Polyethylene glycol hypersensitivity, patient outcomes in a 7-year retrospective study.

BACKGROUND: Immediate IgE-mediated hypersensitivity reactions to polyethylene glycol (PEG) are rare. Our understanding of PEG hypersensitivity is limited. OBJECTIVE: To evaluate the clinical characteristics and investigation outcomes of the largest cohort of patients with PEG allergy reported. METHODS: A total of 44 patients investigated for suspected PEG allergy across 4 United Kingdom tertiary allergy centers between October 2013 and December 2020 were studied. Clinical characteristics, index reaction, and approaches to and outcomes of allergy investigations were analyzed. RESULTS: PEG hypersensitivity was confirmed in 42 of 44 cases. Macrogol laxatives were the most common index drugs reported (23%), followed by depo-medroxyprogesterone (19%), oral penicillin V (10%), and depo-methylprednisolone (10%). In general, 61% experienced grade III anaphylaxis. Intradermal testing (IDT) increased the diagnostic sensitivity from 51% to 85%. Five patients experienced systemic reactions during IDT. Of the 5 patients, 2 were skin prick test positive to a high molecular weight PEG. Three patients with negative skin test results had positive drug provocation test results. Seven patients with PEG allergy reported tolerance to H1-antihistamines containing PEG. Administration of messenger RNA COVID-19 or Oxford/AstraZeneca COVID-19 vaccines was tolerated in all 16 patients to whom they were administered. CONCLUSION: PEG hypersensitivity is an uncommon cause of drug-induced anaphylaxis. Four index drugs accounted for two-thirds of the cases, and reactions to these drugs should prompt PEG hypersensitivity investigations. PEG IDT increases diagnostic yield. The role of skin prick test with higher molecular weight PEGs requires further attention. Further studies are required to understand PEG thresholds and PEG equivalent doses of various administration routes. COVID-19 vaccines were tolerated by all exposed.

Amoxicillin hypersensitivity: Patient outcomes in a seven-year retrospective study.

BACKGROUND: The beta-lactam antibiotic amoxicillin and the beta-lactamase inhibitor clavulanic acid in combination with amoxicillin are known to cause both immediate- and nonimmediate-type hypersensitivity. OBJECTIVE: To characterize a large cohort of patients with a history of amoxicillin or amoxicillin-clavulanic acid hypersensitivity. METHODS: A retrospective analysis was conducted of the demographics, presentation, investigation, and management of 331 patients presenting to 1 allergy center with a history of hypersensitivity to amoxicillin or amoxicillin-clavulanic acid. RESULTS: Hypersensitivity was confirmed in 37 of 221 patients (17%) who took amoxicillin and 47 of 110 patients (43%) who took amoxicillin-clavulanic acid as the index drug. In immediate hypersensitivity, skin test results confirmed the diagnosis in 66 of 139 patients (47%). Penicillin cross-reactivity was observed in 16 of 36 patients (44%). Of the 16 patients who were cross-reactive, 13 (81%) reacted to amoxicillin-clavulanic acid as the index drug. All patients who had negative skin test results (73/139) underwent drug provocation. The negative predictive value of skin tests was 89%. In nonimmediate hypersensitivity, delayed intradermal tests confirmed diagnosis in 12 of 170 patients (7%). Of the 12 patients whose skin test results were positive, 8 (67%) presented with drug reaction with eosinophilia and systemic symptoms. All patients with a negative skin test result (158/170) underwent drug provocation. The negative predictive value of skin tests was 95%. Penicillin cross-reactivity was observed in 3 of 12 patients (25%). Ten patients were diagnosed with hypersensitivity to clavulanic acid. CONCLUSION: The negative predictive value of skin tests in both immediate and nonimmediate hypersensitivity reactions is excellent and excludes severe allergy. Nonimmediate hypersensitivity is rare. Confirmed hypersensitivity is more likely if amoxicillin-clavulanic acid is the index drug. Cross-reactivity was more common in patients presenting with immediate hypersensitivity, typically involving benzylpenicillin. A minority of patients were allergic to clavulanic acid.

Adverse reactions to COVID-19 vaccines: A practical approach.

COVID-19-related mortality in high-risk individuals is substantial and current treatment options are limited. There is convincing evidence that the COVID-19 vaccines reduce the severity of infection and prevent deaths. Three COVID-19 vaccines are approved in the United Kingdom with many more in development. There are limited data on the triggers and mechanisms of anaphylaxis to these vaccines. We review the potential allergenic compounds in the COVID-19 vaccines and describe an innovative allergy support model for the vaccination hubs that allows most patients with severe allergy be immunized. Finally, we propose a practical algorithm for the investigations of anaphylaxis to these vaccines.

