020; 124: 526-535.e2Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar and on the Joint Task Force on Allergy Practice Parameters website (https://www.allergyparameters.org/resources-for-understanding-grade/). The expert panel suggested that diagnostic testing for peanut allergy be used in patients with a high pretest probability of peanut allergy, or prior to an OFC for patients with moderate pretest probability of peanut allergy, as a preference-sensitive choice, but discourages testing in patients with a low or very low pretest probability of peanut allergy. If a single diagnostic test were to be used, testing for the Ara h 2 component would provide the most diagnostic accuracy, as determined by the more optimal positive/negative likelihood ratio among the presently available testing options. However, this is contingent on Ara h 2 component testing becoming more commonly available as a stand-alone test, as opposed to being primarily offered by laboratories as a panel with other peanut components. The literature search did not provide patient-level data to determine the value of testing for peanut components in addition to SPT or sIgE to whole peanut to increase diagnostic accuracy, including isolated Ara h 2 in that context. The clinician should not use the results of a SPT, sIgE to whole peanut extract, or sIgE to peanut components to determine an allergy phenotype or to predict the severity of a future reaction (eg, will the patient have anaphylaxis to peanut). An additional supplemental cost-effectiveness analysis of the potential testing options presented in the Online Repository (available at www.jacionline.org) confirms use of Ara h 2 as the optimal choice when compared to peanut SPT and whole peanut sIgE. There remain important knowledge gaps and the need for well-designed studies to address these questions, as well as the need for patient-level data to be made available when reporting test sensitivity/specificity to enhance the ability to perform future meta-analyses that can explore different cutoff levels. These recommendations, which are detailed below, are summarized in Table II.1Shaker M.S. Oppenheimer J. Wallace D.V. Golden D.B.K. Lang D.M. Joint Task Force for Allergy Practice PMaking the GRADE in anaphylaxis management: Toward recommendations integrating values, preferences, context, and shared decision making.Ann Allergy Asthma Immunol. 2020; 124: 526-535.e2Abstract Full Text Full Text PDF PubMed Scopus (15) Google ScholarTable IISummary recommendations in evaluating the patient with suspected peanut allergyQuestionRecommendationEvidence certaintyRisk of bias1. Should diagnostic testing for peanut allergy be performed in adults and children with a history of suspected peanut allergy who are requesting evaluation for peanut allergy?1, A. We suggest in favor of diagnostic (SPT or sIgE) testing for peanut allergy (1) when patients have physician-judged high pretest probability of peanut allergy, or (2) prior to an OFC for patients with moderate pretest probability of peanut allergy. For both situations, shared decision making has been employed to arrive at the final decision.1, B. We suggest against diagnostic testing in patients where there is low or very low pretest probability of peanut allergy.Very lowNot rated2, A. In the patient presenting for evaluation of suspected peanut allergy, which of the 3 tests—SPT, sIgE to whole peanut, or Ara h2—would provide the highest diagnostic accuracy as determined by the more optimal positive/negative likelihood ratio?2, A. We suggest in favor of Ara h 2 diagnostic testing in a patient presenting for evaluation of suspected peanut allergy for which a single diagnostic test is to be used, as Ara h 2 would provide the best diagnostic accuracy as determined by virtue of more optimal positive/negative likelihood ratios. However, while Ara h 2 has the greatest specificity, it has lower sensitivity than SPT and sIgE, and in a patient with a high prior probability, the clinician may use Ara h 2, SPT, or sIgE to confirm the diagnosis of peanut allergy.LowHigh2, B. In a patient presenting for evaluation of suspected peanut allergy, does testing for peanut components in addition to either SPT or sIgE to whole peanut increase the diagnostic accuracy?2, B. We suggest against routine use of component testing in addition to either to SPT or sIgE to whole peanut to increase diagnostic accuracy.Very lowHigh3. In the patient presenting for evaluation of suspected peanut allergy, can the results of a diagnostic test be used to predict the severity of a future allergic reaction?3. We suggest against the clinician using the results of a SPT, sIgE to whole peanut extract, or sIgE to peanut components to determine the severity of an allergy phenotype or to predict the severity of a future reaction.Very lowHigh Open table in a new tab Recommendation 1, A. We suggest in favor of diagnostic (SPT or sIgE) testing for peanut allergy (1) when patients have physician-judged high pretest probability of peanut allergy, or (2) prior to an OFC for patients with moderate pretest probability of peanut allergy. For both situations, shared decision making has been employed to arrive at the final decision. Conditional recommendation. Certainty of evidence: Very low. Recommendation 1, B. We suggest against diagnostic testing in patients where there is low or very low pretest probability of peanut allergy. Conditional recommendation. Certainty of evidence: Very low. This question was not searched in a systematic manner as the content experts were unaware of any single research study that addressed this question. The work group performed a PubMed literature search that did not identify