Table 2.

Summary of articles categorized as observational, organized by specific drug classes, general or specific adverse drug reactions, or both

Article	EHR Database/Data Source	Sample Size	Primary EHR Components*	Findings: Prevalence/Incidence, Risk Factors, Outcome, Other
DRUG: Antibiotics (n=15)
Apter et al. (2004) 21	UK General Practice Research Database	3.4 million	D	57 out of 3,014 (0.15%) patients who had an allergic-like event after the first prescription experienced another event to the second prescription.
Albin et al. (2014) 7	Internal Medicine Associates Clinic of Mount Sinai Hospital/ Epic EHR	1,348	A, D	Documented reactions to penicillin allergy are rash (37%), hives (18.9%), and swelling (11.8%) and was most prevalent in African Americans, then Caucasians and Asians. Risk factors for penicillin allergy: sex (female)
May et al. (2016) 22	Mayo Clinic	927	A, D	IV penicillin did not increase risk of allergy in children (OR: 0.84).
Crotty et al. (2017) 10	NSLIJ Huntington Hospital, Huntington, NY	175	A, D	89% of 175 patients who received at least one dose of cefepime, ceftriaxone, cefoxitin, cephalexin, or meropenem had self-reported allergy to penicillin. 20% reported incidence of rash while 63% said unknown reaction. 8 patients had an allergic reaction to penicillin while 2 patients had an adverse drug reaction (ADR) to amoxicillin and piperacillin/tazobactam. Risk factor: history of self-reported allergy can increase risk of cross-sensitivity reactions, type of drug (cephalosporin)
West et al. (2019) 12	ResearchOne, UK	2.3 million	A, D	The prevalence of penicillin allergy was 5.9%. Risk factors: age (older), sex (female), comorbidities
Liang et al. (2020) 13	Kaiser Permanente Southern California	6.1 million	A, B	More patients who received parenteral penicillin reported new allergic reactions (0.84%) than those who received oral penicillin (0.74%). 0.097% and 0.065% of parenteral and oral exposures respectively were confirmed anaphylaxis cases.
Lager et al. (2009) 6	University of Michigan Health System	211	A, D	Incidence of allergic-type reaction to carbapenem was 11% in patients with reported penicillin allergy, 5.2x greater than those who did not report a penicillin allergy. Risk factor: documented Penicillin allergy
Beltran et al. (2015) 8	Nationwide Children's Hospital Enterprise Data Warehouse (Epic EHR)	513	A, D	Cephalosporin resulted in one documented case of nonanaphylactic reaction when used as surgical prophylaxis. Clindamycin, most common cephalosporin, produced an adverse rate of 1.5% in patients with Penicillin allergy.
Macy et al. (2015) 23	Kaiser Permanente Southern California (Health Connect)	1.0 million	A, B, D	There were higher reports of allergy to cephalosporin among women (0.56%) than among men (0.43%). Anaphylaxis occurred in 5 oral exposures and 8 parenteral exposures. Clostridium difficile infection within 90 days (0.91%), nephropathy (0.15%), and all-cause death within 1 day (0.10%) were most common, serious ADR. No correlation with drug allergy history.
Blumenthal et al. (2016) 9	Partners Healthcare System-Mass General Brigham (Epic EHR)	96	A, D	ADR was observed in 21% of inpatient patients who received ceftaroline. No increased risk of ADR for patients with reported B-lactam allergy.
Alvarez-Arango et al. (2021) 24	Johns Hopkins Health System Corporation (JHHS) and Mass General Brigham (MGB) (Epic EHR)	4.5 million	A, D	0.3% of patients had documented vancomycin allergy with 42.1% reporting immediate phenotypes and 20.7% delayed reactions. 32% hypersensitivity reactions presented as rash and 16% as Red Man Syndrome.
Butler et al. (2018) 11	Seattle Children’s Hospital, University of Washington School of Medicine	17,496	B, D	1% of penicillin allergic patients who received cefazolin experienced perioperative adverse drug reactions, Vancomycin associated with greater rates of ADR as prophylaxis.
Fosnot et al. (2021) 25	UCHealth System-Health Data Compass Data Warehouse project	690	A, D	Probable DHRs occurred in 0.9% patients who received cefazolin, 1.4% patients who received clindamycin, and 1.1% patients who received vancomycin, not varying significantly.