Piperacillin-Tazobactam Hypersensitivity: A Large, Multicenter Analysis.

BACKGROUND: Piperacillin/tazobactam is a broad-spectrum penicillin. Hypersensitivity reactions are less commonly reported than with other penicillins except in patients with cystic fibrosis. OBJECTIVE: Detailed clinical characterization of a patient cohort referred with suspected piperacillin-tazobactam hypersensitivity. METHODS: Retrospective analysis of the demographic characteristics, clinical presentation, investigation, and management of 87 patients presenting to 5 European allergy centers. Patients underwent skin prick and intradermal testing with piperacillin/tazobactam, major (penicilloyl-polylysine) and minor (sodium penilloate) determinants, amoxicillin, benzylpenicillin, flucloxacillin, co-amoxiclav, clavulanic acid, and meropenem with immediate and, where appropriate, delayed reading of tests. Skin test-negative patients underwent drug provocation to piperacillin/tazobactam and/or other penicillins. A multistep protocol was used, depending on risk assessment. RESULTS: Forty-eight of 87 (55%) patients were diagnosed with hypersensitivity to piperacillin/tazobactam with either positive skin or drug provocation test results, of whom 10 (21%) had a diagnosis of cystic fibrosis. Twenty-six (54%) patients presented with immediate and 22 (45%) with nonimmediate hypersensitivity. Patients with cystic fibrosis predominantly presented with nonimmediate hypersensitivity (70%). Reactions were severe in 52% of immediate reactors (Brown's anaphylaxis grade 3) and moderately severe (systemic involvement) in 75% of nonimmediate reactors. The number of patients with negative skin test results tolerating reintroduction was comparable in immediate (80%) and nonimmediate (88%) hypersensitivity. One-third of patients were cross-sensitized to other penicillins. The cross-sensitization pattern raised the possibility of tazobactam allergy in 3 patients. In 21 patients selectively sensitized to piperacillin/tazobactam (12 immediate, 9 nonimmediate), tolerance to other beta-lactams was demonstrated by drug provocation testing. CONCLUSIONS: Piperacillin-tazobactam caused immediate and nonimmediate hypersensitivity with similar frequency. Most patients were selectively sensitized and tolerated other penicillins. Some patients may be allergic to the beta-lactamase inhibitor only.

Flucloxacillin Hypersensitivity: Patient Outcomes in a Multicenter Retrospective Study.

BACKGROUND: Flucloxacillin is a narrow-spectrum, beta-lactamase-resistant penicillin. Type I (IgE-mediated) and type IV (T-cell-mediated) reactions are less frequently reported than with other penicillins. OBJECTIVE: To undertake a detailed clinical characterization of a cohort of patients referred with suspected flucloxacillin hypersensitivity. METHODS: We retrospectively analyzed demographic characteristics, presentation, investigation, and management of 108 patients presenting to 4 UK centers. Patients underwent skin prick and intradermal testing with flucloxacillin, major (benzylpenicilloyl poly-l-lysine) and minor determinants, amoxicillin, and benzylpenicillin with immediate and, where appropriate, delayed reading of the test. In the immediate group, a further 14 patients were tested to ampicillin and 16 to Augmentin (co-amoxiclav-combination of clavulanic acid and amoxicillin). Skin test-negative patients underwent oral drug provocation. A multistep protocol was used, depending on risk assessment. RESULTS: Forty of 108 (37%) patients were diagnosed with hypersensitivity to flucloxacillin, of whom 33 (82.5%) showed immediate and 7 (17.5%) nonimmediate hypersensitivity, respectively. In the immediate group, most reactions were severe: 19 of 33 (58%). Intradermal testing had a higher negative predictive value (86%) in the immediate group than in the nonimmediate group (67%). Only a minority of patients (6 of 17 [35%]) with IgE-mediated allergy were cross-sensitized on intradermal testing with other penicillins, compared with 3 of 4 (75%) in the delayed group. CONCLUSIONS: Immediate hypersensitivity reactions to flucloxacillin are more common than delayed. Cross-sensitization to other penicillins appears higher in delayed reactions than in immediate. The negative predictive value of intradermal testing is higher in the immediate group than in the nonimmediate group. Drug provocation testing remains the diagnostic criterion standard.

