Sepsis is a significant public health concern, particularly affecting individuals above 70 years in developed countries. This is a crucial fact due to the increasing aging population, their heightened vulnerability to sepsis, and the associated high mortality rates. However, the morbidity and long-term outcomes are even more notable. While many patients respond well to timely and appropriate interventions, it is imperative to enhance efforts in identifying, documenting, preventing, and treating sepsis. Managing sepsis in older patients poses greater challenges and necessitates a comprehensive understanding of predisposing factors and a heightened suspicion for diagnosing infections and assessing the risk of sudden deterioration into sepsis. Despite age often being considered an independent risk factor for mortality and morbidity, recent research emphasizes the pivotal roles of frailty, disease severity, and comorbid conditions in influencing health outcomes. In addition, it is important to inquire about the patient's preferences and establish a personalized treatment plan that considers their potential for recovery with quality of life and functional outcomes. This review provides a summary of the most crucial aspects to consider when dealing with an old critically ill patient with sepsis.

The number of intensive care patients aged ≥ 80 years (Very old Intensive Care Patients; VIPs) is growing. VIPs have high mortality and morbidity and the benefits of ICU admission are frequently questioned. Sepsis incidence has risen in recent years and identification of outcomes is of considerable public importance. We aimed to determine whether VIPs admitted for sepsis had different outcomes than those admitted for other acute reasons and identify potential prognostic factors for 30-day survival. This prospective study included VIPs with Sequential Organ Failure Assessment (SOFA) scores ≥ 2 acutely admitted to 307 ICUs in 21 European countries. Of 3869 acutely admitted VIPs, 493 (12.7%) [53.8% male, median age 83 (81–86) years] were admitted for sepsis. Sepsis was defined according to clinical criteria; suspected or demonstrated focus of infection and SOFA score ≥ 2 points. Compared to VIPs admitted for other acute reasons, VIPs admitted for sepsis were younger, had a higher SOFA score (9 vs. 7, p < 0.0001), required more vasoactive drugs [82.2% vs. 55.1%, p < 0.0001] and renal replacement therapies [17.4% vs. 9.9%; p < 0.0001], and had more life-sustaining treatment limitations [37.3% vs. 32.1%; p = 0.02]. Frailty was similar in both groups. Unadjusted 30-day survival was not significantly different between the two groups. After adjustment for age, gender, frailty, and SOFA score, sepsis had no impact on 30-day survival [HR 0.99 (95% CI 0.86–1.15), p = 0.917]. Inverse-probability weight (IPW)-adjusted survival curves for the first 30 days after ICU admission were similar for acute septic and non-septic patients [HR: 1.00 (95% CI 0.87–1.17), p = 0.95]. A matched-pair analysis in which patients with sepsis were matched with two control patients of the same gender with the same age, SOFA score, and level of frailty was also performed. A Cox proportional hazard regression model stratified on the matched pairs showed that 30-day survival was similar in both groups [57.2% (95% CI 52.7–60.7) vs. 57.1% (95% CI 53.7–60.1), p = 0.85]. After adjusting for organ dysfunction, sepsis at admission was not independently associated with decreased 30-day survival in this multinational study of 3869 VIPs. Age, frailty, and SOFA score were independently associated with survival.

During the COVID-19 pandemic, Mesenchymal Stromal Cells (MSCs) were rapidly proposed as a therapeutic option for Acute Respiratory Distress Syndrome (ARDS) based on their immunomodulatory properties. We report the results of COVIDMES, a multicenter trial initiated within a public blood and tissue bank infrastructure during unprecedented period of volatility and scientific uncertainty of the first pandemic waves. To evaluate the safety, feasibility and exploratory efficacy of Wharton's Jelly-derived MSCs (WJ-MSCs) in hospitalized patients with moderate-to-severe COVID-19 associated ARDS. This was a multicenter, prospective, double-blind, randomized, placebo-controlled Phase I/II pilot trial. The primary endpoint was all-cause 28-day mortality. Secondary endpoints included duration of mechanical ventilation, length of intensive care unit (ICU) stay, and longitudinal inflammatory biomarker kinetics. Twenty-six patients were enrolled between July 15th, 2020, and June 30th, 2021, of whom 25 received two intravenous doses of either 1 × 10⁶ viable WJ-MSCs/kg (n = 13) or placebo (n = 12) on days 1 and 3. WJ-MSC administration was safe and well tolerated, with no treatment-related serious adverse events. No statistically significant differences were observed between groups in 28-day mortality (no deaths in the treatment group versus 2 in the placebo group, P = 0.18), duration of mechanical ventilation (18.3 versus 10.6 days; P = 0.08), or ICU stay (17.1 versus 11.9 days; P = 0.11). Ferritin levels showed a significantly different temporal evolution, with more pronounced reduction over time in the WJ-MSC group (P < 0.0001 from baseline; P = 0.0057 for group-time interactions), however this biological effect was not associated with clinical improvement. In this exploratory pilot study, WJ-MSCs demonstrated a favorable safety profile and evidence of biochemical immunomodulation but no clinical efficacy in moderate-to-severe COVID-19 associated ARDS. These findings highlight the challenges of evaluating advanced therapy medicinal products within a rapidly evolving standard of care and support the need for biomarker-guided patient stratification and optimized dosing strategies in future MSC trials. The successful execution of this trial also validates the resilience of academic "donor-to-patient" networks in global health emergencies.