Clinical trial NCT05591924: Early Severe Illness TrAnslational BioLogy InformaticS in Humans
Official title: Prospective Observational Study of Biology of Critical Illness
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Sepsis
ARDS
Critical Illness
Neurocognitive Dysfunction
Shock, Septic
Ventilator Associated Pneumonia
Immune Suppression
Inflammation
SIRS
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
Collaborators: name: London Health Sciences Centre
name: Western University, Canada
name: Western University
First posted: 2022-10-24
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Critically ill adults with early critical illness

Brief summary: Advanced stages of the response to life-threatening infection, severe trauma, or other physiological insults often lead to exhaustion of the homeostatic mechanisms that sustain normal blood pressure and oxygenation. These syndromic presentations often meet the diagnostic criteria of sepsis and/or the acute respiratory distress syndrome (ARDS), the two most common syndromes encountered in the intensive care unit (ICU). Although critical illness syndromes, such as sepsis and ARDS, have separate clinical definitions, they often overlap clinically and share several common injury mechanisms. Moreover, there are no specific therapies for critically ill patients, and as a consequence, approximately 1 in 4 patients admitted to the ICU will not survive.

The purpose of this observational study is to identify early patient biologic factors that are present at the time of ICU admission that will help diagnose critical illness syndromes earlier, identify who could benefit most from specific therapies, and enable the discovery of new treatments for syndromes such as sepsis and ARDS.

Detailed description: Background:

Critical illness syndromes, such as sepsis and ARDS, are associated with tremendous heterogeneity in patient predisposing risk factors, mechanisms of acute insult contributing to infection, presenting symptoms, response to therapies, as well as short and long-term outcomes. Since the first standardization of sepsis and ARDS definitions \>30 years ago, significant insight into biological mechanisms contributing to critical illness syndromes have been made. However, there are many important unanswered questions that prevent accurate diagnosis, treatment, and prognosis of patients who present to the ICU with early symptoms consistent with critical illness.

Of the many gaps about the biology of sepsis and ARDS that remain unanswered, the following are particularly important: (1) what constitutes immune system dysregulation; (2) how the immune system response depends on interaction with the infecting pathogens; (3) what biologic traits distinguish other diagnoses that mimic these syndromes; (4) what are the mechanisms of genetic polymorphisms in patient outcomes. To address these questions and to improve our understanding of these complex and heterogenous syndromes, a multifaceted and collaborative approach is needed. This study will investigate the biology of early sepsis in critically ill patients by developing a longitudinal prospective observational cohort called Early Severe illness TrAnslational BioLogy InformaticS in Humans (ESTABLISH).

Specific objectives:

Objective 1: To study biologic mechanisms of immune system regulation during early critical illness. The main questions that will be addressed include: (1) how immune function at the time of admission and over the course of the ICU stay is related to clinical complications; (2) how anatomic compartmentalization of immune responses is associated with clinical complications; (3) how immune responses in different anatomic locations contribute to endothelial cell injury; (4) how macrophages contribute to distal organ injury and long-term clinical complications.

Objective 2: To characterize the host-pathogen interaction during early critical illness. The main question that will be addressed include: (1) how the microbial composition at the time of ICU admission affects the immune response; (2) how the change in host-pathogen interactions over time influence clinical complications.

Objective 3: To identify biologic traits that distinguish patients with early sepsis and ARDS from other critically ill patients. The main questions that will be addressed include: (1) are biological trains unique to sepsis and/or ARDS, or are they shared by other clinical diagnoses that mimic these syndromes?; (2) can accurately prognosticate clinically important short and long-term patient outcomes?; (3) are biologic traits associated with differential responses to therapies?

Objective 4: To study the molecular mechanisms of genetic polymorphisms associated with critical illness using induced pluripotent stem cells (iPSCs) derived from polymorphonuclear cells (PBMCs) from critically ill patients. The main questions that will be addressed include: (1) how do autologous iPSC-derived cell lineages interact with autologous plasma?; (2) how do iPSC-derived cell lineages respond to treatment with drugs related to genetic polymorphisms function?; (3) how do iPSC-derived lineages respond to treatment with drugs commonly used in the ICU?

Methods:

The ESTABLISH cohort will enroll patients within 48 hours of ICU admission who presented to the emergency department within 72 hours of ICU admission. Patients will be enrolled with deferred consent to enable the earliest possible collection of biological specimen. The biological specimen will include anticoagulated blood, a PAX gene tube, and a bronchioalveolar lavage fluid (BALF) sample (in mechanically ventilated patients, when bronchoscopy is clinically indicated) collected at the time of ICU admission (Day 0), and on 4 subsequent timepoints during the ICU admission (Days 1,3,7,14,21).

