Defining ENDOtypes in Perioperative Hypersensitivity by Extensive Cellular and Molecular PHENotyping (ENDOPHEN)

NCT04006106 | Completed

• 1 other identifier: APHP180157
• Study Type: observational
• Target: 103
• Locations: 1 country
• Sites: 7

Brief Summary

Perioperative Acute Hypersensitivity (PAH) is a systemic reaction that occurs rapidly following injection of a drug during anesthesia.The HSA-PA reaction must occur within a maximum of one hour after the induction of anesthesia or a new product by the anesthetist. The main mechanism evoked is an immune response of immediate systemic hypersensitivity or anaphylaxis. Anaphylactic reactions are classically described as IgE-dependent and triggered by the injection of allergen which by bridging specific IgE present on the surface of mast cells, induces a massive release of histamine responsible for the observed symptoms. The diagnosis of this mechanism (IgE endotype) requires the determination of associated circulating mediators (histamine and mast cell tryptase) as well as skin tests performed during an allergologic evaluation. However, our previous work on patients with PAH (NASA study, ClinicalTrials.gov: NCT01637220) demonstrated that classical markers of IgE endotype are present in only 42% of patients. This finding has three consequences:

• a diagnostic inaccuracy with deleterious consequences for the patient,
• the existence of undocumented endotypes explaining the observed clinical manifestations,
• a lack of formal identification of culprit drug, with uncertainty about the eviction recommendations leading to consequences for the safety of the patient. The investigators hypothesize that symptoms associated with PAH are caused by several distinct endotypes involving different cellular effectors and molecular mediators. These endotypes may be related to the immune system but independent of IgE, or independent of the immune system. To assess these endotypes, The investigators will be measuring the activation status of blood cells and a wide range of secreted mediators in blood drawn as soon as possible after PAH onset, and at steady state during a subsequent allergology visit. These data will be analyzed along with clinical data in multivariate analysis and clustering to define coherent profiles among patients. Definition of previously unexplored endotypes will allow to explain more PAH reactions and to design new diagnostic and therapeutic strategies. During the ENDOPHEN protocol, the measurement of a large number of biological parameters will be correlated with the clinical phenotype in patients who have presented a PAH. However, the procedures of general anesthesia themselves lead to a certain number of physiological modifications likely to modify the parameters measured in the ENDOPHEN protocol. This is why it was decided to carry out an ancillary study, the PHENZERO study, the objective of which is to measure the reference values of the parameters provided for in ENDOPHEN in an anesthetized population without any hypersensitivity phenotype ("zero" phenotype).

Conditions

Perioperative Complication; Hypersensitivity

Keywords

Drug hypersensitivity; Endotypes; Anaphylaxis

Outcome Measures

Primary Outcomes (4)

• Change in activation status of blood cells between inclusion and 10 weeks, measured by CD62L mean fluorescent intensity on neutrophils by flow cytometry.

  Measures on patients with hypersensitivity phenotype

  0 and 10 weeks

• Change in inflammatory mediators concentrations (CRP, IL-6, leukotrien B4; in pg/mL) between inclusion and 10 weeks, measured by ELISA.

  Measures on patients with hypersensitivity phenotype

  0 and 10 weeks

• Change in activation status of blood cells between inclusion and 1 month, measured by CD62L mean fluorescent intensity on neutrophils by flow cytometry.

  Measures on patients without any hypersensitivity phenotype

  0 and 1 month

• Change in inflammatory mediators concentrations (CRP, IL-6, leukotrien B4; in pg/mL) between inclusion and 1 month, measured by ELISA.

  Measures on patients without any hypersensitivity phenotype

  0 and 1 month

Secondary Outcomes (4)

• Establish a correlation between change in activation status of blood cells as defined in the outcome 1 and severity of the PAH reaction as measured by the Ring and Messmer classification.

  0 and 10 weeks

• Establish a correlation between change in inflammatory mediators concentrations (CRP, IL-6, leukotrien B4; in pg/mL) between inclusion and 10 weeks and severity of the PAH reaction as measured by the Ring and Messmer classification.

  0 and 10 weeks

• Constitute a biobank (serum, plasma, DNA) to be able to continue the exploration of the different endotype

  0 and 10 weeks

• Constitute a biobank (serum, plasma, DNA) to be able to continue the exploration of the different endotype

  0 and 1 month

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

ENDOPHEN protocol Patient presenting, during a general anesthesia, clinical signs compatible with an PAH sufficiently severe for the anesthetist to request biological exploration using the "anaphylaxis kit" present in all operating theaters PHENZERO protocol Patient who do not present clinical signs consistent with PAH during general anesthesia

You may qualify if:

• Age ≥18 years
• Patient presenting, during a general anesthesia, clinical signs compatible with an PAH sufficiently severe for the anesthetist to request biological exploration using the "anaphylaxis kit" present in all operating theaters

You may not qualify if:

• Protected person: under guardianship or curatorship
• Person deprived of liberty by judicial or administrative decision
• Person under psychiatric care
• Patient not affiliated to social security
• Refusal to sign a written consent to continue participation
• PHENZERO protocol
• Age ≥18 years
• Patient undergoing scheduled cardiac surgery under general anesthesia
• Refusal to sign a free, informed and written consent
• Weight \<= 57kg
• Patient with severe systemic infection, (CTCAE ≥ 3)
• Patient coming from resuscitation or intensive care unit
• Patient in shock (grade I to IV)
• Patient on immunosuppressants
• Protected person: under guardianship or curatorship

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (7)

Ambroise Paré Hospital

Boulogne-Billancourt, France

Location

Beaujon Hospital

Clichy, France

Location

Louis Mourier Hospital

Colombes, France

Location

Bichat Hospital

Paris, France

Location

Européen Georges Pompidou Hospital

Paris, France

Location

La Pitié Salpêtrière Hospital

Paris, France

Location

Saint Louis Hospital

Paris, France

Location

Biospecimen

Retention: SAMPLES WITH DNA

serum, plasma, peripheral blood mononuclear cell (PBMC), blood DNA

MeSH Terms

Conditions

Hypersensitivity; Drug Hypersensitivity; Anaphylaxis

Condition Hierarchy (Ancestors)

Immune System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Hypersensitivity, Immediate

Study Officials

• Luc DE CHAISEMARTIN, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 29, 2019
• First Posted: July 2, 2019
• Study Start: October 6, 2020
• Primary Completion: October 6, 2022
• Study Completion: April 30, 2024
• Last Updated: December 20, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (7)