Penicillin Skin Testing, Challenge, and Desensitization in Pregnancy: A Systematic Review.

OBJECTIVE: This study sought to evaluate available evidence of the safety of penicillin skin testing (PST), challenge, and desensitization in pregnancy, with efforts to improve perinatal care for patients with a penicillin allergy history and mitigate the negative sequelae of unverified penicillin allergy labels. METHODS: A systematic review of studies was conducted using Cochrane Library, Medline, EMBASE, and International Pharmaceutical Abstracts. Included were peer-reviewed studies without date restrictions, published in English or French, relating to PST, challenge, or desensitization in pregnancy. Editorials, opinion pieces, and letters were excluded. Review authors independently screened citations and full-text articles, extracted data, and conducted quality assessment. Given the heterogeneity of study designs, a narrative synthesis was conducted. RESULTS: The search identified 1195 references, of which 18 studies met inclusion criteria. In total there were 231 patients with varying histories of penicillin allergy, the majority requiring treatment for syphilis or group B streptococcal (GBS) disease during pregnancy. Of the 203 participants who underwent PST, 83.7% had negative test results. Allergy-related reactions were rare in PST (1.5%) and challenge (0%), and although these reactions were more common in desensitization (19.7%), most were benign. Among the 231 cases, only one adverse pregnancy outcome was reported (0.4%). CONCLUSION: This review demonstrates that the known prevalence of true penicillin allergy extends to pregnant women. PST and desensitization can be safely applied during pregnancy and are tools that should be used more frequently. Further data on the safety of challenge during pregnancy are recommended.

Revaccination outcomes among adolescents and adults with suspected hypersensitivity reactions following COVID-19 vaccination: A Canadian immunization research network study.

BACKGROUND: COVID-19 vaccination has been associated with anaphylaxis and hypersensitivity reactions. Infectious disease physicians and allergists in the Canadian Special Immunization Clinic (SIC) Network developed guidance for evaluating patients with adverse events following immunization (AEFI) including suspected hypersensitivity. This study evaluated management and adverse event recurrence following subsequent COVID-19 vaccinations. METHODS: Individuals aged 12 years and older enrolled at participating SICs before February 28, 2023 who were referred for suspected or diagnosed hypersensitivity reaction following COVID-19 vaccination, or for prevaccination assessment of suspected allergy to a COVID-19 vaccine component were included. De-identified clinical assessments and revaccination data, captured in a centralized database, were analyzed. The Brighton Collaboration case definition (BCCD) for anaphylaxis (2023 version) was applied. RESULTS: The analysis included 206 participants from 13 sites: 26 participants referred for pre-vaccination assessment and 180 participants referred for adverse events following COVID-19 vaccination (15/180 [8.3%] with BCCD confirmed anaphylaxis, 84 [46.7%] with immediate hypersensitivity symptoms not meeting BCCD, 33 [18.3%] with other diagnosed hypersensitivity reactions, and 48 [26.7%] participants with a final diagnosis of non-hypersensitivity AEFI). Among participants referred for AEFIs following COVID-19 vaccination, 166/180 (92.2%) were recommended for COVID-19 revaccination after risk assessment, of whom 158/166 (95.2%) were revaccinated (all with a COVID-19 mRNA vaccine). After revaccination, 1/15 (6.7%) participants with prior anaphylaxis, 1/77 (1.3%) with immediate hypersensitivity not meeting criteria for anaphylaxis and 1/24 (4.2%) with other physician diagnosed hypersensitivity developed recurrent AEFI symptoms that met the BCCD for anaphylaxis. All 26 participants referred pre-vaccination, including 9 (34.6%) with history of polyethylene glycol-asparaginase reactions, were vaccinated without occurrence of immediate hypersensitivity symptoms. CONCLUSIONS: Most individuals in this national cohort who experienced a hypersensitivity event following COVID-19 vaccination and were referred for specialist review were revaccinated without AEFI recurrence, suggesting that specialist evaluation can facilitate safe revaccination.

