Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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

Is There a Role for Albumin Administration in Nutrition Support?

OBJECTIVE: To review the administration of exogenous albumin in patients receiving nutritional support and determine if the use of albumin is supported by controlled trials. DATA SOURCES: MEDLINE search of English-language literature using the key terms albumin, parenteral nutrition, and enteral nutrition. The references of articles identified were also searched. STUDY SELECTION: Studies examining the administration of exogenous albumin to hypoalbuminemic patients receiving nutrition support. DATA EXTRACTION: Results from prospective randomized trials are presented in detail. Data from noncontrolled and animal studies are presented in areas where human controlled trials are limited. DATA SYNTHESIS: Albumin is a marker of malnutrition and numerous studies have demonstrated that a low serum albumin concentration is associated with increased morbidity and mortality. Investigators have attempted to improve outcome through the administration of exogenous albumin. The results of controlled trials examining exogenous albumin administration have been equivocal. One study demonstrated a significant decrease in overall complications, pneumonia, and sepsis. In two other controlled trials, albumin administration failed to decrease complications. None of the studies demonstrated a significant decrease in mortality or length of stay. A low serum albumin concentration has also been linked to intolerance to enteral feedings. Although case reports and one study support the administration of albumin, two prospective controlled trials have failed to demonstrate improved tolerance to enteral feeding in hypoalbuminemic patients receiving exogenous albumin. CONCLUSIONS: Evidence to date is insufficient to support the routine administration of exogenous albumin to hypoalbuminemic patients receiving nutrition support. </jats:sec

Nonsteroidal Antiinflammatory Drug-Induced Renal Dysfunction Related to Inhibition of Renal Prostaglandins

This article reviews the role of prostaglandins (PG) in maintaining renal function in the face of vasoconstrictive substances and decreased renal blood flow. Inhibition of the synthesis of renal PG by nonsteroidal antiinflammatory drugs (NSAID) may lead to the development of hemodynamically induced renal dysfunction in patients with a decreased effective plasma volume or chronic renal insufficiency. The importance of stimulation of renal PG activity to the action of diuretics and a pharmacodynamic mechanism for NSAID-induced diuretic resistance are presented. Evidence for the relative selectivity of sulindac in inhibiting systemic PG without inhibiting renal PG is also reviewed. Inhibition of renal PG synthesis has been postulated to be a contributing factor for other forms of NSAID-induced renal dysfunction (interstitial nephritis, analgesic-associated nephropathy). The relationship between renal PG inhibition by NSAID and these syndromes is briefly discussed. Considering the frequent use of NSAID, it is important that practitioners are aware of the mechanisms whereby patients may develop NSAID-induced renal dysfunction and that they are able to identify patients at risk. </jats:p

Time to Steady State following a Change in Dosing Rate

Drugs administered at fixed intervals or by continuous infusion will accumulate in the body until steady state is achieved. The time to a given percentage of the eventual steady-state concentration has previously been considered to be dependent only on the elimination half-life. This is incorrect. Although the rate of drug accumulation in the body is dependent only on the elimination half-life, the time to a given percentage of steady state is dependent on both the elimination half-life of the drug and the initial concentration. This paper presents the mathematical proof of this concept, computer simulations demonstrating the use of these equations, and nomograms for use in clinical practice. The use of this method allows serum drug concentrations to be evaluated earlier than previously predicted after changes in the dosing rate. </jats:p

Effect of the Mode of Lipid Administration on Parenteral Nutrition-Related Infections

OBJECTIVE: To determine if total nutrient admixtures (TNAs) influence the rate of infection in clinical practice. DESIGN: Prospective, randomized trial. SETTING: Department of Veterans Affairs Medical Center. PATIENTS: All patients were administered parenteral nutrition (PN) via a central venous catheter and received daily lipids. INTERVENTION: Patients were randomized as to the mode of administration of lipids. Lipids were either administered with other PN components in a TNA or were piggybacked (PB) into the PN solution. MAIN OUTCOME MEASURES: Treatment groups were compared for the rate of occurrence of PN-related infections. Infections were classified as catheter infections or catheter sepsis. RESULTS: Ninety-eight patients were entered into the trial. Data from % patients (44 TNA, 52 PB) were available for analysis. Treatment groups were well matched for age, baseline albumin, days of PN, predicted basal metabolic rate, and calorie and protein requirements. TNA patients received a significantly greater percentage of nonprotein calories as lipid. The incidence of infection was 12.6 and 10.3 per 1000 days of PN in the TNA and PB groups, respectively (p=0.89). The microorganisms responsible for infection and the type of infections that developed were similar in both groups. CONCLUSIONS: Use of TNAs does not influence the rate of infection in patients receiving PN. </jats:sec