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.

We report that the afferent relays of visceral (cardiovascular, digestive and respiratory) reflexes, differentiate under the control of the paired-like homeobox gene Phox2b: the neural crest-derived carotid body, a chemosensor organ, degenerates in homozygous mutants, as do the three epibranchial placode-derived visceral sensory ganglia (geniculate, petrosal and nodose), while their central target, the nucleus of the solitary tract,which integrates all visceral information, never forms. These data establish Phox2b as an unusual `circuit-specific' transcription factor devoted to the formation of autonomic reflex pathways. We also show that Phox2b heterozygous mutants have an altered response to hypoxia and hypercapnia at birth and a decreased tyrosine hydroxylase expression in the petrosal chemosensory neurons, thus providing mechanistic insight into congenital central hypoventilation syndrome, which is associated with heterozygous mutations in PHOX2B.

Background The COVID-19 pandemic has led highly developed healthcare systems to the brink of collapse due to the large numbers of patients being admitted into hospitals. One of the potential prognostic indicators in patients with COVID-19 is frailty. The degree of frailty could be used to assist both the triage into intensive care, and decisions regarding treatment limitations. Our study sought to determine the interaction of frailty and age in elderly COVID-19 ICU patients. Methods A prospective multicentre study of COVID-19 patients ≥ 70 years admitted to intensive care in 138 ICUs from 28 countries was conducted. The primary endpoint was 30-day mortality. Frailty was assessed using the clinical frailty scale. Additionally, comorbidities, management strategies and treatment limitations were recorded. Results The study included 1346 patients (28% female) with a median age of 75 years (IQR 72–78, range 70–96), 16.3% were older than 80 years, and 21% of the patients were frail. The overall survival at 30 days was 59% (95% CI 56–62), with 66% (63–69) in fit, 53% (47–61) in vulnerable and 41% (35–47) in frail patients (p < 0.001). In frail patients, there was no difference in 30-day survival between different age categories. Frailty was linked to an increased use of treatment limitations and less use of mechanical ventilation. In a model controlling for age, disease severity, sex, treatment limitations and comorbidities, frailty was independently associated with lower survival. Conclusion Frailty provides relevant prognostic information in elderly COVID-19 patients in addition to age and comorbidities. Trial registration Clinicaltrials.gov: NCT04321265, registered 19 March 2020.