Clinical Immunology Research Articles

Australian Infant Food Allergy Emergency Presentations Following Updated Early Food Introduction Guidelines

The Australasian Society of Clinical Immunology and Allergy food allergy prevention guidelines were updated in 2016 to recommend home introduction of allergenic foods actively in the first year of life, including to infants at high risk of allergy. An important consideration for parents and providers is whether this practice increases food allergy reactions or anaphylaxis. We aimed to determine whether the 2016 update of food allergy prevention guidelines was associated with an increase in food allergy or anaphylaxis emergency department (ED) presentations. We obtained hospital electronic medical records for infants aged 4 to 12 months who attended the Royal Children's Hospital Melbourne ED in 2015 or in 2018 with a presenting problem or an encounter diagnosis of food allergy or anaphylaxis. Emergency department presentations owing to food allergy increased from 1.0% (95% CI, 0.85-1.23) in 2015 to 1.4% (95% CI, 1.22-1.67) in 2018 (P= .006). There was no increase in the number of anaphylaxis presentations (28 in 2015 and 22 in 2018) or peanut anaphylaxis presentations (three in 2015 and three in 2018). Overall, the proportion of food allergy presentations attributed to IgE-mediated food allergy was similar (82.1% in 2015 and 84.1% in 2018), whereas peanut allergy presentations increased slightly, although not statically significantly, from 14.6% to 21.2% (P= .09). Food protein-induced enterocolitis syndrome ED presentations were five in 2015 (4.3%) and 12 in 2018(7.6%), although not statistically significant (P= .25). Changes to food allergy prevention guidelines recommending the earlier introduction of allergenic food may have led to a small increase in ED presentations for food allergy but not anaphylaxis.

Standardization of clinical outcomes used in allergen immunotherapy in allergic asthma: An EAACI position paper.

In allergic asthma patients, one of the more common phenotypes might benefit from allergen immunotherapy (AIT) as add-on intervention to pharmacological treatment. AIT is a treatment with disease-modifying modalities, the evidence for efficacy is based on controlled clinical trials following standardized endpoint measures. However, so far there is a lack of a consensus for asthma endpoints in AIT trials. The aim of a task force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) is evaluating several outcome measures for AIT in allergic asthma. The following domains of outcome measures in asthmatic patients have been evaluated for this position paper (PP): (i) exacerbation rate, (ii) lung function, (iii) ICS withdrawal, (iv) symptoms and rescue medication use, (v) questionnaires (PROMS), (vi) bronchial/nasal provocation, (vii) allergen exposure chambers (AEC) and (viii) biomarkers. Exacerbation rate can be used as a reliable objective primary outcome; however, there is limited evidence due to different definitions of exacerbation. The time after ICS withdrawal to first exacerbation is considered a primary outcome measure. Besides, the advantages and disadvantages and clinical implications of further domains of asthma endpoints in AIT trials are elaborated in this PP. This EAACI-PP aims to highlight important aspects of current asthma measures by critically evaluating their applicability for controlled trials of AIT.

Leukotriene receptor antagonists in the treatment of bronchial asthma: Consensus agreement “Bronchial Asthma and LEukoTriene receptor antagonists (BALET)”

Under the auspices of the Russian Association of Allergists and Clinical Immunologists and the Russian Pediatric Respiratory Society, an expert meeting on Leukotriene receptor antagonists in the treatment of bronchial asthma was held.
 Asthma is a common noncommunicable chronic disorder of the airways, characterized by variable and recurring symptoms, airflow obstruction, bronchial hyper-responsiveness, and underlying inflammation.
 The creation and widespread use of inhaled corticosteroids and other innovative classes of drugs for treating bronchial asthma have remarkably affected the ability to achieve control over the course of the disease. Regardless, in most European countries, more than half of patients with bronchial asthma have suboptimal disease control. Recently, a class of leukotriene receptor blockers that contribute to the suppression of chronic allergic inflammation in patients with asthma has been actively studied. The majority of studies confirmed the usefulness of montelukast as monotherapy and as an add-on therapy to inhaled corticosteroids in mild to moderate asthma across all age groups. However, experts noted that in practical medicine, healthcare providers continuously inquire about the effectiveness and safety of this class of medicines in patients with bronchial asthma.
 In this consensus document, the experts considered the importance of providing an answer to several topical questions regarding the use of antileukotriene therapy in clinical practice.

Podcasting in Clinical Allergy and Immunology: Our Experience and a Review of the Current Landscape.