Assessment of epicutaneous testing of a monovalent Influenza A (H1N1) 2009 vaccine in egg allergic patients.

BACKGROUND: H1N1 is responsible for the first influenza pandemic in 41 years. In the fall of 2009, an H1N1 vaccine became available in Canada with the hopes of reducing the overall effect of the pandemic. The purpose of this study was to assess the safety of administering 2 different doses of a monovalent split virus 2009 H1N1 vaccine in egg allergic patients. METHODS: Patients were skin tested to the H1N1 vaccine in the outpatient paediatric and adult allergy and immunology clinics of the Health Sciences Centre and Children's Hospital of Winnipeg, Manitoba Canada. Individuals <9 years of age were administered 1.88 µg's of hem-agglutinin antigen per 0.25 ml dose and individuals ≥9 years were administered 3.75 µg's of hemagglutinin antigen per 0.5 ml dose. Upon determination of a negative skin test, the vaccine was administered with a 30 minute observation period. RESULTS: A total of 61 patients with egg allergy (history of an allergic reaction to egg with either positive skin test &/or specific IgE to egg >0.35 Ku/L) were referred to our allergy clinics for skin testing to the H1N1 vaccine. 2 patients were excluded, one did not have a skin prick test to the H1N1 vaccine (only vaccine administration) and the other passed an egg challenge during the study period. Ages ranged from 1 to 27 years (mean 5.6 years). There were 41(69.5%) males and 18(30.5%) females. All but one patient with a history of egg allergy, positive skin test to egg and/or elevated specific IgE level to egg had negative skin tests to the H1N1 vaccine. The 58 patients with negative skin testing to the H1N1 vaccine were administered the vaccine and observed for 30 minutes post vaccination with no adverse results. The patient with the positive skin test to the H1N1 vaccine was also administered the vaccine intramuscularly with no adverse results. CONCLUSIONS: Despite concern regarding possible anaphylaxis to the H1N1 vaccine in egg allergic patients, in our case series 1/59(1.7%) patients with sensitization to egg were also sensitized to the H1N1 vaccine. Administration of the H1N1 vaccine in egg allergic patients with negative H1N1 skin tests and observation is safe. Administering the vaccine in a 1 or 2 dose protocol without skin testing is a reasonable alternative as per the CSACI guidelines.

Effectiveness of C1-INH therapy in angiotensin converting enzyme inhibitor induced angioedema.

INTRODUCTION: Angiotensin Converting Enzyme Inhibitors (ACEI) are a common cause of Emergency Room presentation for angioedema. Although no treatment guidelines exist, C1 esterase inhibitor concentrate (C1-INH) is used on an off label basis for management of ACEI acquired angioedema (ACEI AAE). OBJECTIVE: To evaluate the efficacy of C1-INH in management of ACEI AAE at our local centers. RESULTS: Nine patients, from 3 academic sites, were identified through Allergy Service consultation data and records from Diagnostic Services Manitoba, Canada from 2010-2020. The majority of the patients (n = 8/9) required endotracheal intubation prior to the initiation of C1-INH. Overall, approximately 56% of patients (n = 5/9) had resolution of angioedema ranging between 12 and 17 h, with a median time of 13.5 h, and no recurrence after the administration of C1-INH concentrate. One patient had transient symptom resolution in 14 h, however, recurrence of angioedema required re-intubation. The remainder of patients (n = 4/9), had resolution of angioedema between 22 and 72 h, with a median time of 33.75 h. CONCLUSION: Our findings demonstrate continued ambivalence of the efficacy and role of C1-INH concentrate in the treatment of ACEI AAE, secondary to multiple uncontrolled confounding factors. Further research into characterizing a subgroup of intubated patients in our study that responded to C1-INH concentrate needs to be completed.

