The appropriateness of penicillin allergy de-labelling by non-allergist clinical ward teams.

OBJECTIVES: We aimed to assess the appropriateness of penicillin allergy (PenA) assessment conducted by clinical teams and to review the safety of subsequent exposure of these patients to penicillin. METHODS: Opportunistic, prospective observational study of usual clinical care, between 16 May 2023 and 14 August 2023, of inpatients with a PenA and requiring antibiotics, in a 750-bed hospital in England. To assess the appropriateness of management, PenA patients prescribed penicillins were grouped into risk categories using a validated antibiotic allergy assessment tool: eligible for de-label on history alone (direct de-label; DDL), eligible for direct oral challenge (DOC), high risk or unable to obtain history. RESULTS: Of the 123 patients admitted with a PenA (or sensitivity record) and exposed to a penicillin, data were collected for 50. Their PenA records were grouped follows: eligible for DDL 34 (68%), eligible for DOC 11 (22%), high risk 4 (8%) and unable to obtain history 1 (2%). In 14/50 (28%) patients there was no evidence of a current PenA assessment in the medical notes. CONCLUSIONS: Using the allergy risk tool, most patients with PenA records were exposed to penicillin appropriately. However, patients meeting high-risk criteria were also exposed to penicillin when the tool excluded them. PenA assessment needs to be carried out with appropriate training and governance structures in place.

Prophylaxis in hereditary angioedema: a United Kingdom Delphi consensus.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

Penicillin allergy de-labelling by non-allergists: a comparison of testing protocols.

Optimizing penicillin allergy de-labelling (PADL) to ensure patients with an incorrect penicillin allergy record are de-labelled with minimal patient harm is important for antibiotic stewardship. The heterogeneity of inclusion and exclusion criteria in the published penicillin allergy testing protocols risks suboptimal delivery of PADL. We compared the similarities and the differences between non-allergist-delivered PADL testing protocols and make suggestions for harmonization. The observed variation in testing practice has two broad elements: (i) definitions and terminology; and (ii) differences in the acceptability of perceived risk. All direct drug provocation testing (DDPT) protocols included patients with benign delayed rash as eligible for testing, although the remoteness of the rash, and the terminology used to describe the rash, differed. Patients with features of potential IgE reactions were excluded from most DDPT protocols, but not all of them. There was differing advice on how to manage patients who had subsequently tolerated penicillin since the index reaction and differences in which patients were considered ineligible for DDPT due to acuity of illness, comorbidities and concomitant medications. Standardization of the terminology used in penicillin allergy testing protocols and consensus on inclusion and exclusion criteria are required for safe and efficient PADL delivery at scale by non-allergists.

Etiology and clinical characteristics of a non-cystic fibrosis bronchiectasis cohort in a middle eastern population.

BACKGROUND: Bronchiectasis is a widely prevalent airway disease characterized by airway dilatation and recurrent infections, that can lead to respiratory failure in severe cases. The etiology of bronchiectasis varies geographically, but there is a lack of published data examining its etiology specifically within the Middle Eastern population. METHODS: We conducted a retrospective analysis of our bronchiectasis patient registry, extracting clinical and demographic characteristics from electronic medical records. Quantitative variables were presented as the median and interquartile range (IQR), while categorical variables were expressed as numbers and percentages. Statistical comparisons for continuous characteristics were performed using the t-test, and significance was determined by a p-value less than 0.05. RESULTS: In total we analysed 260 records (63% female, 37% male), with median age of 58 years (interquartile range (IQR) 38-71), Body Mass Index (BMI) 25.8(IQR 22-30), forced expiratory volume in the first second (FEV1) %predicted 65 (IQR 43-79) and FEV1/forced vital capacity (FVC) 0.76 (0.67-0.86). Sixty-five cases (25%) were post-infectious in aetiology (excluding post-TB - n:27 10.4%). Forty-eight (18.5%) patients were labelled idiopathic, while Primary Ciliary Dyskinesia (PCD) accounted for 23 (8.8%) cases. Pseudomonas aeruginosa was the most common colonizing organism (32.7%), followed by Haemophilus influenzae (9.2%) and Methicillin-Sensitive Staphylococcus aureus(6.9%). At the time of review, 11 patients had died (median age, FEV %predicted, and bronchiectasis severity index (BSI) 59 years, 38% and 15.5 respectively), all due to respiratory failure, and as expected, all were classed severe on BSI. The BSI score was available for 109 patients, of which 31(28%) were classed mild, 29(27%) were moderate, and 49 (45%) were classed severe. The median BSI score was 8 (IQR 4-11). On dividing the patients according to obstructive vs. restrictive spirometry, we found that patients with FEV1/FVC < 0.70 had significantly higher BSI (10.1 vs. 6.9, p-value < 0.001) and that 8 out of the 11 deceased patients had FEV1/FVC < 70%. CONCLUSIONS: In our study, post-infectious, idiopathic, and PCD were identified as the most common etiologies of bronchiectasis. Additionally, patients with obstructive spirometry appeared to have a worse prognosis compared to those with restrictive spirometry.