Macy et al. (2009) 14	Kaiser Permanente	1,127	A	15.3% of drug allergy reports reported at least one allergy to one antibiotic class. Risk factors: female, older age, drug type (highest incidence w/ sulfa class)
Salden et al. (2015) 17	Academic Health Care Centre Terwijde at Leidsche Rijn Utrecht	8,288	A	2.0% of sample had recorded allergy to B-lactams in Dutch primary care system. Risk factors: age (very young), sex (female), comorbidities (asthma, allergies, skin disorders)
DRUG: Cancer therapy-related drugs (n=7)
Lal et al. (2009) 26	University of Texas M. D.- Anderson Cancer Center	3,746	D	Weekly paclitaxel infusions result in 1.5% rate of DHRs.
Kim et al. (2012) 27	Seoul National University Bundang Hospital	393	D	The prevalence rate of DHRs to oxaliplatin is 10.7%. Risk factors: higher dosage of oxaliplatin and lower dosage of dexamethasone
Jung et al. (2014) 28	Seoul National University Hospital	658	B, D	49.5% of patients who received rituximab experienced infusion related reactions. Risk factors: certain types of lymphoma (CLL, intravascular B cell lymphoma), high dosage and rate of injection in 1st 30 min
Levin et al. (2017) 29	Partners Healthcare System- Mass General Brigham	67	A, D	51% of patients who experienced grade 1 reaction to rituximab can be safely rechallenged.
Welborn et al. (2018) 30	University of Texas MD Anderson Cancer Center	17	D	70.6% of patients with cutaneous ADE to tremelimumab experienced pruritis. Other reactions include eczematous dermatitis, morbilliform rash, vitiligo, xerosis, acneiform rash, and psoriasiform dermatitis.
Shazib et al. (2020) 31	Dana-Farber/Brigham and Women's Cancer Center	13	D	Of 13 patients, 4 had oral-only immune-related ADEs to programmed cell death-1 inhibitors. 10 had lichenoid lesions, 2 with erythema multiforme, 1 with graft vs host disease reactivation, and 8 with or without ulcerations.
Keiser et al. (2021) 32	University of Texas MD Anderson Cancer Center	64	B, D	91% of patients with cutaneous adverse events to immune checkpoint inhibitors treated with topical steroids, oral antihistamines, or topical antihistamines and 70% recovered from rash over 4 months.
DRUG: Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2)
Blumenthal et al. (2017) 33	Partners HealthCare System (PHS) - Partners Enterprise Allergy Repository (PEAR)	62,719	A, B, C, D	1.7% had an ADR to prescription NSAIDs, 18.3% of which were hypersensitivity reactions. Risk factors: drug hypersensitivity reaction history, sex (female), autoimmune disease, and those who were prescribed the maximum standing NSAIDs dose
Li et al. (2021) 34	Partners HealthCare System	47,114	A, B, D	7.7% of patients with chronic back pain had active aspirin or NSAID adverse reaction.
DRUG: Opioids (n=1)
Inglis et al. (2021) 35	Royal Adelaide Hospital, Australia (Sunrise)	231,623	A, C, D	15.9% of ADR reports were due to opioids, with 64.7% reported as allergy and 35.3% as intolerance.
DRUG: Radiocontrast media (RCM)-related compounds (n=4)
Dillman et al. (2007) 36	University of Michigan Health System	78,353	D	The reaction frequency to IV gadolinium is 007%. 74% of reactions were mild, 19% were moderate and 7% were severe. 50% had at least one risk factor to IV gadolinium reaction. Risk factors: allergic-like contrast reaction, a prior allergic reaction to a substance other than contrast media, or documented asthma
Power et al. (2016) 37	University Health Network, Toronto	19,074	D	The reaction rate to gadobutrol is 0.32% and the per patient reaction basis was 0.43%. Risk factors: previous allergic-like reaction to gadolinium, previous reaction to any substance, history of asthma
Young et al. (2019) 38	NHS Tayside, Health Informatics Centre, University of Dundee	22,897	D	0.01% of patients had DHRs to gadolinium-based contrast agents.
Lakshmanadoss et al. (2012) 39	Johns Hopkins Health System	234	D	71% of patients had previous recorded allergy to iodinated contrast agents, 24% to iodine, and 5% to both. Most patients (77%) had skin rashes or unspecified reaction while 8.5% had anaphylaxis.
DRUG: Statin (n=1)
Robison et al. (2014) 40	Intermountain Healthcare system (Murray, UT)	10,789	B, D	Patients with statin intolerance had a higher history of hypothyroidism (30.2%) compared to the control group (21.5%).
DRUG: Other (n=3)
Paisansinsup et al. (2013) 41	Park Nicollet Health Services EHR	1,268	D	3.79% of patients prescribed allopurinol experienced an ADR. Risk factors: sex (female), older age, diabetes mellitus, diuretic use, presence of tophi associated with possible ADR
Hall et al. (2018) 42	The Health Improvement Network, UK	70	C, D	Observed-to-expected ratio was 3.3 and 1.5 for convulsions and thrombocytopenia for those who received Optaflu, a trivalent seasonal influenza vaccine.