This review aims to improve our understanding of podcasts in the field of Allergy and Immunology and to share our experience in creating and hosting The Itch Podcast. To our knowledge, this is the first review providing an overview of podcasting in the field. We found forty-seven podcasts in our search. Tenof these podcasts were specifically focused on Immunology and the other thirty seven covered allergy topics in general.Of the allergy podcasts, the majority,sixteen out of thirty-seven,were produced and hosted by patients and caregivers of patients living with allergies. Our extensive research on podcasts and our own experience in podcast development has led us to recognize the crucial role that Allergy and Immunology podcasts can play in disseminating medical knowledge and clinical information to the public, while also enhancing the exposure of trainees to this specialty and supporting the professional growth and practice of Allergists and Immunologists.

Clinical Features, Immunological Characteristics, and Treatment Outcomes of Campylobacter spp. Infections in Patients With Common Variable Immunodeficiency

Campylobacter infection usually causes a self-limited clinical illness lasting 5 to 7 days, resolving without antimicrobial treatment in immunocompetent subjects. However, an inadequate immune response can lead to a prolonged and severe disease requiring antibiotics and more aggressive therapeutic approaches. To comprehensively describe Campylobacter spp. infections in patients with common variable immunodeficiency (CVID). A retrospective cohort of 14 CVID patients with Campylobacter infection and 95 CVID controls attending the immunology clinic at a large tertiary hospital was assessed. Immunological, clinical, and microbiological parameters were measured with median follow-up over 20 years in both cohorts. Patients were treated according to a novel algorithm for Campylobacter in antibody-deficient patients. Campylobacter patients had a higher proportion of CD21lowCD38low and transitional B cells (median 38.0% vs 14.2% and 5.4% vs 3.2%) and lower long-term average CD19+ B cells (median 0.06 vs 0.18× 109/L) and CD4+ T cells (0.41 vs 0.62× 109/L) in comparison with the controls. Similarly, Campylobacter patients showed a decline in B cells (median 0.02 vs 0.14× 109/L), CD4+ T cells (0.33 vs 0.59× 109/L), CD8+ T cells (0.26 vs 0.62× 109/L), and natural killer cells (0.08 vs 0.18× 109/L) over time. Antimicrobial resistance, especially to macrolides and fluoroquinolones, was common. Bacterial clearance with associated clinical improvement was obtained after a median of 20 and 113 days for acute Campylobacter (resolution within 3 mo of onset) and chronic Campylobacter (>3 mo) infections, respectively. Seven received first-line treatment (azithromycin or chloramphenicol), 4 second-line (neomycin), and 3 third-line (combination of tigecycline, chloramphenicol, and ertapenem; 1 received gentamicin owing to resistance to carbapenems). Our study highlights immunological and clinical characteristics of recurrent Campylobacter infections in patients with CVID. Our treatment algorithm was successful and should be evaluated in a larger cohort.

UKRAINE AND THE WORLD IN CONDITIONS OF WAR: THE ROLE OF SCIENTIFIC, PROFESSION AND PUBLIC ORGANIZATIONS

UKRAINE AND THE WORLD IN CONDITIONS OF WAR: THE ROLE OF SCIENTIFIC, PROFESSION AND PUBLIC ORGANIZATIONS

Patient-centred digital biomarkers for allergic respiratory diseases and asthma: the ARIA-EAACI approach.

Biomarkers for the diagnosis, treatment and follow-up of patients with rhinitis and/or asthma are urgently needed. Although some biologic biomarkers exist in specialist care for asthma, they cannot be largely used in primary care. There are no validated biomarkers in rhinitis or allergen immunotherapy (AIT) that can be used in clinical practice. The digital transformation of health and health care (including mHealth) places the patient at the centre of the health system and is likely to optimise the practice of allergy. ARIA (Allergic Rhinitis and its Impact on Asthma) and EAACI (European Academy of Allergy and Clinical Immunology) developed a Task Force aimed at proposing patient-reported outcome measures (PROMs) as digital biomarkers that can be easily used for different purposes in rhinitis and asthma. It first defined control digital biomarkers that should make a bridge between clinical practice, randomised controlled trials, observational real-life studies and allergen challenges. Using the MASK-air app as a model, a daily electronic combined symptom-medication score for allergic diseases (CSMS) or for asthma (e-DASTHMA), combined with a monthly control questionnaire, were embedded in a strategy similar to the diabetes approach for disease control. To mimic real-life, it secondly proposed quality-of-life digital biomarkers including daily EQ-5D visual analogue scales and the bi-weekly RhinAsthma Patient Perspective (RAAP). The potential implications for the management of allergic respiratory diseases were proposed.