Audit of nasal lysine aspirin therapy in recalcitrant aspirin exacerbated respiratory disease.

BACKGROUND: Aspirin - exacerbated respiratory disease can prove difficult to control. Oral aspirin desensitization is effective, but has adverse effects and may not be cardio-protective at the high doses needed. OBJECTIVE: To examine the effectiveness of aspirin administered in lower doses via the nose. METHODS: An audit of 121 patients with aspirin exacerbated respiratory disease (AERD), 105 of whom were treated with intranasal lysine aspirin in gradually increasing doses following positive lysine aspirin challenge. RESULTS: Treatment was associated with subjective symptomatic improvement or stabilization in 60 of 78 patients at 3 months and 19 of 27 at 12 months. Nasal inspiratory peak flow, olfaction, exhaled and nasal nitric oxide levels were significantly improved (p < 0.05 for all). Patients with positive skin prick tests and those with later onset (>40 years) AERD improved more than non-atopics and those with early onset AERD. Asthma outcomes over 1 year were assessed by questionnaire in 22 patients on lysine aspirin and in 20 who were positive on challenge but who either refused treatment or took it only briefly (less than or equal to 3 months). There was a significant decrease in emergency visits (p = 0.0182), hospitalization (p = 0.0074) and oral steroid use (p = 0.004) in those on nasal lysine aspirin for a year. Gastrointestinal side effects occurred in 3.8%, lower than those reported for oral aspirin therapy. Conclusions and Clinical Relevance This form of therapy might reduce the need for expensive monoclonal antibodies in AERD patients.

A world allergy organization international survey on diagnostic procedures and therapies in drug allergy/hypersensitivity.

OBJECTIVE: To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among members of the World Allergy Organization (WAO). METHODS: A questionnaire comprising 39 questions was circulated electronically to member societies, associate member societies, and regional and affiliate organizations of WAO between June 29, 2009, and August 9, 2009. RESULTS: Eighty-two responses were received. Skin testing was used by 74.7%, with only 71.4% having access to penicillin skin test reagents. In vitro-specific IgE tests were used by 67.4%, and basophil activation test was used by 54.4%. Lymphocyte transformation tests were used by 36.8% and patch tests by 54.7%. Drug provocation tests were used by 68.4%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (76.9%). Rapid desensitization for chemotherapy, antibiotics, or biologic agents was used by 69.6%. Systemic corticosteroid was used in the treatment of Stevens-Johnson syndrome by 72.3%, and high-dose intravenous immunoglobulins in toxic epidermal necrolysis by 50.8%. Human leukocyte antigen screening before prescription of abacavir was used by 92.9% and before prescription of carbamazepine by 21.4%. CONCLUSIONS: Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across WAO member societies.

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor-associated periodic syndrome interacts with wild-type tumor necrosis factor receptor I and induces ligand-independent NF-kappaB activation.

OBJECTIVE: To investigate the molecular consequences of expressing mutated forms of tumor necrosis factor receptor I (TNFRI) as found in patients with TNFR-associated periodic syndrome (TRAPS). METHODS: We cloned and expressed full-length wild-type (WT) and T50K and P46L variants of TNFRI using a new tightly regulated doxycycline-dependent expression system. This system enabled the study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression. RESULTS: We used chemical crosslinking on the cell surface to show that WT and mutant forms of TNFRI, derived from TRAPS patients, interact in the absence of TNF ligand. Doxycycline-controlled up-regulation of one TNFRI allele, either WT or mutant, caused down-regulation of the other allele, indicating dynamic control of cell surface assembly. We also demonstrated that increased expression of mutant TNFRI (T50K) was associated with a parallel increase in NF-kappaB p65 (RelA) subunit activation, which did not occur with increased expression of WT TNFRI. CONCLUSION: The T50K TRAPS-related variant is capable of sustaining inappropriate NF-kappaB activation, resulting in persistent auto-inflammation in target organs such as skin, synovial membrane, and the central nervous system. We conclude that some of the inflammatory processes seen in TRAPS do not involve direct interaction of TNF with its receptors, but that other proinflammatory mechanisms capable of up-regulating TNFRI expression may cause cellular activation through the NF-kappaB signaling pathway.

Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.

OBJECTIVE: To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS. METHODS: Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes. RESULTS: Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (Delta D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants. CONCLUSION: The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without a TNFRSF1A mutation indicates that the genetic basis among patients with "TRAPS-like" features is heterogeneous. TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.