Removal of incorrect penicillin allergy labels in a UK hospital.

OBJECTIVES: Penicillin allergy records are common, often incorrect and are associated with broad spectrum antibiotic use. We piloted a pharmacist-led multidisciplinary penicillin allergy de-labelling daily ward round to determine the opportunity for penicillin allergy de-labelling in a UK hospital. METHODS: A daily ward round, delivered by antibiotic pharmacists or junior doctors, identified adult medical and surgical patients between 7 November 2022 and 31 January 2023 with a penicillin allergy record that was preventing first-line penicillin use. An allergy history was taken before risk stratifying likelihood of future harm from penicillin re-exposure and an allergy testing method was determined (direct de-label on history alone or after direct drug provocation testing). After successful allergy de-label, the antibiotic was switched to a penicillin antibiotic. RESULTS: Of 7214 inpatients during the study period, 1133 (15.7%) had a penicillin allergy record. Of 285 allergy histories taken, 105 (36.8%) met high-risk criteria, 45 (15.8%) met low-risk criteria eligible for direct de-label and 73 (25.6%) met criteria eligible for direct drug provocation testing. We were unable to obtain a history for 61 (21.4%) patients. Of 45 low-risk patients eligible for direct de-label, 40 (88.9%) were de-labelled of whom 24 (53.3%) were switched to a penicillin antibiotic. Of 73 patients with a low-risk allergy history eligible for direct drug provocation testing, 16 (21.9%) received direct drug provocation testing, of whom 9 were switched to a penicillin antibiotic. Two direct de-label patients experienced harm (thrush within 5 days and delayed skin reaction after day 5); none of the direct drug provocation testing patients had a reaction by day 5. The switches resulted in reduced alternative antibiotic use by 173 Daily Defined Doses (DDDs). DISCUSSION: Penicillin allergy de-labelling patient pathway delivered by pharmacists and junior doctors was safe and effective and well accepted by patients and the wider clinical teams.

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.

Addressing the Challenges of Penicillin Allergy Delabeling With Electronic Health Records and Mobile Applications.

Allergy labels are common, often incorrect, and potentially harmful. There are many opportunities for clinical decision support (CDS) tools integrated in the electronic health record (EHR) and mobile apps to address the challenges with drug allergy management, including penicillin allergy delabeling (PADL). Effective delabeling solutions must consider multidisciplinary clinical workflow and multistep processes, including documentation, assessment, plan (eg, allergy testing and referral), record update, drug allergy alert management, and allergy reconciliation over time. Developing a systematic infrastructure to manage allergies across the EHR is critical to improve the accuracy and completeness of a patient's allergy and avoid inadvertently relabeling. Improving the appropriateness and relevancy of drug allergy alerts is important to reduce alert fatigue. Using alerts to guide clinicians on appropriate antibiotic use may reduce unnecessary ß-lactam avoidance. To date, EHR CDS tools have facilitated non-allergists to provide PADL at the point of care. A mobile app was shown to support PADL and provide specialist support and education. Future research is needed to standardize, integrate, and evaluate innovative CDS tools in the EHR to demonstrate patient safety and clinical utility and facilitate wider adoption.

Increased Seroprevalence and Improved Antibody Responses Following Third Primary SARS-CoV-2 Immunisation: An Update From the COV-AD Study.

