Bacterial and Human Biomarkers of Prognostic Value for Severe Legionnaire’s Disease

Overview

Legionnaires' disease (LD) is a relatively common pneumonia in France (1200 cases/year), 98% of cases are hospitalized and 40% require intensive care unit (ICU) admission. Risk factors that may predispose to acquisition of LD are well known. Some studies suggest that genetic factor may also enhance susceptibility to LD. The mortality rate remains high (10% to 33% in ICUs) despite improved diagnostic and therapeutic management of patients. Few prospective studies have assessed the factors associated with LD outcomes, particularly death, and most of them involved a limited number of patients. In a multicentre cohort study, the investigators recently identified risk factors associated with higher mortality such as female sex, age, ICU stay, renal failure, corticosteroid treatment and enhanced pro-inflammatory status, as assessed by higher C-reactive protein level (PMID: 22005914). Other factors are suspected but their involvement has not been formally demonstrated including a high infectious bacterial load, particular virulence of Legionella strain, and an in vivo selection of mutants resistant to prescribed antibiotics. Disease progression is highly variable from one patient to another, and usually remains unpredictable. There are no objective criteria to predict the prognosis of these patients. The clinical course of patients with LD remains difficult to predict because no predictive biomarkers have yet been characterized and the demonstration of the presence of mutants to antibiotics in vivo has never been done. The main objective of the study is to correlate the L. pneumophila load (detected by PCR) to the clinical outcome of the LD infection. Clinical severity will measured by the SOFA score (Sepsis -Related Organ Failure Assessment) or the PELOD score (Pediatric Logistic Organ Dysfunction). Secondary objectives are to identify new host and bacterial biomarkers associated with poor outcome of LD.

Full Title of Study: “Bacterial and Human Biomarkers of Prognostic Value for Severe Legionnaire’s Disease”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Diagnostic
    • Masking: None (Open Label)
  • Study Primary Completion Date: May 23, 2020

Interventions

  • Other: Skin biopsy for genetic analyze
    • It will be offered to a subgroup of adult patients carrying genetic markers predisposing to the severity of the LD infection, a skin biopsy in order to realize genetic analyses. This visit will be conducted once the results of genetic markers obtained (between 30 and 36 months), a specific consent will be required to patients. The skin biopsy will be performed according to the Clinical Department use.

Arms, Groups and Cohorts

  • Other: This study is a non-drug one arm study
    • Skin biopsy for genetic analyze

Clinical Trial Outcome Measures

Primary Measures

  • Legionnaire’s disease severity measured by SOFA/PELOD score
    • Time Frame: At Hospital Output, on average 1 Day
    • No other specific timeframe could be provided, it will depend on patients’ condition. The study will evaluate correlation between the L. pneumophila load (quantify by molecular method) to the clinical outcome of the LD infection
  • Bacterial load measured by PCR
    • Time Frame: At Hospital Output, on average 1 Day
    • No other specific timeframe could be provided, it will depend on patients’ condition. The study will evaluate correlation between the L. pneumophila load (quantify by molecular method) to the clinical outcome of the LD infection

Secondary Measures

  • Specific cytokine profile
    • Time Frame: Up to Day 5
    • Cytokine profile will be measured at local level (pulmonary) and/ or systemic level (serum) and associated with severity
  • Genomic analyzes
    • Time Frame: At inclusion, up to 48 hours
    • Genomic analyzes of bacterial genes will be associated with the legionella severity
  • Pulmonary microbiota
    • Time Frame: At inclusion, up to 48 hours
    • Metagenomic approaches and NGS will be used to associate a specific microbiota, or changes in the severity of LD infection

Participating in This Clinical Trial

Inclusion Criteria

  • Adult patients with medical and biological signs of legionnaires' disease. – Pediatric patients regardless of age but with a minimum weight of 7.5 kg with medical and biological signs of legionnaires' disease. – Patient and/or his/her legal representative have reviewed the patient information/informed consent form and have given written informed consent. Exclusion Criteria:

  • None Legionella pneumophila Legionnaires' disease. – None serogroup 1 Legionella pneumophila Legionnaires' disease. – Patients for whom respiratory secretions can't be obtained. – Cases diagnosed only by serology. – Outpatients.

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Hospices Civils de Lyon
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Gérard LINA, Study Chair, Hospices Civils of Lyon
  • Overall Contact(s)
    • Gérard LINA, MD PhD, +33 4 78 86 44 93, gerard.lina@chu-lyon.fr

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