Laird et al. (2020) 43	UCHealth System	868	B, D	0.461% of patients who received Fosaprepitant as a prophylaxis for chemotherapy related nausea had a systemic hypersensitivity reaction.
Adverse Drug Reaction (ADR): Broad/general overview (n=6)
Kidon and See (2004) 44	KK Women’s and Children’s Hospital, Singapore	672	D	2.2% of pediatric patients had recorded ADR, 70% of which were due to antibiotics, specifically B-lactams. 18.5% were due to NSAIDs in Singapore. Risk factors: older age, male gender, presence of asthma or other chronic disease
Macy et al. (2014) 15	Kaiser Permanente Southern California, Health Connect	105,61 4	B, D	The most common allergies in hospitalized patients were due to penicillin (16.7%), other nonantibiotics (12.7%), narcotics (11.7%), sulfonamides antibiotics (10.2%) and NSAIDs (7.1%), which altogether accounted for 58.4% of reported allergies. Risk factors: sex (female), age (older)
Saager et al. (2015) 45	Cleveland Clinic Perioperative Health Documentation System	264	D	Overall incidence of intraoperative hypersensitivity reaction was 0.148%. 2 out of 10,000 operations resulted in severe hypersensitivity reactions.
Zhou et al. (2016) 16	Partners HealthCare System/ Partners’ Enterprise-wide Allergy Repository (PEAR)	1.8 million	A, D	35.5% of patients reported at least one drug allergy with 1.95 allergies/patient. Risk factors: female sex, Caucasian race, antibiotic, statin, and ACE inhibitor use
Mendes et al. (2019) 46	Portuguese Catalogue of Allergies and Other Adverse Reactions (CPARA)	380	D	0.4% inpatients (380 patients) had DHRs over 5-year period, 52.8% of which were associated with antibiotics, mainly beta lactam antibacterial use. 47.6% ADR were skin and subcutaneous tissue disorders and 41.3% were immune system disorders, specifically anaphylactic Reactions (37.4%).
Wong et al. (2019) 20	Partners HealthCare System/ Partners’ Enterprise-wide Allergy Repository (PEAR)	2.7 million	A, C, D	13.8% of patient population had documented DHRs. 53.1% were associated with immediate reaction phenotypes. Risk factors: female sex, race/ethnicity, drug type
ADR: Anaphylaxis (n=3)
Goh et al. (2018) 47	National University Hospital, KK Women’s and Children’s Hospital, and Tan Tock Seng Hospital, Singapore	426	B	45% of anaphylaxis cases were children in Singapore. Risk factors: food type, drug type
Dhopeshwarkar et al. (2019) 48	Partners HealthCare System/ Partners’ Enterprise-wide Allergy Repository (PEAR)	1.7 million	A, D	1.1% of patient population had at least one drug-induced anaphylaxis reaction. Risk factor: female sex, white race, drug type
Rangkakulnuwat et al. (2020) 49	Chiang Mai University (CMU) Hospital, Chiang Mai, Thailand	433	B	Overall incidence of anaphylaxis in Asia was 3.9 cases out of 100,000 visits, 84% of which were experienced in adults. Drug-induced anaphylaxis was more common in adults than children (19.8% vs. 8.1%). NSAIDs (7.4%) and antimicrobials were most common culprit drugs. 11.4% of cases had unknown cause. Risk factors: food, drug exposure, age, sex
ADR: severe cutaneous adverse reactions (SCAR) (n=6)
Ou-Yang et al. (2013) 50	Taiwan National Health Insurance Research Database	554	D	15.5% of outpatient and hospitalized patients in Taiwan were hospitalized twice due to SJS/TEN. Penicillin and cephalosporin (27%, 27%) were the main culprit agents for 1st hospitalization.
Micheletti et al. (2018) 51	18 US academic medical centers	377	D	89.7% of SJS/TEN cases were due to medication, mainly trimethoprim/sulfamethoxazole (26.3%) and b- lactams (12.4%).
Park et al. (2019) 52	Multicenter, Gangnam Severance Hospital, South Korea	745	D	Allopurinol was the causative drug in 14.2% of SCAR cases. Other culprit drugs are anticonvulsants (22.5%), b-lactams (21.1%) and NSAIDs (10.3%).
De Bustros et al. (2021) 53	Loyola University Medical Center	163	D	Anticonvulsants (30%), Trimethoprim-Sulfamethoxazole (19%), Beta-lactams (11%), NSAIDs (8.4%) and allopurinol (8.4%) were identified the most probable culprit in SJS/TEN cases.