Background: Patients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity. Objectives: To determine the immunogenicity of the third primary SARS-CoV-2 immunisation in a heterogeneous cohort of patients with antibody deficiency. Methods: Participants enrolled in the COV-AD study were sampled before and after their third vaccine dose. Serological and cellular responses were determined using ELISA, live-virus neutralisation and ELISPOT assays. Results: Following a two-dose schedule, 100% of healthy controls mounted a serological response to SARS-CoV-2 vaccination, however, 38.6% of individuals with antibody deficiency remained seronegative. A third primary SARS-CoV-2 vaccine significantly increased anti-spike glycoprotein antibody seroprevalence from 61.4% to 76.0%, the magnitude of the antibody response, its neutralising capacity and induced seroconversion in individuals who were seronegative after two vaccine doses. Vaccine-induced serological responses were broadly cross-reactive against the SARS-CoV-2 B.1.1.529 variant of concern, however, seroprevalence and antibody levels remained significantly lower than healthy controls. No differences in serological responses were observed between individuals who received AstraZeneca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b2 during their initial two-dose vaccine schedule. SARS-CoV-2 infection-naive participants who had received a heterologous vaccine as a third dose were significantly more likely to have a detectable T cell response following their third vaccine dose (61.5% vs 11.1%). Conclusion: These data support the widespread use of third primary immunisations to enhance humoral immunity against SARS-CoV-2 in individuals with antibody deficiency.

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK.

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Time Trade-Off Utilities for Hereditary Angioedema Health and Caregiver States.

BACKGROUND: Hereditary angioedema (HAE) is an inherited chronic rare disease characterised by recurrent swelling attacks that are associated with significant physical and psychological burden. There is limited understanding of the effect of attack location on this burden and of caregiver burden. OBJECTIVE: Our objective was to capture the relative burden of HAE health and caregiver states, including different attack locations, through a time trade-off (TTO) analysis involving participants from the general public. METHODS: Qualitative interviews were undertaken to inform vignette development for the TTO study, including vignettes for abdominal, facial, hand and laryngeal attack health states, and an attack-free and caregiver state. Members of the general public in England rated vignettes in TTO interviews, which included a visual analogue scale (VAS) component. For the development of the health state vignettes, qualitative interviews with 15 patients, 5 caregivers and 1 clinical expert were performed. TTO analysis was based on vignette valuation completed by 100 members of the general public. RESULTS: The TTO values were as follows: attack-free, 0.783 (standard deviation [SD] 0.316); hand: 0.582 (SD 0.380); facial: 0.483 (SD 0.448); abdominal: 0.345 (SD 0.458); and laryngeal: 0.128 (SD 0.529). The caregiver rating was 0.762 (SD 0.303). V' scores were similar and consistent with TTO values. CONCLUSION: TTO utility values demonstrate that HAE places a significant burden on patients, which is influenced by attack location, and on caregivers. These utility weights can provide important information on quality of life for future economic evaluations of treatments.

The systemic immunosuppressive effects of peripheral corticosteroid injections: A narrative review of the evidence in the context of COVID-19.

INTRODUCTION: Injected glucocorticoid's (corticosteroids) are commonly used in musculoskeletal practice. The current global COVID-19 pandemic has increased attention on the potential for locally injected corticosteroids to exert a systemic immunosuppressive effect and the implications this may have in relation to COVID-19 infection and vaccination. AIM: This narrative review summarises the evidence regarding the potential systemic immunosuppressive effects of peripheral corticosteroid injections in relation to the ongoing COVID-19 pandemic. METHOD: A narrative review was selected to allow inclusion of evidence related to a diverse range of topics relevant to this subject in order to provide the most comprehensive and clinically relevant guidance for clinicians. RESULTS/DISCUSSION: Current evidence demonstrates that cytotoxic, phagocytic and antigen presenting cells involved in both the innate and adaptive immune responses are suppressed for 48 h post-injection and messenger cytokines that are integral to immune function are suppressed for over 96 h post-injection. This potentially reduces an individual's ability to prevent viral infection, limit early viral replication, and delays activation of adaptive immune mechanisms (T and B lymphocytes) and subsequent viral clearance and elimination. The hypothalamic-pituitary-adrenal (HPA) axis can be suppressed for 2-4 weeks or longer following peripheral corticosteroid injections. The role of the HPA axis in immune function is not fully understood, however this could potentially indicate longer lasting immunosuppression. CONCLUSIONS: This review found evidence of suppression of immune cell numbers for the first 48 h post-injection, cytokines for over 96 h post-injection and HPA axis suppression lasting for 2-4 weeks or longer. There is currently no evidence that these physiological changes translate into a clinically meaningful increased risk of COVID-19 infection or related morbidity or mortality, but there is also no persuasive evidence that they do not. This review discusses the implications of the current evidence in relation to shared decision making, informed consent, risk management and COVID-19 vaccination to provide clinicians with a pragmatic guide to help navigate the current uncertainty regarding the potential immunosuppressive effects of peripheral corticosteroid injections.