any articles that address this question, which by default limits the certainty of evidence. For this reason, the work group and Joint Task Force on Practice Parameters (JTFPP) felt that it would therefore not be an appropriate utilization of valuable resources to perform a librarian-conducted formal literature search. However, expert evidence was collected both from the content experts and the JTFPP. Expert evidence differs from expert opinion in that the former does not include a judgment on the evidence and offers a systematic and transparent appraisal of the evidence, which differentiates this as an acceptable alternative to making a recommendation under GRADE. The guideline working group related that when evaluating their collective patient experiences, diagnostic testing could be of value to confirm peanut allergy in high-risk individuals for which an oral challenge might not be advisable or agreed to by patients. However, the work group also acknowledged that in a patient presenting with a classical history, the diagnosis could be made on the basis of history alone without further testing in some circumstances. The expert panel related that they suggested an OFC when there was a moderate probability of peanut allergy but that a large proportion of their patients may prefer a diagnostic test prior to the OFC. Similarly, the collective personal experience of the expert panel was that diagnostic testing in patients with a low probability of peanut allergy (eg, sibling has peanut allergy and patient has never ingested peanut) often identified patients who were sensitized but not truly allergic. Unfortunately, many of these patients refused an OFC and likely avoided peanut unnecessarily. These recommendations are in alignment with previous expert guidelines and practice parameters on food allergy diagnosis and management, which provide similar consensus regarding the indications for testing for the presence of food sensitization, including peanut, in evaluating a possible diagnosis of food allergy. While screening of foods in infants prior to initial food introduction is discouraged, testing to peanut in infants who are at high risk for peanut allergy (under the very prescribed context of those infants with either severe eczema and/or egg allergy) is the one notable exception, which was recommended prior to initial peanut introduction per the 2017 National Institutes of Allergy and Infectious Disease (NIAID) addendum guidelines. Question 2, B. In a patient presenting for evaluation of suspected peanut allergy, does testing for peanut components in addition to either SPT or sIgE to whole peanut increase the diagnostic accuracy? Recommendation 2, A. We suggest in favor of Ara h 2 diagnostic testing in a patient presenting for evaluation of suspected peanut allergy for which a single diagnostic test is to be used, as Ara h 2 would provide the best diagnostic accuracy as determined by virtue of more optimal positive/negative likelihood ratios. However, while Ara h 2 has the greatest specificity, it has lower sensitivity than SPT and sIgE, and in a patient with a high prior probability, the clinician may use Ara h 2, SPT, or sIgE to confirm the diagnosis of peanut allergy. Conditional recommendation. Certainty of evidence: Low. Recommendation 2, B. We suggest against routine use of component testing in addition to either SPT or sIgE to whole peanut to increase diagnostic accuracy. Conditional recommendation. Certainty of evidence: Very low. For GRADE analysis, Ara h 2 was compared with SPT and sIgE to whole peanut for the diagnosis of peanut allergy. The literature search did not provide patient-level data to determine the value of testing for peanut components in addition to or reflexively with SPT or sIgE to whole peanut to increase diagnostic accuracy. In addition, expert evidence was not available to assist in answering this question. Thus, the use and value of components, including reflexive use of Ara h 2, remains a knowledge gap. There is an unclear utility for measuring sIgE to any other commercially available peanut components given the limited available data on performance of components beyond Ara h 2. Further research is needed to clarify the value of tandem testing, particularly with regard to Ara h 2, Ara h 6, and Ara h 8. While Ara h 2 had the greatest specificity in confirming the diagnosis, it had lower sensitivity when compared with SPT or sIgE. In evaluating diagnostic accuracy, the summary receiver operating characteristic curves demonstrated greatest area under the curve for Ara h 2 (0.92) when compared with those for SPT (0.89) and sIgE (0.81). We caution the clinician that despite undetectable sensitization on SPT, sIgE, or Ara h 2 testing, that there is a small possibility the individual could still be allergic to peanut and similarly that detection of sensitization does not always infer clinical allergy. If clinical suspicion remains elevated, further evaluation through an OFC is potentially indicated. Recommendation 3. We suggest against the clinician using the results of a SPT, sIgE to whole peanut extract, or sIgE to peanut components to determine the severity of an allergy phenotype or to predict the severity of a future reaction. Conditional recommendation. Certainty of evidence: Very low. There were inadequate patient-level data to formulate a GRADE recommendation on the use of a peanut diagnostic test for predicting the severity of a future allergic reaction across a continuous range of test result values; however, dichotomous cutoff values of 10 mm (SPT), 50 KUA/L (peanut sIgE), and 2 KUA/L (Ara h 2 [sIgE]) demonstrated low sensitivity and specificity for a future severe reaction.