key: cord-0746142-ikr0ipih
authors: Kaminsky, Lauren W.; Dalessio, Shannon; Al-Shaikhly, Taha; Al-Sadi, Rana
title: Penicillin allergy label increases risk of worse clinical outcomes in COVID-19
date: 2021-07-19
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.06.054
sha: 906a46a180c3604588485c307a9f994fe7629cb0
doc_id: 746142
cord_uid: ikr0ipih

Background Coronavirus disease-2019 (COVID-19) ranges from asymptomatic to severe. Several co-morbidities are associated with worse clinical outcomes. Antibiotic use is common in COVID-19 and penicillin (PCN) allergy can impact antibiotic choice and may influence COVID-19 outcomes. Objective To investigate the impact of PCN allergy label on COVID-19 outcomes. Methods For this retrospective, cohort study, a web-based tool for population cohort research, TriNetX, was used to identify adult COVID-19 patients with and without PCN allergy label. The two cohorts were matched using 1:1 propensity score matching (PSM) for baseline demographics and conditions associated with risk of severe COVID-19. The 30-day risks of hospitalization, acute respiratory failure, intensive care unit (ICU) requirement, mechanical ventilation requirement, and mortality were then compared between the two groups. As bacterial infection can drive alternative antibiotic regimens, additional analyses focused on patients without bacterial infection. Results After PSM, each cohort consisted of 13,183 patients. COVID-19 patients with PCN allergy had higher risks of hospitalization (RR, 1.46; 95% CI, 1.41 to 1.52) acute respiratory failure (RR, 1.25; 95% CI, 1.19 to 1.31), ICU requirement (RR, 1.20; 95% CI, 1.08 to 1.34), and mechanical ventilation (RR, 1.17; 95% CI 1.03 to 1.32) when compared to patients without PCN allergy; however, there was no mortality difference (RR, 1.09; 95% CI 0.96 to 1.23). Although the bacterial infection risk was higher in PCN allergic COVID-19 patients, exclusion of patients with bacterial infections yielded similar results. Conclusion PCN allergic patients have higher risk of worse COVID-19 outcomes and should be considered for risk mitigation strategies.

that may put the patient at risk of poorer response to treatment, longer hospital stay, increased 91 healthcare costs, and increased frequency of infection with drug-resistant organisms. 13, 14 92 Surgical patients with reported PCN allergy have higher probability of a surgical site infection. 15 93 PCN allergy label is common with up to 10% of patients reporting PCN allergy with symptoms 94 varying from rash and hives to severe drug reactions including anaphylaxis. 16 However, the 95 majority of patients with PCN allergy label do not have the allergy after undergoing further 96 evaluation with less than 10% of patients with documented PCN allergy testing positive by PCN 97 skin testing and/or drug challenge. 17-19 98 Since there is frequent use of empiric antibiotics and increased risk of bacterial infection 99 during the course of COVID-19 treatment, we hypothesized that the presence of PCN allergy 100 label would be associated with worse clinical outcomes in COVID-19 patients. Herein, we 101 present a retrospective cohort study of population-based data that examined the 30-day risk of 102 hospitalization, acute respiratory failure, intensive care unit (ICU) requirement, mechanical 103 ventilation, and mortality in COVID-19 patients with PCN allergy label. We also investigated 104 the use of antibiotics in these patients. 105 The use of the macrolide, azithromycin, was also investigated. 175 176

Analyses were performed in real-time using TriNetX analytics built-in feature. 178

Continuous variables were described as means with standard deviations (SD) and categorical 179 variables were described as numbers (N) and proportions (%). A two-tailed t-test was used to 180 compare continuous data and Chi Square was used to compare categorical data. We estimated 181 the absolute risk, risk ratio (RR) and 95% confidence interval (CI) of the various study outcomes 182 across the different study cohorts. We used 1:1 propensity score matching (PSM) to match the 183 cohorts for baseline characteristics. A standardized mean difference (SMD) of less than 0.1 was 184 used to indicate adequate balance in PSM. An alpha level of less than 0.05 was set to indicate 185 statistical significance. We identified 13,186 COVID-19 patients with PCN allergy label and 525,562 patients 190 with COVID-19 but without PCN allergy between January 20, 2020 and January 20, 2021. After 191 1:1 PSM for the baseline variables, each cohort consisted of 13,183 patients, which were well-192 balanced with SMD < 0.1. Baseline characteristics before and after PSM are listed in Table II . and vancomycin (RR, 1.62; 95% CI, 1.48 to 1.77; P < .001) (Figure 2) . Azithromycin, a 215 macrolide antibiotic, was used in 1,803 (13.7%) patients with PCN allergy compared to 1,382 216 (Table  255 E2 in the Online Repository).

This is the first large retrospective cohort study that assessed the impact of PCN allergy 258 label on clinical outcomes in COVID-19. Although not clearly defined, the development of 259 symptoms and clinical outcomes in COVID-19 patients has been shown to take days to weeks. 25 260

We showed that PCN allergy is associated with a 1.5-fold increased risk of hospitalization, a 1. Due to the risks of PCN allergy label including use of broader antibiotics, longer 289 hospitalization, poorer response to treatment, 13, 14 and concern for antibiotic resistance, the 290 position statement from the American Academy of Allergy, Asthma, and Immunology supports 291 further work-up and testing for patients with documented PCN allergy 29 as greater than 90% of 292 patients, if properly evaluated, are able to be cleared of their PCN allergy label. [17] [18] [19] The findings 293 that COVID-19 patients with PCN allergy are at increased risk of severe outcomes further 294 supports the evaluation of patients with PCN allergy label as clearance of the PCN allergy might 295 reduce risk of poorer outcomes in COVID-19. This is an area for further investigation. 296

We acknowledge several limitations to our study: 1) Using ICD-10 codes is subjected to 297 reported bias; however, we expect this to affect both study cohorts equally, 2) While the cohorts 298 were matched for multiple underlying conditions that are associated with increased risk for 299 severe disease in COVID-19, we could not account for other diagnoses such as cancer because of 300 not yet been identified, which could represent confounding variables in these cohorts, 3) Not 302 every patient in the no PCN allergy cohort was tested for an allergy to PCNs and so some 303 patients in this cohort could have an unrecognized PCN allergy, 4) Lastly, since the majority of 304 patients with PCN allergy label may not prove to have true PCN allergy when properly 305 evaluated, our results should be interpreted with caution. 306

Based on these findings of higher risk of severe outcomes in COVID-19, patients with 307 PCN allergy could be prioritized to a higher risk group. Strategies for mitigating these increased 308 risks for patients with PCN allergy should be considered including evaluation of PCN allergy for 309 possible de-labeling and early vaccination. J o u r n a l P r e -p r o o f 

Clinical features of patients infected 312 with 2019 novel coronavirus in Wuhan, China

314 clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, 315 and outcomes in adult and pediatric patients with COVID-19: A systematic review and 316 meta-analysis

Clinical symptoms, 318 comorbidities and complications in severe and non-severe patients with COVID-19: A 319 systematic review and meta-analysis without cases duplication

Determine the most common 322 clinical symptoms in COVID-19 patients: a systematic review and meta-analysis

The 325 prevalence of symptoms in 24

COVID-19): A systematic review and meta-analysis of 148 studies from 9 countries

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