Data generated during ESTABLISH will be analyzed in batches on an ongoing, regular basis and will be objective-specific. Batch sample preparation and data analysis will minimize biological assay and methodological heterogeneity. Objective 1 and 2 data will be analyzed after enrollment of the first 50 patients, and every 50 patients after this. Objective 3 data will be analyzed after enrollment of the first 200 patients and every 200 patients after this.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years old
* ≤48h since ICU admission
* ICU admission within 72h of presentation to the emergency department (ER)
* Clinical critical illness suspected on the basis of any one of the following:

  1. Altered mental status (GCS\<15)
  2. Cardiovascular collapse (presence of any: Heart rate \>90, systolic blood pressure \<90, presence of vasopressors, lactate \>2.0)
  3. Respiratory collapse (presence of any: respiratory rate \>20, PaCO₂ \<32 mm Hg, supplemental oxygen, invasive or non-invasive ventilation)
  4. Suspected severe infection (presence of any: temperature \>38°C or \<36°C, white blood cell (WBC) count \>12,000/mm³ or \<4,000/mm³, presence of 1 or more antibiotics at the time of ICU admission)

Exclusion Criteria:

* Age \<18 years old
* \>48h since ICU admission
* Admission to ICU in patients \>72h after the presentation to the ER
* No evidence of critical illness (ICU admission due to bed-spacing)

Primary outcomes:
measure: Risk of developing nosocomial infections during ICU admission
timeFrame: Assessed daily until discharge from ICU, through study completion, an average of 1 year
measure: Severity of illness measured by APACHE score
timeFrame: At the time of ICU admission
measure: Severity of illness measured by SOFA score
timeFrame: At the time of ICU admission
measure: Severity of illness measured by MODS score
timeFrame: At the time of ICU admission
measure: Change in severity of illness measured by APACHE score
timeFrame: From the time of ICU admission, assessed daily until death or discharge from ICU, up to 12 months
measure: Change in severity of illness measured by SOFA score
timeFrame: From the time of ICU admission, assessed daily until death or discharge from ICU, up to 12 months
measure: Change in severity of illness measured by MODS score
timeFrame: From the time of ICU admission, assessed daily until death or discharge from ICU, up to 12 months
measure: Hospital disposition
timeFrame: Determined at the time of discharge from the hospital, through study completion, an average of 1 year
Secondary outcomes:
measure: Neurocognitive dysfunction
timeFrame: 1, 6, and 12 months after ICU discharge
measure: Physiological outcomes
timeFrame: 0, 24, 48, and 72 hours after ICU admission
Other outcomes:
Locations:
city: London
country: Canada
facility: Aleks Leligdowicz
state: Ontario
Study officials:
affiliation: Western University
name: Aleks Leligdowicz, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Leligdowicz A, Matthay MA. Heterogeneity in sepsis: new biological evidence with clinical applications. Crit Care. 2019 Mar 9;23(1):80. doi: 10.1186/s13054-019-2372-2.
citation: Maslove DM, Tang B, Shankar-Hari M, Lawler PR, Angus DC, Baillie JK, Baron RM, Bauer M, Buchman TG, Calfee CS, Dos Santos CC, Giamarellos-Bourboulis EJ, Gordon AC, Kellum JA, Knight JC, Leligdowicz A, McAuley DF, McLean AS, Menon DK, Meyer NJ, Moldawer LL, Reddy K, Reilly JP, Russell JA, Sevransky JE, Seymour CW, Shapiro NI, Singer M, Summers C, Sweeney TE, Thompson BT, van der Poll T, Venkatesh B, Walley KR, Walsh TS, Ware LB, Wong HR, Zador ZE, Marshall JC. Redefining critical illness. Nat Med. 2022 Jun;28(6):1141-1148. doi: 10.1038/s41591-022-01843-x. Epub 2022 Jun 17.
citation: Leligdowicz A, Kamm J, Kalantar K, Jauregui A, Vessel K, Caldera S, Serpa PH, Abbott J, Fang X, Tian X, Prakash A, Kangelaris KN, Liu KD, Calfee CS, Langelier C, Matthay MA. Functional Transcriptomic Studies of Immune Responses and Endotoxin Tolerance in Early Human Sepsis. Shock. 2022 Jun 1;57(6):180-190. doi: 10.1097/SHK.0000000000001915. Epub 2022 Jan 20.
citation: Leligdowicz A, Conroy AL, Hawkes M, Richard-Greenblatt M, Zhong K, Opoka RO, Namasopo S, Bell D, Liles WC, da Costa BR, Juni P, Kain KC. Risk-stratification of febrile African children at risk of sepsis using sTREM-1 as basis for a rapid triage test. Nat Commun. 2021 Nov 25;12(1):6832. doi: 10.1038/s41467-021-27215-6.
citation: Leligdowicz A, Conroy AL, Hawkes M, Zhong K, Lebovic G, Matthay MA, Kain KC. Validation of two multiplex platforms to quantify circulating markers of inflammation and endothelial injury in severe infection. PLoS One. 2017 Apr 18;12(4):e0175130. doi: 10.1371/journal.pone.0175130. eCollection 2017.
citation: Leligdowicz A, Chun LF, Jauregui A, Vessel K, Liu KD, Calfee CS, Matthay MA. Human pulmonary endothelial cell permeability after exposure to LPS-stimulated leukocyte supernatants derived from patients with early sepsis. Am J Physiol Lung Cell Mol Physiol. 2018 Nov 1;315(5):L638-L644. doi: 10.1152/ajplung.00286.2018. Epub 2018 Jul 19.
citation: Marshall JC, Leligdowicz A. Gaps and opportunities in sepsis translational research. EBioMedicine. 2022 Dec;86:104387. doi: 10.1016/j.ebiom.2022.104387. Epub 2022 Dec 2.
citation: Shah FA, Meyer NJ, Angus DC, Awdish R, Azoulay E, Calfee CS, Clermont G, Gordon AC, Kwizera A, Leligdowicz A, Marshall JC, Mikacenic C, Sinha P, Venkatesh B, Wong HR, Zampieri FG, Yende S. A Research Agenda for Precision Medicine in Sepsis and Acute Respiratory Distress Syndrome: An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med. 2021 Oct 15;204(8):891-901. doi: 10.1164/rccm.202108-1908ST.