Updated guidance regarding the risk of allergic reactions to COVID-19 vaccines and recommended evaluation and management: A GRADE assessment and international consensus approach.

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.

Wild-type SARS-CoV-2 neutralizing immunity decreases across variants and over time but correlates well with diagnostic testing.

Importance: The degree of immune protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants provided by infection versus vaccination with wild-type virus remains unresolved, which could influence future vaccine strategies. The gold-standard for assessing immune protection is viral neutralization; however, few studies involve a large-scale analysis of viral neutralization against the Omicron variant by sera from individuals infected with wild-type virus. Objectives: 1) To define the degree to which infection versus vaccination with wild-type SARS-CoV-2 induced neutralizing antibodies against Delta and Omicron variants.2) To determine whether clinically available data, such as infection/vaccination timing or antibody status, can predict variant neutralization. Methods: We examined a longitudinal cohort of 653 subjects with sera collected three times at 3-to-6-month intervals from April 2020 to June 2021. Individuals were categorized according to SARS-CoV-2 infection and vaccination status. Spike and nucleocapsid antibodies were detected via ADVIA Centaur® (Siemens) and Elecsys® (Roche) assays, respectively. The Healgen Scientific® lateral flow assay was used to detect IgG and IgM spike antibody responses. Pseudoviral neutralization assays were performed on all samples using human ACE2 receptor-expressing HEK-293T cells infected with SARS-CoV-2 spike protein pseudotyped lentiviral particles for wild-type (WT), B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants. Results: Vaccination after infection led to the highest neutralization titers at all timepoints for all variants. Neutralization was also more durable in the setting of prior infection versus vaccination alone. Spike antibody clinical testing effectively predicted neutralization for wild-type and Delta. However, nucleocapsid antibody presence was the best independent predictor of Omicron neutralization. Neutralization of Omicron was lower than neutralization of either wild-type or Delta virus across all groups and timepoints, with significant activity only present in patients that were first infected and later immunized. Conclusions: Participants having both infection and vaccination with wild-type virus had the highest neutralizing antibody levels against all variants and had persistence of activity. Neutralization of WT and Delta virus correlated with spike antibody levels against wild-type and Delta variants, but Omicron neutralization was better correlated with evidence of prior infection. These data help explain why 'breakthrough' Omicron infections occurred in previously vaccinated individuals and suggest better protection is observed in those with both vaccination and previous infection. This study also supports the concept of future SARS-CoV-2 Omicron-specific vaccine boosters.

Vaccination counseling with and without excipient skin testing in patients with suspected allergic reactions to mRNA COVID-19 vaccines and patients with atopy.

Background: Allergic reactions have been reported with mRNA vaccines for COVID-19 prevention. Patients perceived to be at higher risk for a reaction may be referred to an allergist, although evaluation strategies may differ between allergists. Objective: Our aim was to determine outcomes of COVID-19 vaccinations in patients evaluated by an allergist using different approaches. Methods: We conducted a retrospective case series evaluation of 98 patients seen at the University of Michigan Allergy Clinic for concerns regarding COVID-19 vaccination. Of these 98 patients, 34 underwent skin testing with polyethylene glycol (PEG) 2000 with or without PEG 3350/polysorbate 80 testing. Results: Of the 34 patients on whom skin testing was performed, 16 underwent testing before vaccination and 18 underwent testing after a reported vaccine-related event. One patient had a positive skin testing result in response to PEG 3350 following a vaccination reaction and natural infection and was advised against a second dose. One patient with a significant history concerning of anaphylaxis in response to PEG had positive results of testing to identify allergy to PEG 2000, PEG 3350, and polysorbate 80 and was advised against vaccination. Of the 98 patients, 63 (64%) tolerated COVID-19 vaccination without complication after evaluation by an allergist. Conclusion: No significant differences were found between vaccination counseling with and without skin testing to excipients. Patients who presented before the first dose of vaccination were more likely to proceed with COVID-19 vaccination and tolerate vaccination without complication.

Mild SARS-CoV-2 Illness Is Not Associated with Reinfections and Provides Persistent Spike, Nucleocapsid, and Virus-Neutralizing Antibodies.