Adult-onset IgE-mediated food allergy at a Winnipeg allergy clinic: a case series.

BACKGROUND: It is a putatively understood phenomenon that the overall prevalence of allergic disease has been increasing in recent decades-particularly in industrialized nations. Despite this, there is a relative scarcity of data concerning the development of food-related allergic disease in the adult population. In addition, the paucity of data as it pertains to the Canadian population is particularly marked when compared to other nations. We sought to determine common culprit foods and the reactions they elicited in a series of 14 patients seen in the Winnipeg allergy and immunology clinic. METHODS: We conducted a retrospective review of patients identified by academic allergists in Winnipeg, Manitoba as fitting criteria for adult-onset IgE-mediated food allergy from May 2018-July 2020. We included patients with IgE-mediated symptoms, including the pollen-food syndrome which developed at the age of 16 or later. We collected data regarding the food which induced the reaction, what the reaction was, and any concomitant atopic disease. RESULTS: The most common culprit food identified was shellfish, followed by finfish, pollen-food syndrome, and wheat/flour. The most common reaction experienced was anaphylaxis, followed by food-dependent exercise-induced anaphylaxis and isolated (muco)cutaneous symptoms. With regard to concomitant atopic disease, allergic rhinitis/rhinoconjunctivitis stood out as the most prevalent. CONCLUSIONS: Adult-onset food allergy-particularly with resultant anaphylaxis-is an important phenomenon to recognize, even when patients have previously tolerated the food in question.

Review of icatibant use in the Winnipeg Regional Health Authority.

BACKGROUND: This is a retrospective review of the Winnipeg Regional Health Authority's (WRHA) angioedema patients who were dispensed icatibant in hospital. Icatibant is a bradykinin B2 receptor antagonist indicated for Hereditary Angioedema (HAE) types I and II and is used off-label for HAE with normal C1INH (HAE-nC1INH) and ACE-inhibitor induced angioedema (ACEIIAE). The WRHA's use of icatibant is regulated by the Allergist on call. We characterized icatibant's use and the timeline from patient presentation, compared the real-world experience with the FAST-3 trial and hypothesized the factors which may affect response to icatibant. METHODS: Background data were collected on patients. Angioedema attack-related data included administered medications, performed investigations and the timeline to endpoints such as onset of symptom relief. Data was analyzed in R with the package "survival." Time-to-event data was analyzed using the Peto-Peto Prentice method or Mann-Whitney U-test. Data was also compared with published clinical trial data using the Sign Test. Fisher's Exact Test was used to produce descriptive statistics. RESULTS: Overall, 21 patients accounted for 23 angioedema attacks treated with icatibant. Approximately half the patients had a diagnosis of HAE-nC1IHN and half of ACEIIAE. Of those presenting with angioedema, 65% were first treated with conventional medication. Patients without a prior angioedema diagnosis were evaluated only 40-50% of the time for C4 levels or C1INH function or level. The median time from patients' arrival to the emergency department until the Allergy consultant's response was 1.77 h. Patients with HAE-nC1IHN had median times to onset of symptom relief and final clinical outcome (1.13 h, p = 0.34; 3.50 h, p = 0.11) similar to those reported in FAST-3 for HAE I/II. Patients with ACEIIAE had longer median times to onset of symptom relief (4.86 h, p = 0.01) than predicted. CONCLUSIONS: HAE-nC1INH may be an appropriate indication for treatment with icatibant. Conversely, the results of this study do not support the use of icatibant for the treatment of ACEIIAE, concordant with a growing body of literature. Patients should be stratified into groups of more- or less-likely icatibant-responders through history and laboratory investigations in order to prevent potential delays.

Delivery of subcutaneous immunoglobulin by rapid "push" infusion for primary immunodeficiency patients in Manitoba: a retrospective review.