Evaluation and treatment of rhinosinusitis with primary antibody deficiency in adults: Evidence-based review with recommendations.

There is clear evidence that the prevalence of primary antibody deficiency (PAD) is higher in patients with recurrent and chronic rhinosinusitis (CRS) than in the general population. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on rhinosinusitis with PAD, summarize the existing evidence, and provide recommendations on the evaluation and management of rhinosinusitis in patients with PAD. The PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception through August 2022. Studies on the evaluation and management of rhinosinusitis in PAD patients were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on the evaluation and management principles for PAD were generated. A total of 42 studies were included in this evidence-based review. These studies were evaluated on incidence of PAD in rhinosinusitis patients, incidence of rhinosinusitis in PAD patients, and on the different treatment modalities used and their outcome. The aggregate quality of evidence was varied across reviewed domains. Based on the currently available evidence, PAD can occur in up to 50% of patients with recalcitrant CRS. Despite the presence of multiple studies addressing rhinosinusitis and PAD, the level of evidence supporting different treatment options continues to be lacking. Optimal management requires a multidisciplinary approach through collaboration with clinical immunology. There is need for higher-level studies that compare different treatments in patients with PAD and rhinosinusitis.

Industry–sponsored research funding to allergists and clinical immunologists in the United States

Industry–sponsored research funding to allergists and clinical immunologists in the United States

Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) affects up to 4% of couples attempting to conceive. RPL is unexplained in over 50% of cases and no effective treatments exist. Due to the immune system's pivotal role during implantation and pregnancy, immune-mediated RPL may be suspected and immunomodulatory treatments like intravenous immunoglobulin (IVIg) have been administered but remain controversial. The goal of our study was to evaluate our center's 6year-outcomes and to develop a framework for IVIg use in RPL. Retrospective, single-center cohort study. All patients having received IVIg for unexplained RPL at the McGill Reproductive Immunology Clinic (MRIC) from January 2014 to December 2020 were included if maternal age was <42years, body mass index (BMI)<35kg/m2 , non-smoker and having had ≥3 consecutive RPL despite previous treatment with aspirin and progesterone. IVIg 0.6-0.8g/kg was given prior to conception and monthly during pregnancy until 16-20weeks' gestation. We compared IVIg treated patient's outcomes to a separate "natural history cohort". This cohort was composed of patients consulting at the McGill recurrent pregnancy loss clinic and the MRIC over a 2-year period (January 2020 to December 2021) with similar inclusion criteria as the treatment cohort but did not receive IVIg or other immunomodulatory treatments. The association of IVIg with outcomes (compared to no IVIg) was evaluated among the groups of patients with primary RPL and secondary RPL. The primary outcome was live birth rate (LBR), secondary outcomes included IVIg safety, obstetrical, and neonatal complications. Among 169 patients with unexplained RPL that were included in the study, 111 had primary RPL (38 exposed to IVIg and 83 controls) and 58 had secondary RPL (nine exposed to IVIG and 49 controls). Among patients with primary RPL (n=111), the LBR was 64.3% (18/28) among patient exposed to IVIg compared to 43.4% (36/83) in controls (p=0.079); regression analysis adjusting for BMI and number of previous miscarriages showed benefit favoring the use of IVIg (OR=3.27, CI 95% (1.15-10.2), p=0.03) when evaluating for live birth. In the subgroup of patients with ≥5 previous RPL and primary RPL (n=31), IVIg was associated with higher LBR compared to control (10/15 (66.7%) vs. 3/16 (18.8%); p=0.0113) but not the in the sub-group of patients with <5 miscarriages and primary RPL (8/13 (61.5%) vs. 33/67 (49.3%); p=0.548). IVIG treatment did not improve LBR in patients with secondary RPL in our study (3/9 (33.3%) vs. 23/49 (47%); p=0.495). There were no serious adverse events in the IVIg treatment group, obstetrical/neonatal complications were similar between groups. IVIg may be an effective treatment for patients with RPL if appropriately used in specific groups of patients. IVIg is a blood product and subject to shortages especially with unrestricted off-label use. We propose considering IVIg in well-selected patients with high order RPL who have failed standard medical therapy. Further mechanistic studies are needed to understand immune-mediated RPL and IVIg's mode of action. This will enable further refinement of treatment criteria and the development of standardized protocol for its use in RPL.

