Clinical trial NCT05020327: Inpatient Penicillin Allergy Delabeling Study
Official title: Inpatient Penicillin Allergy Delabeling Pilot Project at University Hospitals-Rainbow Babies and Children's Hospital in Cleveland, Ohio
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Penicillin Allergy
Penicillin Sensitivity
Penicillin Reaction
Penicillin Intolerance
Keywords: Penicillin allergy
Penicillin delabeling
Lead sponsor: University Hospitals Cleveland Medical Center
Sponsor class: OTHER
First posted: 2021-08-25
Enrollment: 40
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Patients will be screened by questionnaire to determine No risk, Low risk, or High Risk for penicillin allergic reaction. Those that are deemed Low Risk based on questionnaire, will be subsequently challenged with graded oral amoxicillin challenge.
Primary purpose: OTHER

Brief summary: The study will identify pediatric patients 3-18 years old who have penicillin allergy label in the electronic medical record. Those who are identified will be stratified into no-risk, low-risk and high-risk category using a screening questionnaire. The following definitions will be followed:

No-risk: Patients who are historically labeled with penicillin allergy in the EMR based on family history alone OR those who have tolerated penicillin after a concerning incident without any reaction OR with penicillin allergy label but deny any history of reaction to any form of penicillin on screening questionnaire

Low-risk: Patients with previous reaction not suggestive of anaphylaxis (defined below) AND not requiring hospitalization for the reaction OR reaction considered non- immunologic (e.g. diarrhea, nausea, yeast vaginitis) OR exposure to penicillin- containing antibiotic after the date of reported reaction with no anaphylaxis and hospitalization AND no serious types of delayed reactions such as Steven- Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute interstitial nephritis (AIN), drug-induced hepatitis or other documented organ injury, drug rash eosinophilia systemic symptoms (DRESS), hemolytic anemia, drug-induced cytopenia, and serum sickness. Patients who had delayed reaction (onset more than 24 hours) of isolated, non-progressive symptoms (such as rash/hives alone) also belong to this group.

High-risk: Patients with penicillin allergy label on EMR with previous reaction suggestive of anaphylaxis (defined below) OR requiring hospitalization/epinephrine administration for the reaction OR reactions considered immunologic (angioedema, joint pains) OR involving serious types of reactions such as Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute interstitial nephritis (AIN), drug-induced hepatitis or other documented organ injury, drug rash eosinophilia systemic symptoms (DRESS), hemolytic anemia, drug-induced cytopenia, and serum sickness. Patients who were previously diagnosed with penicillin allergy by an allergist also belong to the high-risk group.

Patients in the no-risk group will be immediately delabeled. Patients in the high-risk group will be referred to allergy/immunology for further work up. The focus of this study is to identify the patients who belong to the low-risk group. This group of patients will be subjected to graded oral amoxicillin challenge testing. Those who will have reactions compatible with allergy will have their allergy status retained in the electronic medical record. Those that will not have reactions or those that will have reactions that are not compatible with allergy will be delabeled in the electronic medical record.

Detailed description: A. Specific Aims and Hypotheses

General Objective:

To verify pediatric patients with reported penicillin allergy in electronic medical record (EMR) by performing direct oral amoxicillin challenge testing.

Hypothesis: Pediatric patients with reported penicillin allergy in EMR can be verified by performing direct oral amoxicillin challenge testing.

Specific objectives:

1. To identify no-risk, low-risk and high-risk patients among pediatric patients with reported penicillin allergy in EMR through a questionnaire.

   Hypothesis: No-risk, low-risk and high-risk pediatric patients with reported penicillin allergy in EMR can be identified using a questionnaire.
2. To be able to delabel pediatric patients with reported penicillin allergy in EMR who are identified as no-risk.

   Hypothesis: No-risk pediatric patients with reported penicillin allergy in EMR can be delabeled using a questionnaire.
3. To be able to delabel identified low-risk pediatric patients with reported penicillin allergy in EMR who are verified not allergic to penicillin by direct oral amoxicillin challenge testing.