Zhang et al. (2019) 54	Penn State Hershey Medical Center	35	B, D	35 patients (5.9% of larger patient cohort) had documented SCAR, including 54.3% of DRESS, 22.8% of SJS, 17.1% of AGEP, 2.9% of TEN and SJS/TEN overlap.
Ma et al. (2021) 55	Chang Gung Memorial Hospital Linkou Branch, Taiwan	119	D	Of patients with SJS/TEN and overlap syndrome, 46.2% had severe ocular complications.
ADR: Other (n=7)
Macy et al. (2012) 18	Kaiser Permanente Southern California (Health Connect)	2.4 million	A	2.1% of health plan members had 3 or more allergies reported and can be diagnosed with multiple drug intolerance syndrome. Risk factors: female sex, age, drug type, anxiety associated
Banerji et al. (2017) 56	Partners HealthCare System	135,000	A, C, D	Incidence of ACE inhibitor angioedema is 0.07% and 0.23% within the 1st month and 1st year of use, respectively.
Read et al. (2017) 57	Royal Brisbane and Women's Hospital, Gold Coast University Hospital, Australia	70	D	Only 9 cases of 70 reported erythema multiforme diagnoses in children met criteria for erythema multiforme, with most being misdiagnosed.
Blumenthal et al. (2018) 58	Partners HealthCare System/ Partners’ Enterprise-wide Allergy Repository (PEAR)	746,88 8	A, B, C, D	The overall prevalence rate was multiple drug intolerance syndrome was 6.4% and 1.2% for multiple drug allergy syndrome. Risk factors for MDIS: female sex, older age, greater weight, prior hospitalizations, and multiple medical comorbidities
Braswell et al. (2019) 59	University of Florida, the Medical College of Wisconsin, and Inform Diagnostics Research Institute	56	D	Of patients with lichenoid granulomatous dermatitis, most were diagnosed with drug eruption (39.3%, n = 22) and lichenoid keratosis (19.6%, n = 11).
Jimenez et al. (2019) 19	Cleveland Clinic	2.0 million	D	70.9% had no allergies; 27.4% had 1-4 allergies; 1.5% had 5-9 allergies; 0.22% had >9 allergies in the patient population. Rates of mental health and somatic syndrome disorder increased with more allergies. Risk factors: female sex
Leigh et al. (2019) 60	University of Pennsylvania Health Systems	1,218	A, B, D	Overall incidence of Eosinophilic esophagitis is 0.034% in patient population. There may be a correlation with smoking.
BOTH Drug/ADR (n=6)
Silverman et al. (2016) 61	University of Pennsylvania Health Systems	220	A	12.4% of patients without chronic urticaria had self-reported penicillin allergy. there was a 14.5% rate and 4.6% of chronic urticaria in patients with and without self-reported penicillin allergy, respectively.
Lin et al. (2017) 62	Penn State College of Medicine/ Medical Center	138	D	In 78 pediatric reactions to vancomycin, 92% were consistent with Red Man Syndrome. Of 60 children prescribed linezolid, 82% were unnecessarily avoiding vancomycin without prior reaction to vancomycin.
Coleman et al. (2019) 63	Yale-New Haven Hospital	98	D	Most rashes were associated with immune checkpoint inhibitors: pembrolizumab (35/103 rashes), nivolumab (33/103 rashes), and ipilimumab/nivolumab (17/103 rashes).
Jung et al. (2019) 64	Yonsei University Wonju College of Medicine, South Korea	1,253	D	The prevalence of DRESS cases among patients prescribed antituberculosis drugs is 1.2%. Ethambol (53.5%) and rifampin (26.7%) are the most common culprit drugs.
Fukasawa et al. (2021) 65	JMDC Claims Database, Japan	355	B, D	In Japan the odds ratio of SJS/TEN for anti-convulsant, including carbamazepine (OR 68.00) and lamotrigine (OR 36.00) were significantly increased.
Sim et al. (2021) 66	Chonnam National University Hospital, South Korea	27	D	48% of 27 patients with drug fever or maculopapular exanthem had Multiple Drug Hypersensitivity Syndrome. Most common culprit agent was ethambutol and rifampin, followed by pyrazinamide and isoniazid.

^*(A=Allergy List/Problem List, B=ICD Codes, C=free-text or structured data in the allergy list, D=Other/Unspecified)

Abbreviations: NSAIDs, Non-steroidal anti-inflammatory drugs; RCM, Radiocontrast media; ADR, adverse drug reaction; SCAR, severe cutaneous adverse reactions; DRESS, drug reaction with eosinophilia and systemic symptoms