Uncertainty exists whether mild COVID-19 confers immunity to reinfection. Questions also remain regarding the persistence of antibodies against SARS-CoV-2 after mild infection. We prospectively followed at-risk individuals with and without SARS-CoV-2 for reinfection and monitored the spike and nucleocapsid antibodies. This prospective cohort study was conducted over two visits, 3 to 6 months apart, between May 2020 and February 2021. Adults with and without COVID-19, verified by FDA EUA-approved SARS-CoV-2 RT-PCR assays, were screened for spike and nucleocapsid antibody responses using FDA EUA-approved immunoassays and for pseudoviral neutralization activity. The subjects were monitored for symptoms, exposure to COVID-19, COVID-19 testing, seroconversion, reinfection, and vaccination. A total of 653 subjects enrolled; 129 (20%) had a history of COVID-19 verified by RT-PCR at enrollment. Most had mild disease, with only three requiring hospitalization. No initially seropositive subjects experienced a subsequent COVID-19 infection during the follow-up versus 15 infections among initially seronegative subjects (infection rates of 0.00 versus 2.05 per 10,000 days at risk [P = 0.0485]). In all, 90% of SARS-CoV-2-positive subjects produced spike and nucleocapsid responses, and all but one of these had persistent antibody levels at follow-up. Pseudoviral neutralization activity was widespread among participants, did not decrease over time, and correlated with clinical antibody assays. Reinfection with SARS-CoV-2 was not observed among individuals with mild clinical COVID-19, while infections continued in a group without known prior infection. Spike and nucleocapsid COVID-19 antibodies were associated with almost all infections and persisted at stable levels for the study duration. IMPORTANCE This article demonstrates that people who have mild COVID-19 illnesses and produce antibodies are protected from reinfection for up to 6 months afterward. The antibodies that people produce in this situation are stable for up to 6 months as well. Clinical antibody assays correlate well with evidence of antibody-related viral neutralization activity.

The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Accurate point-of-care serology tests for COVID-19.

BACKGROUND: As COVID-19 vaccines become available, screening individuals for prior COVID-19 infection and vaccine response in point-of-care (POC) settings has renewed interest. We prospectively screened at-risk individuals for SARS-CoV-2 spike and nucleocapsid protein antibodies in a POC setting to determine if it was a feasible method to identify antibody from prior infection. METHODS: Three EUA-approved lateral flow antibody assays were performed on POC finger-stick blood and compared with serum and a CLIA nucleocapsid antibody immunoassay. Variables including antibody class, time since PCR, and the assay antigen used were evaluated. RESULTS: 512 subjects enrolled, of which 104 had a COVID-19 history and positive PCR. Only three PCR-positive subjects required hospitalization, with one requiring mechanical ventilation. The POC results correlated well with the immunoassay (93-97% sensitivity) and using serum did not improve the sensitivity or specificity. CONCLUSIONS: Finger-stick, POC COVID-19 antibody testing was highly effective in identifying antibody resulting from prior infections in mildly symptomatic subjects. Using high-complexity serum immunoassays did not improve the screening outcome. Almost all individuals with COVID-19 infection produced detectable antibodies to the virus. POC antibody testing is useful as a screen for prior COVID-19 infection, and should be useful in assessing vaccine response.

Factors correlated with repeated aspirin dosing during aspirin desensitization.

BACKGROUND: Aspirin desensitization is an appropriate procedure for many patients with aspirin-exacerbated respiratory disease (AERD). Patients can require aspirin re-dosing, which prolongs the desensitization process. The frequency of this is not widely reported, nor is it known which patients will require multiple re-dosing. OBJECTIVE: To determine the frequency of and factors associated with repeat aspirin re-dosing during desensitization. METHODS: Charts of aspirin desensitization procedures from 2011 to 2016 at the University of Michigan Allergy/Immunology Clinic were reviewed. Reactions with provoking doses and number of dose repetitions were characterized. Previous AERD history, medical history, medications, and baseline spirometry were also recorded. Bivariate correlation and multivariate logistic regression were used to analyze associations between patient characteristics and need for repeated dosing of aspirin. RESULTS: A total of 84 positive-reacting patients during desensitization were identified. Of these patients, 33% required 2 or more aspirin dose repetitions during desensitization. Requiring 2 or more repeat doses during desensitization was associated with male gender (odds ratio = 6.194, P = .008), forced expiratory volume in 1 second (FEV1) decrease during desensitization (odds ratio = 1.075 per percent point drop, P = .021), and initial aspirin provoking dose during desensitization of 81 mg or lower (odds ratio = 11.111, P = .003). No association was found with pre-desensitization medications, asthma severity, AERD duration, or number/character of reported previous aspirin reactions. CONCLUSION: During aspirin desensitization for AERD, approximately one third of our patients require multiple repeat doses. Risk factors for multiple repeated doses include male gender, drop in FEV1, and lower aspirin provoking doses during desensitization. This information can help inform which patients may require multiple re-dosing for desensitization.