   Hypothesis: Identified low-risk pediatric patients with reported penicillin allergy in EMR using a questionnaire can be verified using direct oral amoxicillin challenge testing.
4. To be able to provide proper referral guidance to patients identified as high-risk and those who failed oral amoxicillin challenge testing to allergy and immunology for further evaluation and management.

Hypothesis: Proper referral guidance to patients identified as high-risk and those who failed oral penicillin challenge testing to allergy and immunology can be provided for their further evaluation and management.

B. Background and Significance Penicillin remains a reliable class of antibiotics that addresses a majority of infections both in outpatient and inpatient settings.(1,2) It is also one of the cheapest antibiotics to use for empiric therapy for susceptible infections.(3,4) Emerging literature suggests that the number of patients with historical penicillin allergy is an overestimate. A growing number of studies show that only approximately 1-10 % of patients with historical penicillin allergy are truly allergic after verified allergy testing is done.(1-3,5,7,8,10,11,12) Despite this, efforts on antibiotic allergy delabeling remains sparse and penicillin allergy remains to be the most common drug allergy reported.

Few institutions have implemented, much less conceptualized, protocols to determine truly allergic patients who have reported penicillin allergy when diagnosed with infections theoretically susceptible to penicillin.(6) One limitation perhaps is the absence of validated questionnaire that uniformly captures accepted levels of risk especially in the pediatric population.(7) As a result, these patients end up receiving alternative antimicrobial agents that pose a risk for emergence of resistance, development of unnecessary intestinal dysbiosis, and increased economic burden to health care resulting in suboptimal clinical outcome. (1-6) Studies aiming to validate direct oral challenge testing as a means of penicillin allergy delabeling is a fertile avenue for this clinical query to be addressed in a cost-effective and timely manner. (8-13)

Identifying patients with no immunologically-mediated penicillin allergy and delabeling them in the electronic medical record (EMR) accordingly will mitigate the use of second-line antibiotics, aid in minimizing development of antimicrobial resistance, ameliorate unnecessary economic burden, and overall lead to positive impact in clinical outcome and patient care. (1,5,7,8,10,11,12) In the same way, this process will also identify patients with true penicillin allergy creating a point-of-care opportunity to provide them proper guidance on the importance of Allergy/Immunology follow-up for further evaluation and management.

C. Methods

Population of Interest:

Patients 3-18 years old admitted at our institution will be screened for inclusion. We will screen approximately 800 patients and enroll 60 patients in our study (based on the weekly census) over a span of 3 months. HIPAA regulations will be strictly observed in data handling to protect patient privacy.

Screening and consenting of patients:

Signed parental consent and verbal consent from study team will be obtained prior to screening. Patients will be screened using a questionnaire to identify risk status. Patients identified as no-risk (EMR label based purely on family history of penicillin allergy, mislabeled patients) will be immediately delabeled in EMR. High-risk patients (those with reaction consistent with IgE mediated reaction or with history of anaphylaxis) will be excluded. Guidance on further care such as referral to an allergist will be recommended if not yet done. Low-risk patients (those with mild reaction not consistent with IgE mediated reaction, no history of serious delayed reaction or no reaction on subsequent penicillin receipt) will be identified to undergo graded direct oral amoxicillin challenge testing.

Oral Amoxicillin Challenge Testing:

Signed parental consent and patient assent (7 years and older) will be obtained prior to challenge testing. Only low-risk patients with parent/guardian in the room and no receipt of anti-histamine 48 hours prior will be challenged. Only patients who can tolerate enteral amoxicillin will be challenged. Rescue kits (containing diphenhydramine, epinephrine and albuterol) will be ready at bedside prior to challenging. Baseline vital signs will be obtained prior to challenging. Oral challenge testing will be graded: initial 10% of the dose followed by remaining 90% of the dose (total dose 45 mg/kg with maximum of 1000 mg) 30 minutes apart. Vital signs will be repeated 30 minutes after the first dose, 30 minutes after the second dose and finally 60 minutes after the second dose. Study team will administer amoxicillin doses and monitor for signs of amoxicillin allergic reaction. Any reaction during the testing will be assessed by trained study team member. A clinical event note will be written in the EMR for any reaction occurring during the testing as well the management implored to mitigate reaction.

