Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7 , with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10 −4 ) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10 −4 ). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10 −3 ), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10 −8 ). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10 −5 ). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Abstract Background Vitamin C has potential protective effects through anti-oxydant and anti-inflammatory properties. However, the effect of Vitamin C supplementation on microvascular function and peripheral tissue perfusion in human sepsis remains unknown. We aimed to determine vitamin C effect on microvascular endothelial dysfunction and peripheral tissue perfusion in septic shock patients. Methods Patients with septic shock were prospectively included after initial resuscitation. Bedside peripheral tissue perfusion and skin microvascular reactivity in response to acetylcholine iontophoresis in the forearm area were measured before and 1 hour after intravenous Vitamin C supplementation (40 mg/kg). Norepinephrine dose was not modified during the studied period. Results We included 30 patients with septic shock. SOFA score was 11 [8–14], SAPS II was 66 [54-79] and in-hospital mortality was 33%. Half of these patients had vitamin C deficiency at inclusion. Vitamin C supplementation strongly improved microvascular reactivity (AUC 2263 [430-4246] vs 5362 [1744-10585] UI, p=0.0004). In addition, Vitamin C supplementation improved mottling score (p=0.06), finger-tip (p=0.0003) and knee capillary refill time (3.7 [2.6-5.5] vs 2.9 [1.9-4.7] s, p<0.0001), as well as and central-to-periphery temperature gradient (6.1 [4.9-7.4] vs 4.6 [3.4-7.0] °C, p<0.0001). The beneficial effects of Vitamin C were observed both in patients with or without Vitamin C deficiency. Conclusion In resuscitated septic shock patients, vitamin C supplementation improved peripheral tissue perfusion and microvascular reactivity whatever plasma levels of vitamin C.
We assessed the potential impact of infusion tubing on blood glucose imbalance in ICU patients given intensive insulin therapy (IIT). We compared the incidence of blood glucose imbalance in patients equipped, in a nonrandomized fashion, with either conventional tubing or with a multiport infusion device.We retrospectively analyzed the nursing files of 35 patients given IIT through the distal line of a double-lumen central venous catheter. A total of 1389 hours of IIT were analyzed for occurrence of hypoglycemic events [defined as arterial blood glucose below 90 mg/dL requiring discontinuation of insulin].Twenty-one hypoglycemic events were noted (density of incidence 15 for 1000 hours of ITT). In 17 of these 21 events (81%), medication had been administered during the previous hour through the line connected to the distal lumen of the catheter. Conventional tubing use was associated with a higher density of incidence of hypoglycemic events than multiport infusion device use (23 vs. 2 for 1,000 hours of IIT; rate ratio = 11.5; 95% confidence interval, 2.71-48.8; p < 0.001).The administration of on-demand medication through tubing carrying other medications can lead to the delivery of significant amounts of unscheduled products. Hypoglycaemia observed during IIT could be related to this phenomenon. The use of a multiport infusion device with a limited dead volume could limit hypoglycemia in patients on IIT.
In intensive care unit (ICU), infection and colonization by resistant Gram-negative bacteria increase costs, length of stay and mortality. Extended-spectrum beta-lactamase − producing Enterobacteriaceae (ESBL-E) is a group of pathogens increasingly encountered in ICU setting. Conditions that promote ESBL-E acquisition are not completely understood. The increasing incidence of infections related to ESBL-E and the unsolved issues related to ESBL-E cross-transmission, prompted us to assess the rates of referred and acquired cases of ESBL-E in ICU and to assess patient-to-patient cross-transmission of ESBL-E using a multimodal microbiological analysis. During a 5-month period, all patients admitted to a medical ICU were tested for ESBL-E carriage. A rectal swab was performed at admission and then twice a week until discharge or death. ESBL-E strains were analyzed according to antibiotic susceptibility pattern, rep-PCR (repetitive-element Polymerase chain reaction) chromosomal analysis, and plasmid PCR (Polymerase chain reaction) analysis of ESBL genes. Patient-to-patient transmission was deemed likely when 2 identical strains were found in 2 patients hospitalized simultaneously in the ICU. Among the 309 patients assessed for ESBL-E carriage on admission, 25 were found to carry ESBL-E (importation rate: 8 %). During follow-up, acquisition was observed among 19 of them (acquisition rate: 6.5 %). Using the multimodal microbiological approach, we found only one case of likely patient-to-patient ESBL-E transmission. In unselected ICU patients, we found rather low rates of ESBL-E referred and acquired cases. Only 5 % of acquisitions appeared to be related to patient-to-patient transmission. These data highlight the importance of jointly analyzing phenotypic profile and molecular data to discriminate strains of ESBL-E.
OBJECTIVES: Mean arterial hypotension between 55 and 65 mm Hg could be tolerated safely in the absence of tissue hypoperfusion, but the consequences on fluid balance and kidney function remain unknown. DESIGN: During a 1-year period, we retrospectively collected data of consecutive septic patients admitted for sepsis with a mean arterial pressure (MAP) less than 65 mm Hg despite fluid resuscitation. SETTING: Medical 18-bed ICU in a tertiary teaching hospital. PATIENTS: Septic patients with a MAP less than 65 mm Hg despite initial resuscitation. INTERVENTIONS: In our ICU, MAP between 55 and 65 mm Hg was tolerated in the absence of peripheral hypoperfusion (permissive hypotension) or corrected using norepinephrine (septic shock group) when peripheral tissue hypoperfusion was present. MEASUREMENTS AND MAIN RESULTS: Ninety-four consecutive septic patients were included, 15 in the permissive hypotension group and 79 in the septic shock group. Median age was 66 years (57–77 yr) and 42% were women. The main sources of infection were respiratory (45%) and abdominal (18%). Severity was more important in septic shock group with higher Sequential Organ Failure Assessment score (7 [5–10] vs. 4 [1–6]; p < 0.0001), more frequent organ support therapy and ultimately higher mortality (38 vs. 0%; p < 0.01). The total volume of crystalloids infused before ICU admission was not different between groups (1930 ± 250 vs. 1850 ± 150 mL; p = 0.40). Within the 6 first hours of ICU stay, patients in the permissive hypotension group received less fluids (530 ± 170 vs. 1100 ± 110 mL; p = 0.03) and had higher urinary output (1.4 mL [0.88–2.34 mL] vs. 0.47 mL/kg/hr [0.08–1.25 mL/kg/hr]; p < 0.001). In addition, kidney injury evaluated using KDIGO score was lower in the permissive hypotension group at 48 hours (0 hr [0–1 hr] vs. 1 hr [0–2 hr]; p < 0.05). CONCLUSIONS: In septic patients without clinical peripheral hypoperfusion, mean arterial hypotension between 55 and 65 mm Hg could be tolerated safely without vasopressor infusion and was not associated with excessive fluid administration or kidney damage.