BACKGROUND: Both intravenous and subcutaneous human immune globin G (IgG) replacement (IVIG and SCIG, respectively) reduce severe infection and increase serum IgG levels in primary immune deficiency disorder (PIDD) patients who require replacement. SCIG can be administered either with the aid of an infusion pump, or by patients or caregivers themselves, using butterfly needles and a syringe ("SCIG push"). SCIG offers advantages over IVIG, including higher steady state IgG levels, improved patient quality of life indicators, and decreased cost to the healthcare system, and for these reasons, SCIG has been increasingly used in Manitoba starting in 2007. We sought to determine the effectiveness of SCIG push in our local adult PIDD population. METHODS: We conducted a retrospective chart review of all adult patients enrolled in the SCIG push program in Manitoba, Canada from its inception in November 2007 through September 2018. We included patients who were naïve to IgG replacement prior to SCIG, and those who had received IVIG immediately prior. We collected data regarding serum IgG levels, antibiotic prescriptions, hospital admissions, and adverse events during a pre-defined period prior to and following SCIG initiation. Statistical significance was determined via two-tailed t-test. RESULTS: 62 patients met inclusion criteria, of whom 35 were on IVIG prior and 27 were IgG replacement naïve. SCIG push resulted in an increase in serum IgG levels in those naïve to IgG replacement, as well as in those who received IVIG prior. SCIG push also resulted in a statistically significant reduction in number of antibiotic prescriptions filled in the naïve subgroup, and no significant change in antibiotics filled in the IVIG prior group. 8/62 PIDD patients (12.9%) left the SCIG program during our review period for varying reasons, including side-effects. CONCLUSIONS: In a real-life setting, in the Manitoba adult PIDD population, SCIG push is an effective method of preventing severe infections, with most patients preferring to continue this therapy once initiated.

Review of the Manitoba cohort of patients with hereditary angioedema with normal C1 inhibitor.

BACKGROUND: Hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) is a rare, underappreciated condition characterized by recurrent subcutaneous angioedema. The underlying pathophysiology and diagnostic criteria continues to evolve. There is a significant overlap between HAE-nC1 INH and idiopathic nonhistaminergic angioedema, ultimately this may be found to be the same condition. Characterization of cohorts suspected to have either of these conditions is warranted to help refine diagnosis, pathophysiology, and treatment response. METHODS: A retrospective chart review of 418 patients diagnosed with angioedema was conducted. The following inclusion criteria was used: lack of response to antihistamines, steroids, and epinephrine; normal C4, C1 inhibitor (C1 INH) level and function; lack of urticaria or pruritus; occurrence without offending drugs; and positive family history. Enzyme immunoassays for C1 INH function were performed at the Mayo Clinic. Charts meeting these criteria were reviewed for frequency and type of episodes as well as use and response to therapies. RESULTS: 6 patients met the above criteria. 3 of these completed genetic testing, none were found to have factor XII abnormalities. None had angiopoietin 1 or plasminogen gene sequencing. 5 of 6 patients were successfully treated with C1 INH or tranexamic acid for acute treatment of attacks (4 with C1 INH and 1 with tranexamic acid). 4 patients have used Icatibant with good response (typically under 40 min for near full recovery); of these, 3 required Icatibant as acute treatment after other therapies (C1 inhibitor and tranexamic acid) were ineffective. There were 9 patients who otherwise met criteria, but due to a lack of family history were classified as having idiopathic non-histaminergic angioedema. CONCLUSIONS: This retrospective chart review found 6 HAE-nC1 INH patients in Manitoba. 1 responded to tranexamic acid and not C1 INH, 4 typically responded to C1 INH, and 1 responded exclusively to Icatibant. All patients-4 total-who used Icatibant responded; of these 4 patients, 3 required Icatibant after other therapies had failed.

A novel combination of an IgE mediated adult onset food allergy and a suspected mast cell activation syndrome presenting as anaphylaxis.