Vaccination approach in patients with an allergic reaction to COVID-19 vaccines or at risk of developing allergic reactions

There is consensus that patients at risk of developing an allergic reaction to COVID-19 vaccines should be evaluated by an immunologist-allergist to determine whether vaccination should be recommended. We wanted to share our experiences in the management of these high-risk patients, from diagnostic tests in allergological evaluation to the vaccination process. Our retrospective cross-sectional study included patients who had previously developed an allergic reaction to COVID-19 vaccines or drugs and therefore were referred to our allergy and immunology clinic. Prick and intradermal tests were performed on all patients with methylprednisolone acetate (Depo-Medrol®, Pfizer) 40 mg/mL containing polyethylene Glycol (PEG) and triamcinolone acetonide (Kenacort®, Deva) 40 mg/mL containing polysorbate 80. While vaccination with desensitization was recommended for all patients with positive skin tests, split-dose vaccination was recommended for patients with negative skin tests. After explaining the risks and benefits, the choice of the vaccine (Pfizer/BioNTech or Sinovac/ CoronoVac) was left to the patients' discretion. A total of 41 patients, 10 males, and 31 females, with a mean age of 42.37 ± 14.177 years were included. Eighteen patients with a history of allergy after COVID-19 vaccines were analyzed according to the type of reaction and type of vaccine administered (Pfizer/BioNTech/Coronovac; Anaphylaxis: 4/1, Urticaria: 11/2). Moreover, there was a history of drug allergy in 23 patients who had not been vaccinated before. Skin tests with PEG were positive in a total of seven patients while skin tests with polysorbate 80 were negative in all patients. No allergic reaction developed in seven patients who underwent desensitization and in 34 patients who received a split dose. Considering the potentially life-saving benefits of vaccination in a global pandemic environment, it is a safe and effective method to administer vaccines to at-risk patients using desensitization or split dosing techniques, based on their sensitivity status determined through a PEG skin test. This approach allows for the avoidance of preventing access to vaccines, while still ensuring the safety of patients.

Does Socioeconomic Status Affect Mental Well-being Among Children with Asthma in Kosovo?

The aim of this study was to investigate the relationship between mental well-being – as assessed by the SDQ among children with asthma in Kosovo and SES. Methods and Results: For this cross-sectional observational study, data were collected from five regions of Kosovo, public and private institutions, public hospitals and primary healthcare facilities in each area, a tertiary level hospital, and two private immunology clinics in the capital city. The survey included 161 Kosovar children (mean age of 11.1±2.7 years) with asthma, aged 7-16 years, and their caregivers. The survey questionnaires used were those of the American Academy of Pediatrics: The Children's Health Survey for Asthma (CHSA), the parent and child version (CHSA-C), and the Strengths and Difficulties Questionnaire (SDQ). SDQ showed conspicuous (borderline or abnormal) results in 25.1% of children. None of the scales of the SDQ, except prosocial behavior, showed statistically significant differences across SES categories. Prosocial behavior scores increased significantly with increasing SES. Conclusion: Children with asthma from lower SES families in Kosovo have more social contact problems but do not show reduced mental well-being nor more conduct problems.

Editorial introductions.

Editorial introductions.

Improving Access to Therapy for Patients With Inborn Errors of Immunity: A Call to Action.

Breakthroughs in sequencing technology, targeted immunotherapy, and immune reconstituting treatment have increased the pool of patients with inborn errors of immunity, requiring expertise from clinical immunologists. A growing category of immunodeficiency, presenting as primary immune regulatory disorder and secondary immunodeficiency due to targeted immune therapy for cancer and autoimmunity, has added to the growing burden of patients needing access to immune-supportive therapy. The confluence of a growing population of patients needing a clinical immunologist, complex payer structures, and inadequate health care representation will exacerbate current problems with access to therapy. Patients, health care providers, researchers, public and private payers, and industry must come together to find solutions to improve access to therapy. In this article, we reviewed the major topics regarding access to therapy for patients with immunodeficiency.

Case Series on DRESS: An Unpredictable Adverse Drug Reaction.