Hidden Causes of Anaphylaxis.

PURPOSE OF REVIEW: This study aimed to review important hidden causes of anaphylaxis in ingestants, non-ingestants, and uncommon settings. RECENT FINDINGS: Multiple new and elusive causes of anaphylaxis have been described over the past 35 years. Further research is required to identify the epidemiology, pathophysiology, and clinical impact of these hidden causes. Although these culprits should be considered in the appropriate clinical scenarios, many remain exceedingly rare.

Frequency and severity of reactions to a 325-mg aspirin dose during desensitization.

BACKGROUND: The frequency with which patients with aspirin-exacerbated respiratory disease (AERD) react to 325 mg of aspirin during aspirin desensitization, or fail to react at all, is not fully known. OBJECTIVE: To determine the rate and type of reaction at 325 mg of aspirin during desensitization. METHODS: A retrospective study of 104 patients who underwent aspirin desensitization from 2010 to 2016 was performed. A standard desensitization protocol (starting at 20-40 mg, progressing through 325 mg, and extinguishing reactions by dose repetition) was used. Reactions were defined by upper respiratory tract symptoms, lower respiratory tract symptoms, and/or forced expiratory volume in 1 second decrease of 15% or greater. Patients who did and did not react were compared by logistic regression. RESULTS: Eighty-four patients reacted (81%) and 20 did not (19%). Seventy-seven patients who had a provoking reaction at 162 mg of aspirin or less subsequently extinguished their reactions before they reached a dose of 325 mg and had no problems at that dose; one subsequent 325-mg reaction occurred during a protocol violation. One initial provoking reaction to 325 mg occurred. Both 325-mg reactions were mild, and neither met the forced expiratory volume in 1 second criterion for a clinically meaningful change. The remaining 5 patients could not complete the protocol because of persistent reactions or social reasons. Reactors were more likely to have had asthma for more than 10 years than nonreactors (odds ratio, 3.2; 95% confidence interval, 1.0-10.3; P = .05). CONCLUSION: During aspirin desensitization for AERD, provoking reactions at the 325-mg dose are rare (1%) and mild. Patients who react at 162 mg or less and extinguish their reactions may be able to administer the 325-mg dose at home.

A 60-year-old woman with recurrent episodes of flushing, urticaria, and angioedema.

Recurrent episodes of flushing, urticaria, and angioedema raise suspicion for many conditions with a wide differential diagnosis. The diagnostic approach involves consideration of allergic, cardiovascular, gastrointestinal, endocrine, infectious, neurologic, dermatologic, and drug-related causes. We describe a unique case of recurrent episodes of flushing, urticaria, and angioedema that has gone into remission after a novel therapeutic intervention.

Systemic reactions to inhalant immunotherapy using 1:1 target dosing.

BACKGROUND: The 2007 immunotherapy practice parameters advocate maintenance dosing at 1:1 (1:20 maintenance concentrate). There is limited literature exploring the effect of 1:1 dosing on the rate of systemic reactions to subcutaneous immunotherapy (SRITs). OBJECTIVE: To investigate the effects of 1:1 dosing on SRITs in a large, academic practice. METHODS: We conducted a retrospective cohort study of all nonvenom and noncluster SRITs that occurred between 2005 and 2011. SRITs that occurred from August 2008 through December 2011, postparameter dosing (post-PD) was initiated, were compared to SRITs that occurred from January 2005 to July 2008 with preparameter dosing (pre-PD) using 1:50 as a maintenance concentrate. RESULTS: A total of 269 SRITs occurred in a 7-year period. Significantly more post-PD SRITs (131 of 38,548 injections) occurred than pre-PD SRITs (132 of 52,833 injections) (0.34% vs 0.25%, P = .01). However, when excluding 44 SRITs that occurred in established pre-PD patients transitioned to post-PD, there was no significant difference in SRIT rate (0.25% vs 0.22%), World Allergy Organization (WAO) grade, or SRIT time to onset. Nonred (non-1:1) vials accounted for a significantly larger proportion of all post-PD SRITs compared with all pre-PD SRITs (50.7% vs 31.1%, adjusted P = .009). Prior SRITs were reported less frequently among persons with post-PD SRITs (29.2% vs 70.8%, adjusted P = .009). In an adjusted logistic regression model, male sex (odds ratio, 7.9; 95% CI, 2.4-26) and longer time to reaction onset (odds ratio, 0.94; 95% CI, 0.89-0.99) were associated with higher WAO severity grade reactions. CONCLUSION: Pre-PD vs post-PD SRIT rates were not significantly different, adjusting for patients transitioned from established pre-PD to post-PD. This finding suggests that post-PD is as safe as pre-PD. Male sex and faster time to reaction onset were associated with higher WAO grade reactions.