Delabeling:

Low-risk patients who passed the challenge testing will be delabeled in EMR. Documentation of the result will be sent to patient's primary care doctor (with permission from parent) for guidance on future use of penicillin.

Eligibility criteria: Inclusion Criteria:

Inclusion Criteria for screening

* Patients 3-18 years old admitted at our institution with penicillin allergy label in electronic medical record
* Patients with available parent/s or legal guardian who can give both written and verbal consent to the oral challenge testing
* Patients with available parent/s or legal guardian during the conduct of oral amoxicillin challenge testing

Inclusion Criteria for oral challenge test

- Patients who will be identified as low-risk patients based on the standardized screening questionnaire. Low-risk group patients are those patients with previous reaction not suggestive of anaphylaxis AND not requiring hospitalization for the reaction OR reaction considered non-immunologic (e.g. diarrhea, nausea, yeast vaginitis) OR exposure to penicillin-containing antibiotic after the date of reported reaction with no anaphylaxis and hospitalization AND no serious types of delayed reactions such as Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute interstitial nephritis (AIN), drug-induced hepatitis or other documented organ injury, drug rash eosinophilia systemic symptoms (DRESS), hemolytic anemia, drug-induced cytopenia, and serum sickness. - ---- Patients who had delayed reaction (onset more than 24 hours) of isolated, non-progressive symptoms (such as rash/hives alone) also belong to this group.

Exclusion Criteria:

Exclusion Criteria for screening

* Patients who cannot tolerate amoxicillin/penicillin by enteral route.
* Patients with no parents or legal guardian available to give both written and verbal consent to the oral challenge testing
* Patients with no available parents or legal guardian during the conduct of oral amoxicillin challenge testing
* Patients currently on antihistamine or have received antihistamine in the previous 48 hours
* Patients who are critically ill
* Patients who have been vomiting more than twice in the past 24 hours or are actively vomiting
* Patients with respiratory symptoms warranting oxygen therapy or pulmonary finding of wheezing or stridor
* Patients identified as having anaphylactic reaction to penicillin in the electronic medical record

Exclusion Criteria for oral challenge testing

* Patients who will be identified as no-risk patients based on the standardized screening questionnaire. No-risk group patients are those patients who are historically labeled with penicillin allergy in the EMR based on family history alone OR those who have tolerated penicillin after a concerning incident without any reaction OR with penicillin allergy label but deny any history of reaction to any form of penicillin on screening questionnaire
* Patients who will be identified as high-risk patients based on the standardized screening questionnaire. High-risk group patients are those patients with penicillin allergy label on EMR with previous reaction suggestive of anaphylaxis OR requiring hospitalization/epinephrine administration for the reaction OR reactions considered immunologic (angioedema, joint pains) OR involving serious types of reactions such as Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute interstitial nephritis (AIN), drug-induced hepatitis or other documented organ injury, drug rash eosinophilia systemic symptoms (DRESS), hemolytic anemia, drug-induced cytopenia, and serum sickness. Patients who were previously diagnosed with penicillin allergy by an allergist also belong to the high-risk group.

Primary outcomes:
measure: Number of Participants With Confirmed Allergy Status
timeFrame: 3 hours
Secondary outcomes:
measure: Number of Participants With no Penicillin Allergy Confirmed and De-labelled of Penicillin Allergy Based on Results of Questionnaire.
timeFrame: 3 hours
measure: Number of Participants Categorized as Low Risk for Penicillin Allergy Reaction With Confirmed True Penicillin Allergy as Measured by Failed Oral Amoxicillin Challenge
timeFrame: 3 hours
measure: Number of Participants With Confirmed True Allergy Without Challenge
timeFrame: 3 hours
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: University Hospitals Rainbow Babies and Children's Hospital
state: Ohio
Study officials:
affiliation: University Hospitals Cleveland Medical Center
name: Ankita Desai, MD
role: PRINCIPAL_INVESTIGATOR
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