Drug rash with eosinophilia and systemic symptoms syndrome (DRESS) is a potentially life-threatening, drug-induced, multi-organ system reaction. The most frequently involved organ is the liver, followed by the kidneys and lungs. Early detection and diagnosis followed by withdrawal of the offending agent is vital to minimise the associated morbidity and mortality, and a detailed drug history is vital to identify the causative drugs. Although Spanish guidelines were developed by a panel of allergy specialists from the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC) and are available in literature from 2020, many clinicians are still unaware about the management of this syndrome. Framing National guidelines for the early diagnosis and pharmaco-therapeutic management of DRESS will help healthcare professionals to save the patients from unintended vulnerability. We hereby present a case series on DRESS.

Shared decision-making, communicating risk, and food allergy in 2023.

Across the practice of allergy and clinical immunology, disruptive innovations have accelerated the adoption of shared decision-making (SDM) to improve the health of patients and populations, particularly with regard to food allergy prevention and management of food allergy and anaphylaxis. A narrative review was performed to describe recent innovations in shared decision-making, risk communication, and food allergy. Several challenges, primarily related to the coronavirus disease 2019 (COVID-19) pandemic and misinformation campaigns, have catalyzed adaptations to evolve clinical care. Recent pressures have facilitated the rapid adoption of telemedicine. In 2023, many allergist/immunologists routinely incorporate both in-person and virtual visits to contextually deliver value-based care to each patient. SDM may occur in a hybrid model that incorporates both in-person and virtual encounters, with many patients experiencing benefit from a combination approach. This may be facilitated by leveraging previsit web-based SDM tools. Whether in person or by telemedicine, effective risk communication to avoid cognitive overload while appreciating population variation in numeracy is key to competent implementation of SDM. Misinformation continues to disproportionately harm patients who belong to groups that encourage denial of evidence-based medical recommendations and COVID-19 vaccination intent correlating with sociopolitical factors. Still, strategies to address misinformation that leverage empathy, respect, and expertise can help to mitigate these effects. Physician wellness is a key component to realization of the Quadruple Aim of health care, and the use of positive framing and appreciative inquiry can help to optimize outcomes and improve value in health care. SDM is an important component to consider when incorporating recent innovations in allergy and clinical immunology care, particularly in the setting of contextual and conditional medical recommendations. Effective risk communication is critical to SDM that is truly reflective of patient goals and preferences, and can be facilitated through in-person encounters, telemedicine, and hybrid models. It is important to foster physician wellness as a component of the Quadruple Aim, particularly in the recent pandemic climate of misinformation and denial of evidence-based medicine within large groups of society.

Preliminary efficacy, safety, and immunomodulatory effects of PT-112 from a phase 2 proof of concept study in patients (pts) with thymic epithelial tumors (TETs).

e20647 Background: Immune checkpoint inhibitors (ICIs) are associated with a high risk of immune-related adverse events (irAEs) in pts with TETs (thymoma and thymic carcinoma). PT-112, a novel inducer of immunogenic cell death, has demonstrated safety and efficacy in phase I trials. We present results of an unplanned interim analysis of a phase 2, NIH IRB-approved clinical trial to evaluate the clinical activity, tolerability, and correlative immunology of PT-112 in TETs (NCT05104736). Methods: Eligible pts with TETs with progression after prior platinum therapy were treated with PT-112 360 mg/m2 iv on days 1, 8 and 15 of a 28-day cycle until progression or development of intolerable toxicity. Prior history of autoimmunity (AI) or treatment with ICI was permitted. Primary objective is to determine the objective response rate. Immune activation was assessed by flow cytometry and multiplex immunofluorescence. Results: Ten pts have received treatment (median age 54, 3 females, 5 thymic carcinomas, 3 with prior TET-associated AI disease). Median number of prior systemic therapies is 2.5 (range, 1-4) and all pts have received cisplatin, paclitaxel, or both previously. Nine pts are evaluable for response, with stable disease in 8 (89%) and progressive disease in 1 (11%) pt. After a median potential follow-up of 7.4 months (mo) median progression-free survival is not reached in pts with thymoma and is 6.2 mo (95% CI: 1.8- 7.9 mo) in thymic carcinoma. All pts are evaluable for toxicity. The most common (all grades) treatment-related adverse events (TRAEs) are peripheral neuropathy (60%), anemia, fatigue and myalgias (each in 50%). Grade ≥ 3 TRAEs in more than one patient include anemia (30%) and neutropenia (20%). Two (20%) pts experienced relapse of AI: ocular myasthenia and immune cytopenias. The most common reason for treatment hold is peripheral neuropathy (40%). Treatment was discontinued due to TRAE (peripheral neuropathy) in 1 (10%) pt. There are no treatment related deaths. Treatment was associated with an increase in CD8+ T cells, activated CD4+ T cells and NK cells in peripheral blood. There was an increase in pro-inflammatory serum analytes (IFNg, TNFa, sCD27:sCD40L and sCD73) and a decrease in immunosuppressive analytes (VEGF, sCD40L and TGFb) compared with baseline. Paired tumor biopsies are being analyzed by multiplex immunofluorescence and results will be presented. Conclusions: PT-112 is safe and clinically active in pts with recurrent TETs. In contrast to ICIs, no new irAEs were observed. Immune analyses show evidence of early treatment-related immune activation and support the rationale underlying this novel treatment approach for TETs. Enrollment is ongoing with an accrual ceiling of 53. These initial results support further evaluation of PT-112 in TETs as monotherapy and in combination with other immunomodulatory interventions. Clinical trial information: NCT05104736 .