BACKGROUND: Adult onset food allergy is a rare, but increasingly recognized phenomenon. Mast cell activation syndromes present an ongoing diagnostic and classification challenge. The combination of the two has been rarely described in the literature. CASE PRESENTATION: We present a case of a new onset, IgE mediated food allergy in combination with a mast cell activation syndrome in an elderly patient not known to have a history of atopy. He presented to a hospital with a first presentation of anaphylaxis manifesting profound hypotension following consumption of a stew consisting of fish and shellfish. He had a persistently elevated serum tryptase and demonstrated evidence of high titre serum specific IgE to shellfish. He responded well to histaminergic blockade. CONCLUSIONS: Given that mast cell activation syndromes pose an increased risk for recurrent, severe anaphylaxis and that secondary causes of mast cell activation syndromes are more prevalent with aging, this case highlights the importance of considering this entity when evaluating an elderly patient with a first presentation of anaphylaxis.

A retrospective comparison of false negative skin test rates in penicillin allergy, using pencilloyl-poly-lysine and minor determinants or Penicillin G, followed by open challenge.

BACKGROUND: A history of penicillin allergy in patients is common, but only 10-15 % are truly allergic. While the gold standard for diagnosing penicillin allergy is challenge, it is not recommended that this be done without first carrying out diagnostic skin testing. This is carried out with the major determinant benzylpenicilloyl (PPL) and the minor determinant mixture (MDM), consisting of penilloate, penicilloate and Penicillin G. However, since availability of the MDM is limited, Penicillin G alone has been used. METHODS: A retrospective chart review was carried out on patients tested for penicillin allergy in the Clinical Immunology and Allergy Clinic at the Health Sciences Centre, Winnipeg, Canada between 2005 and 2013. A total of 521 patients charts were reviewed, of whom 240 had skin testing, ImmunoCap(®) for IgE to Penicillin G and V and had oral challenges with penicillin, amoxicillin or cloxacillin. RESULTS: 17/240 (7.5 %) were skin test positive, 8 to PPL, 4 to MDM and 5 to Penicillin G. One was also positive on ImmunoCap(®) testing. Three patients had negative skin tests but weakly positive ImmunoCap(®). 222 patients with negative skin tests and serological tests were challenged. Of these, 12 patients reacted to challenge. Three of the challenges were equivocal. Of the nine patients with definite positive challenges, three were tested with Penicillin G and six with MDM. Therefore the false negative rates for testing were 2.3 % with PPL and Penicillin G and 6.97 % for PPL and MDM. The difference was not significant (p = 0.0856). CONCLUSIONS: In this group of patients with a history of penicillin allergy tested with the major determinant of benzyl penicillin and either MDM or Penicillin G, there was no difference in the rate of false negative testing, based on oral penicillin challenges. Therefore, Penicillin G can be safely used as an alternative to MDM in diagnosing penicillin allergy.

Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema.

BACKGROUND: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) in 2004. OBJECTIVE: To ensure that this consensus remains current. METHODS: In collaboration with the Canadian Network of Rare Blood Disorder Organizations, we held the second Canadian Consensus discussion with our international colleagues in Toronto, Ontario, on February 3, 2006, and reviewed its content at the Fifth C1 Inhibitor Deficiency Workshop in Budapest on June 2, 2007. Papers were presented by international investigators, and this consensus algorithm approach resulted. RESULTS: This consensus algorithm outlines the approach recommended for the diagnosis, therapy, and management of HAE, which was agreed on by the authors of this report. This document is only a consensus algorithm approach and continues to require validation. As such, participants agreed to make this a living 2007 algorithm, a work in progress, and to review its content at future international HAE meetings. CONCLUSIONS: There is a paucity of double-blind, placebo-controlled trials on the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Controlled trials currently under way will provide further insight into the management of HAE. As with our Canadian 2003 Consensus, this 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE was formed through the meeting and agreement of patient care professionals along with patient group representatives and individual patients.