Recurrent perioperative anaphylaxis in a 54-year-old man.

Reports suggest that perioperative anaphylaxis in patients undergoing general anesthesia range from 1 in 5000 to 1 in 20,000 with mortality rates as high as 9%. Because of the variety of medications that are used for general anesthesia and the rapid succession in which they are administered, it is often difficult to determine the etiology of a severe allergic episode in this setting. Antibiotics and anesthetics are notorious for precipitating allergic reactions and are often implicated. Other perioperative exposures and patient risk factors must also be considered. In this article, we describe the case of a patient who exhibited recurrent anaphylaxis episodes while trying to undergo a vital cardiac surgery.

Anosmia and an uncommon nonsteroidal anti-inflammatory drug reaction in a 38-year-old man.

Anosmia with asthma and nasal polyposis raises suspicion for aspirin-exacerbated respiratory disease (AERD). Guidelines for desensitization of patients with AERD to prevent recurrent nasal polyposis and improve upper and lower respiratory symptoms are well established. We present a patient with an uncommon reaction to acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs who required deviation from the standard ASA desensitization approach.

Posterior medial meniscus detachment: a unique type of medial meniscal tear.

Patients with posterior medial meniscal detachment, as determined at knee arthroscopy, were evaluated retrospectively. Mean follow-up was 5.3 years for 8 men and 20 women (30 knees; mean age, 57 years). Most patients had acute onset of pain with a minor specific incident. Seventeen patients were obese, 9 were overweight, and 2 were normal. Eleven of 22 magnetic resonance imaging evaluations detected a tear at the site of the posterior medial meniscus root. Nine of 16 bone scan evaluations showed moderate uptake medially. Arthroscopic treatment included partial medial meniscectomy or meniscal repair. Twelve knees (40%) showed significant progression of arthritis. Of the 7 patients with severe arthritic knees, 5 have subsequently undergone total knee arthroplasty, 1 is considering total knee arthroplasty, and the other has minimal symptoms. Patients should be counseled about the clinical course of posterior medial meniscus detachment and its potential for progressive arthritis in the joint.

The anatomy of the medial patellofemoral ligament.

BACKGROUND: Fibrous connections and fibrofatty tissue between the layers of the medial retinaculum have prevented accurate definition of the true anatomy of the medial patellofemoral ligament. This has led to confusion about the origin, form, course, and insertion of this structure. HYPOTHESIS: The medial patellofemoral ligament is a discrete structure that can be approached, isolated, and definitively described. STUDY DESIGN: Descriptive laboratory study. METHODS: Fifty fresh or fresh-frozen human knee specimens were carefully dissected to determine the precise anatomy of the medial patellofemoral ligament. RESULTS: Present in all specimens, the medial patellofemoral ligament was found to have 2 origins: (1) a transverse 10.6-mm origin from the bony groove between the medial epicondyle and the adductor tubercle, and (2) an oblique decussation originating from the proximal 30 mm of the leading edge of the superficial medial collateral ligament. The 2 origins combined and inseparably joined the vastus medialis obliquus tendon and inserted securely into the ventral edge of the bony patella over a span of 28.2 + or - 5.6 mm adjacent to the articular surface of the patella. The length from the femoral origin to the patella was 59.8 + or - 4.8 mm. The key to the dissection was finding the fine capsular vessels from the descending genicular artery that is between layers I and II of the medial retinacular structures. CONCLUSION: The medial patellofemoral ligament is a constant structure in ladouble daggeryer II, with a complex anatomy that can be defined by careful dissection using the capsular branches of the descending genicular artery as a guide. CLINICAL RELEVANCE: This study provides essential new information that could help surgeons safely locate the medial patellofemoral ligament and repair or reconstruct it anatomically.