The Allergen Immunotherapy Adverse Events Registry: Setup &amp; methodology of a European Academy of Allergy and Clinical Immunology taskforce project

The Allergen Immunotherapy Adverse Events Registry: Setup &amp; methodology of a European Academy of Allergy and Clinical Immunology taskforce project

Adverse events in children and adolescents undergoing allergen immunotherapy for respiratory allergies-Report from the Allergen Immunotherapy Adverse Events Registry (ADER), a European Academy of Allergy and Clinical Immunology taskforce.

Although it has been shown that allergen immunotherapy (AIT) is well-tolerated in children, systematic and prospective surveillance of AIT safety in real life settings is needed. The multinational Allergen Immunotherapy Adverse Events Registry (ADER) was designed to address AIT safety in real life clinical practice. Data on children ≤18years old with respiratory allergies undergoing AIT were retrieved. Patient- and AIT-related features were collected and analyzed. The characteristics of adverse events (AE) and risk factors were evaluated. A total of 851 patients, 11.3±3.4years old, with rhinitis only (47.6%); asthma and rhinitis (44.5%); asthma (7.9%), receiving 998 AIT courses were analyzed. Sublingual immunotherapy (SLIT) accounted for 51% of the courses. In 84.5% of patients only one AIT treatment was prescribed. Pollen was the most frequent sensitizer (57.1%), followed by mites (53.4%), molds (18.2%) and epithelia (16.7%). Local and systemic AEs were reported in 85 patients (9.9%). Most AEs (83.1%) were mild and occurred in <30min (87%). Respiratory and cutaneous symptoms were more frequent. Only 4 patients (0.47%) had severe AE (none after 6weeks of maintenance). The risk of AE was higher in patients undergoing SCIT. AIT is safe and well tolerated in children and adolescents with respiratory allergies in real-life clinical practice. Though SCIT is more prone to AE compared to SLIT, overall severe reactions are rare and occur during build-up and early maintenance.

The role of online symptom questionnaires to support the diagnosis of cow's milk allergy in children for healthcare professionals - A Delphi consensus study.

Cow's milk allergy (CMA) is one of the most common food allergies world-wide. The emergence of online CMA symptom questionnaires, aimed at parents and/or healthcare professionals (HCP), may raise awareness about the possible diagnosis of CMA, but also increases the risk for overdiagnosis leading to unnecessary dietary restriction impacting on growth and nutrition. This publication sets out to establish the availability of these CMA symptom questionnaires and critically assesses the development and validity. Thirteen HCP working in the field of CMA, from different countries, were recruited to participate. A combination of a Pubmed and CINAHL literature and online review using the Google search engine in English language was used. Symptoms in the questionnaires were assessed, using the European Academy for Allergy and Clinical Immunology guidelines for food allergy. Following the assessment of both the questionnaires and literature, the authors followed the modified Delphi approach to generate consensus statements. Six hundred and fifty-one publications were identified, of which 29 were suitable for inclusion, with 26 being associated with the Cow's Milk-Related Symptoms Score. The online search yielded 10 available questionnaires: 7/10 were sponsored by formula milk companies and 7/10 were aimed at parents and three at HCP. Following the assessment of data, 19 statements were generated in two rounds of anonymous voting reaching 100% agreement. Online CMA questionnaires, available to parents and HCP's, are varied in symptoms, and most were not validated. The overarching consensus generated from authors is that these questionnaires should not be used without the involvement of HCP.