Development and Validation of a Mobile Clinical Decision Support Tool for the Diagnosis of Drug Allergy in Adults: The Drug Allergy App.

BACKGROUND: Penicillin allergy overdiagnosis has been associated with inappropriate antibiotic prescribing, increased antimicrobial resistance, worse clinical outcomes, and increased health care costs. OBJECTIVE: To develop and validate a questionnaire-based algorithm built in a mobile application to support clinicians in collecting accurate history of previous reactions and diagnosing drug allergy appropriately. METHODS: A survey was completed by 164 medical and nonmedical prescribers to understand barriers to best practice. Based on the survey recommendations, we created a 10-item questionnaire-based algorithm to allow classification of drug allergy history in line with the National Institute for Health and Care Excellence guidelines on drug allergy. The algorithm was incorporated into a mobile application and retrospectively validated using anonymized clinical databases at regional immunology and dermatology centers in Manchester, United Kingdom. RESULTS: A total of 55.2% of prescribers (95% confidence interval, 47% to 63.4%) thought it impossible to draw a firm conclusion based on history alone and 59.4% (95% CI, 51.4% to 67.5%) believed that regardless of the details of the penicillin allergy history, they would avoid all ß-lactams. A drug allergy mobile application was developed and retrospectively validated, which revealed a low risk for misclassification of outcomes compared with reference standard drug allergy investigations in the allergy and dermatology clinics. CONCLUSIONS: Perceived lack of time and preparedness to collect an accurate drug allergy history appear to be important barriers to appropriate antimicrobial prescribing. The Drug Allergy App may represent a useful clinical decision support tool to diagnose drug allergy correctly and support appropriate antibiotic prescribing.

Line blot immunoassays in idiopathic inflammatory myopathies: retrospective review of diagnostic accuracy and factors predicting true positive results.

BACKGROUND: Line blot immunoassays (LIA) for myositis-specific (MSA) and myositis-associated (MAA) autoantibodies have become commercially available. In the largest study of this kind, we evaluated the clinical performance of a widely used LIA for MSAs and MAAs. METHODS: Adults tested for MSA/MAA by LIA at a tertiary myositis centre (January 2016-July 2018) were identified. According to expert-defined diagnoses, true and false positive rates were calculated for strongly and weakly positive autoantibody results within three cohorts: idiopathic inflammatory myopathy (IIM), connective tissue disease (CTD) without myositis, and non-CTD/IIM. Factors associated with true positivity were determined. RESULTS: We analysed 342 cases. 67 (19.6%) had IIM, in whom 71 autoantibodies were detected (50 strong positives [70.4%], 21 weak positives [29.6%]). Of the strong positives, 48/50 (96.0%; 19 MSAs, 29 MAAs) were deemed true positives. Of the weak positives, 15/21 (71.4%; 3 MSAs, 12 MAAs) were deemed true positives.In CTD without myositis cases (n = 120), 31/61 (51.0%; 5 MSAs, 26 MAAs) autoantibodies were strongly positive, with 24/31 (77.4%; 0 MSAs, 24 MAAs) true positives. 30/61 (49.2%; 13 MSAs, 17 MAAs) were weakly positive, with 16/30 (53.3%; 0 MSAs, 16 MAAs) true positives. In non-CTD/IIM cases (n = 155), all 24 MSAs and 22 MAAs were false positives; these results included 17 (37.0%; 7 MSAs, 10 MAAs) strong positives.Individual autoantibody specificities were > 98.2 and > 97.5% for weakly and strongly positive results, respectively. True positivity was associated with high pre-test for IIM (odds ratio 50.8, 95% CI 13.7-189.2, p < 0.001) and strong positive (versus weak positive) results (4.4, 2.3-8.3, p < 0.001). CONCLUSIONS: We demonstrated the high specificity of a myositis LIA in a clinical setting. However, a significant burden of false positive results was evident in those with a low pre-test likelihood of IIM and for weakly positive autoantibodies.