Main objective and primary endpoint: To compare the effect hydrocortisone plus fludrocortisone vs. placebo on a composite of death or persistent organ dysfunction - defined as continued dependency on mechanical ventilation, new renal replacement therapy, or vasopressors - assessed at 90 days on intensive care unit (ICU) adults and having different biological profiles for immune responses and corticosteroids bioactivity.

Secondary objectives and endpoints:

• Mortality and health-related quality of life at 6 months;
• Daily organ function (SOFA score days 1, 2, 3, 4, 7, 10, 14, 28, and 90);
• Daily secondary infections (up to 90 days)
• Daily blood and urinary levels of glucose, sodium and potassium (up to 28 day)
• Daily gastroduodenal bleeding (up to 28 day)
• Daily cognitive function and muscles' strength (days 1 to 28, 90 and 180 days).

The potential benefits of a lower dose ( ≤ 400 mg of hydrocortisone or equivalent per day), and a longer duration at full dose ( ≥ three days) of treatment, have been investigated in numerous randomized controlled trials over the past three decades. In the past two years, guidelines for clinical practices about corticosteroids use in sepsis have been released. All but one of the guidelines, recommended against the use of corticosteroids in sepsis, except in patients with septic shock and poorly responsive to fluid replacement and vasopressor therapy. Some guidelines suggested that corticosteroids should be given as a continuous infusion rather than intermittent boluses.

Corticosteroids survival benefit is not affected by age, gender, disease severity, type of infection, source of infection, or type of pathogens. There is currently no diagnostic test for CS sensitivity/resistance in sepsis. The scientific community is competing to identify markers delineating between patients who draw survival benefit from corticosteroids (CS-sensitive sepsis) and those who may be harmed (CS-resistant sepsis). In sepsis, the deregulated response may result in systemic inflammation and organs damage, or immune paresis and secondary infections. Obviously, patients with systemic inflammation may benefit from CS whereas those with immune paresis may deteriorate. The study team had have looked for an interaction between survival in response to corticosteroids and the presence of CIRCI according to the ACTH test results (cortisol increment of less than 9µg/dL). The benefits from corticosteroids were more important in patients with CIRCI in the Ger-Inf-05 trial but not in the APROCCHS trial. Thus, current sepsis guidelines suggest that the ACTH test may not reliably guide the use of corticosteroids. Indeed, this test provides information neither on corticosteroids bioactivity nor on patient's immune status, when this information should precede any corticotherapy. Recent studies suggested that a transcriptomic signature based on 100 genes may identify a subset of paediatric sepsis that had increased risk of death when exposed to corticosteroids. Another study found transcriptomic based sepsis response signatures (SRS) associated with immune paresis (SRS1) or with systemic inflammation (SRS 2). In this study, patients with a SRS 2 transcriptomic signature had significantly higher mortality when treated with hydrocortisone. Thus, we have started exploring the mechanisms of sensitivity/resistance to corticosteroids in sepsis, namely by investigating endocan, as a surrogate of patient's inflammatory status, and GILZ expression as a marker of corticosteroids bioactivity.

This is a new multicentre concealed-allocation multi-arms, parallel-group, adaptive blinded randomized controlled trial. The overall objective of the trial is to determine whether different signatures of immune status and/or corticosteroids biological activity influence the responses to hydrocortisone plus fludrocortisone of adults with sepsis. To remain pragmatic, this trial has broad eligibility criteria and includes all patients admitted to the ICU with a primary diagnosis of sepsis. Patients will be randomly assigned to hydrocortisone plus fludrocortisone or placebo for 7 days, targeting 1800 patients with full follow-up up to 6 months.

Inclusion Criteria:

1. Patient ≥18 years old;

2. Admitted to ICU with proven or suspected infection as the main diagnosis;

3. Community acquired pneumonia related sepsis or vasopressors dependency (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine) or septic shock (vasopressor to maintain mean blood pressure of at least 65 mmHg and lactate levels above 2 mmol/l) or acute respiratory distress syndrome (ARDS: a- acute onset, i.e. within one week of an apparent clinical insult and with progression of respiratory syndrome, b- bilateral opacities on chest imaging not explained by other pulmonary pathologies, e.g. pleural effusion, atelectasis, nodules etc, c- no evidence for heart failure or volume overload, d- PaO2/FiO2 ≤ 300 mm Hg, - PEEP ≥ 5 cm H2O;

4. Patients who have been tested for one or more RECORDS specific biomarkers:

   1. CIRCI
   2. Endocan
   3. GILZ
   4. DUSP-1
   5. MDW
   6. lymphopenia
   7. Transcriptomic SRS2
   8. Endotype B
   9. PCR COVID-19
   10. PCR Influenza
   11. PCR other respiratory virus
   12. Cutaneous vasoconstrictor response to glucocorticoids

5. Patient who has signed an informed and written consent whevener he/she is able of consent, if not, if not ascent from his/her representant whenever he/she is present at time of screening for inclusion;

6. Patient affiliated to a social security system or to an universal health coverage (Couverture Maladie Universelle (CMU) in France;

7. Patient under guardianship or curatorship will be included;

8. Patient in case of simple emergency (legal definition) will be included;

9. Patients managed with covid 19 and having biological samples available.

Exclusion Criteria:

1. Pregnancy;
2. Expected death or withdrawal of life-sustaining treatments within 48 hours;
3. Previously enrolled in this study
4. Formal indication for corticosteroids according to most recent international guidelines
5. Vaccination with live virus within past 6 months
6. Hypersensitivity to hydrocortisone or fludrocortisone or (microsined betamethasone dipropionate*) or any of their excipients (spc)
7. Women of childbearing potential not using contraception
8. Nursing women * For patients included in this stratum, if applicable, do not apply the cream to an infected or ulcerated area