Evaluation of success of a meniscus repair device for vertical unstable medial meniscus tears in ACL-reconstructed knees.

We retrospectively reviewed the success of meniscus repair with the FasT-Fix meniscus repair device for vertical unstable medial meniscus tears at the time of anterior cruciate ligament (ACL) reconstruction. A repair failure was defined as patients having medial knee symptoms leading to a subsequent arthroscopy confirming a tear at the repair site. Objective follow-up was obtained on 27 patients at a mean of 3.1 years postoperatively (range, 2-5 years). Two of 22 repairs (9%) in the red-red vascular zone and 4 of 5 repairs (80%) in the red-white vascular zone retore at the repair site at an average of 9 months postoperatively (range, 3-20 months). The results of this study showed a high failure rate (22%) of unstable vertical medial meniscus repairs with ACL reconstruction, especially for repairs done to tears in the red-white vascular zone.

Interaction of surfactant protein A with peroxiredoxin 6 regulates phospholipase A2 activity.

Peroxiredoxin 6 (Prdx6) is a "moonlighting" protein with both GSH peroxidase and phospholipase A(2) (PLA(2)) activities. This protein is responsible for degradation of internalized dipalmitoylphosphatidylcholine, the major phospholipid component of lung surfactant. The PLA(2) activity is inhibited by surfactant protein A (SP-A). We postulate that SP-A regulates the PLA(2) activity of Prdx6 through direct protein-protein interaction. Recombinant human Prdx6 and SP-A isolated from human alveolar proteinosis fluid were studied. Measurement of kinetic constants at pH 4.0 (maximal PLA(2) activity) showed K(m)0.35 mm and V(max) 138 nmol/min/mg of protein. SP-A inhibited PLA(2) activity non-competitively with K(i) 10 mug/ml and was Ca(2+) -independent. Activity at pH 7.4 was approximately 50% less, and inhibition by SP-A was partially dependent on Ca(2+). Interaction of SP-A and Prdx6 at pH 7.4 was shown by Prdx6-mediated inhibition of SP-A binding to agarose beads, a pull-down assay using His-tagged Prdx6 and Ni(2) -chelating beads, co-immunoprecipitation from lung epithelial cells and from a binary mixture of the two proteins, binding after treatment with a trifunctional cross-linker, and size-exclusion chromatography. Analysis by static light scattering and surface plasmon resonance showed calcium-independent SP-A binding to Prdx6 at pH 4.0 and partial Ca(2+) dependence of binding at pH 7.4. These results indicate a direct interaction between SP-A and Prdx6, which provides a mechanism for regulation of the PLA(2) activity of Prdx6 by SP-A.

Elective rotations and their impact on resident and faculty decision making.

BACKGROUND: Restrictions on resident-duty work hours have led to fewer opportunities to participate in elective rotations. PURPOSE: To investigate the potential impact of elective rotations on resident and faculty physicians using allergy/immunology (A/I) as a model. METHODS: A questionnaire was sent to 375 primary care physicians. It assessed demographic information, training background, A/I-referral history and intentions, and perceived knowledge of A/I-specific issues. RESULTS: A total of 228 surveys were returned. Resident physicians who were more senior in their training or who had taken an A/I rotation were more likely to have referred a patient to A/I in the past, more likely to refer a patient to A/I for chronic sinusitis, and more likely to report a greater knowledge of A/I topics. Faculty physicians with a history of an A/I rotation were more likely to feel knowledgeable about A/I topics. CONCLUSION: Elective rotations are positively correlated with perceived knowledge, referral intentions, and past history of referrals.

Aquagenic urticaria with extracutaneous manifestations.

Aquagenic urticaria (AU) is a rare form of physical urticaria in which contact with water evokes hives. Extracutaneous manifestations of AU have been described but have not been controlled successfully to date. Selective serotonin reuptake inhibitors (SSRIs) have not been used previously in the treatment of AU. The aim of this study was to describe a case of AU with extracutaneous manifestations, to describe a novel treatment approach, and to review the literature on AU. Our patient presented with urticarial lesions and migraine-like headaches after contact with any type of water. A variety of prophylactic medications including antihistamines, anticholinergics, and SSRIs, were used and, ultimately, were successful in controlling the patient's symptoms. AU is a rare condition that can have extracutaneous manifestations. Multiple classes of medications, including SSRIs, may be necessary in the treatment and prophylaxis of such patients. Additional research is needed into the pathogenesis of AU.