Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

IgG antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anti-cancer therapeutic antibodies for their elevated activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (~6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses, but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high levels of afucosylated IgG antibodies against SARS-CoV-2, amplifying pro-inflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.

IMPORTANCEIntraoperative hypotension is associated with increased morbidity and mortality. A machine learning-derived early warning system to predict hypotension shortly before it occurs has been developed and validated.OBJECTIVE To test whether the clinical application of the early warning system in combination with a hemodynamic diagnostic guidance and treatment protocol reduces intraoperative hypotension.DESIGN, SETTING, AND PARTICIPANTS Preliminary unblinded randomized clinical trial performed in a tertiary center in Amsterdam, the Netherlands, among adult patients scheduled for elective noncardiac surgery under general anesthesia and an indication for continuous invasive blood pressure monitoring, who were enrolled between May 2018 and March 2019. Hypotension was defined as a mean arterial pressure (MAP) below 65 mm Hg for at least 1 minute.INTERVENTIONS Patients were randomly assigned to receive either the early warning system (n = 34) or standard care (n = 34), with a goal MAP of at least 65 mm Hg in both groups. MAIN OUTCOMES AND MEASURESThe primary outcome was time-weighted average of hypotension during surgery, with a unit of measure of millimeters of mercury. This was calculated as the depth of hypotension below a MAP of 65 mm Hg (in millimeters of mercury) × time spent below a MAP of 65 mm Hg (in minutes) divided by total duration of operation (in minutes). RESULTS Among 68 randomized patients, 60 (88%) completed the trial (median age, 64 [interquartile range {IQR}, 57-70] years; 26 [43%] women). The median length of surgery was 256 minutes (IQR,. The median time-weighted average of hypotension was 0.10 mm Hg (IQR, 0.01-0.43 mm Hg) in the intervention group vs 0.44 mm Hg (IQR, 0.23-0.72 mm Hg) in the control group, for a median difference of 0.38 mm Hg (95% CI, 0.14-0.43 mm Hg; P = .001). The median time of hypotension per patient was 8.0 minutes (IQR, 1.33-26.00 minutes) in the intervention group vs 32.7 minutes (IQR, 11.5-59.7 minutes) in the control group, for a median difference of 16.7 minutes (95% CI, 7.7-31.0 minutes; P < .001). In the intervention group, 0 serious adverse events resulting in death occurred vs 2 (7%) in the control group. CONCLUSIONS AND RELEVANCEIn this single-center preliminary study of patients undergoing elective noncardiac surgery, the use of a machine learning-derived early warning system compared with standard care resulted in less intraoperative hypotension. Further research with larger study populations in diverse settings is needed to understand the effect on additional patient outcomes and to fully assess safety and generalizability.

PurposeTo assess the level of agreement between different bedside estimates of effective circulating blood volume—mean systemic filling pressure (Pmsf), arm equilibrium pressure (Parm) and model analog (Pmsa)—in ICU patients.MethodsEleven mechanically ventilated postoperative cardiac surgery patients were studied. Sequential measures were made in the supine position, rotating the bed to a 30° head-up tilt and after fluid loading (500 ml colloid). During each condition four inspiratory hold maneuvers were done to determine Pmsf; arm stop-flow was created by inflating a cuff around the upper arm for 30 s to measure Parm, and Pmsa was estimated from a Guytonian model of the systemic circulation.ResultsMean Pmsf, Parm and Pmsa across all three states were 20.9 ± 5.6, 19.8 ± 5.7 and 14.9 ± 4.0 mmHg, respectively. Bland-Altman analysis for the difference between Parm and Pmsf showed a non-significant bias of −1.0 ± 3.08 mmHg (p = 0.062), a coefficient of variation (COV) of 15 %, and limits of agreement (LOA) of −7.3 and 5.2 mmHg. For the difference between Pmsf and Pmsa we found a bias of −6.0 ± 3.1 mmHg (p < 0.001), COV 17 % and LOA −12.4 and 0.3 mmHg. Changes in Pmsf and Parm and in Pmsf and Pmsa were directionally concordant in response to head-up tilt and volume loading.ConclusionsParm and Pmsf are interchangeable in mechanically ventilated postoperative cardiac surgery patients. Changes in effective circulatory volume are tracked well by changes in Parm and Pmsa.

Pmsf can be determined in intensive care patients with an intact circulation with use of inspiratory pause procedures, making serial measures of circulatory compliance and circulatory stressed volume feasible.

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Netherlands Trial Register: NTR2486.