Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 〈 70 y and in 〉 4% of those 〉 70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals 〈 70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals 〈 40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

Abstract: 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: We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7–9,196.6] ) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2–5.3] ). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6–35.9] ) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1–9.6] ) of IFN-ω and/or IFN-α2.

Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a severe, unexplained complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with an estimated prevalence of ~1 per 10,000 infected children. It typically occurs 4 weeks after infection, without hypoxemic pneumonia. Affected children present with fever, rash, abdominal pain, myocarditis, and other clinical features reminiscent of Kawasaki disease, including lymphadenopathy, coronary aneurysm, and high levels of biological markers of acute inflammation. Sustained monocyte activation is consistently reported as a key immunological feature of MIS-C. A more specific immunological abnormality is the polyclonal expansion of CD4 + and CD8 + T cells bearing the T cell receptor Vβ21.3. The root cause of MIS-C and its immunological and clinical features remains unknown. RATIONALE We hypothesized that monogenic inborn errors of immunity to SARS-CoV-2 may underlie MIS-C in some children. We further hypothesized that the identification of these inborn errors would provide insights into the molecular and cellular mechanisms underlying its immunological and clinical phenotypes. Finally, we hypothesized that a genetic and mechanistic understanding of a few patients would provide a proof of principle that would facilitate studies in other patients. We performed whole-exome or whole-genome sequencing on 558 internationally recruited patients with MIS-C (aged 3 months to 19 years). We searched for rare nonsynonymous biallelic variants of protein-coding genes, testing a hypothesis of genetic homogeneity. RESULTS We found autosomal recessive deficiencies of OAS1 (2′-5′-oligoadenylate synthetase 1), OAS2, or RNase L (ribonuclease L) in five unrelated children of four different ancestries with MIS-C (~1% of our cohort). There were no similar defects in a cohort of 1288 individuals (aged 6 months to 99 years) with asymptomatic or mild infection ( P = 0.001) or 334 young patients (aged 0 to 21 years) with asymptomatic or mild infection or COVID-19 pneumonia ( P = 0.046). The estimated cumulative frequency of these defects in the general population was ~0.00013. The type I interferon (IFN)–inducible double-stranded RNA (dsRNA)–sensing proteins OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A), which activate the antiviral single-stranded RNA (ssRNA)–degrading RNase L, particularly in mononuclear phagocytes. Consistent with the absence of pneumonia in these patients, epithelial cells and fibroblasts defective for this pathway restricted SARS-CoV-2 normally. This contrasted with interferon alpha and beta receptor subunit 1 (IFNAR1)–deficient cells from patients prone to hypoxemic pneumonia without MIS-C. Monocytic cell lines with genetic deficiencies of OAS1, OAS2, or RNase L displayed excessive inflammatory cytokine production in response to intracellular dsRNA. Cytokine production by RNase L–deficient cells was impaired by melanoma differentiation-associated protein 5 (MDA5) or retinoic acid–inducible gene I (RIG-I) deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Exogenous 2-5A suppressed inflammatory responses to these stimuli in control and OAS1-deficient cells but not in RNase L–deficient cells. Finally, monocytic cell lines, primary monocytes, and monocyte-derived dendritic cells with genetic deficiencies of OAS1, OAS2, or RNase L displayed exaggerated inflammatory responses to SARS-CoV-2 as well as SARS-CoV-2–infected cells and their RNA. CONCLUSION We report autosomal recessive deficiencies of OAS1, OAS2, or RNase L in ∼1% of an international cohort of MIS-C patients. The cytosolic OAS–RNase L pathway suppresses RIG-I/MDA5–MAVS–mediated inflammation in dsRNA-stimulated mononuclear phagocytes. Single-gene recessive inborn errors of the OAS–RNase L pathway unleash the production of SARS-CoV-2–triggered inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C. OAS–RNase L deficiency in MIS-C. dsRNAs from SARS-CoV-2 or SARS-CoV-2–permissive cells engulfed by mononuclear phagocytes simultaneously activate the RIG-I/MDA5–MAVS pathway, inducing inflammatory cytokine production, and the OAS–RNase L pathway, exerting posttranscriptional control over inflammatory cytokine production. OAS–RNase L deficiency results in excessive inflammatory cytokine production by myeloid cells, triggering MIS-C, including lymphoid cell activation and multiple tissue lesions. NK, natural killer; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor κB.

Abstract: Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children ( & lt;16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5–13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10−11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.

Abstract: Tofacitinib is an oral JAK inhibitor that is being investigated for JIA. Objectives: To assess tofacitinib efficacy and safety in JIA patients (pts). Methods: This was a Phase 3, randomised, double-blind (DB), placebo (PBO)-controlled withdrawal study in pts aged 2− 〈 18 years with polyarticular course JIA (pcJIA), PsA or ERA ( NCT02592434 ). In the 18-week open-label Part 1, pts received weight-based tofacitinib doses (5 mg BID or lower). Pts with ≥JIA ACR30 response at Week (W)18 were randomised 1:1 in the DB Part 2 (W18−44) to continue tofacitinib or switch to PBO. Primary endpoint: disease flare rate by W44. Key secondary endpoints: JIA ACR50/30/70 response rates; change from Part 2 baseline (Δ) in CHAQ-DI at W44. Other efficacy endpoints: time to disease flare in Part 2; JADAS27-CRP in Parts 1 and 2. PsA/ERA pts were excluded from these efficacy analyses. Safety was evaluated in all pts up to W44. Results: 225 enrolled pts with pcJIA (n=184), PsA (n=20) or ERA (n=21) received tofacitinib in Part 1. At W18, 173/225 (76.9%) pts entered Part 2 (pcJIA n=142, PsA n=15, ERA n=16). In pcJIA pts, disease flare rate in Part 2 was significantly lower with tofacitinib vs PBO by W44 (p=0.0031; Fig 1a). JIA ACR50/30/70 response rates (Fig 1b) and ΔCHAQ-DI (Fig 1c) at W44, and time to disease flare in Part 2 (Fig 2a), were improved with tofacitinib vs PBO. Tofacitinib reduced JADAS27-CRP in Part 1; this effect was sustained in Part 2 (Fig 2b). Overall, safety was similar with tofacitinib or PBO (Table): 77.3% and 74.1% had adverse events (AEs); 1.1% and 2.4% had serious AEs. In Part 1, 2 pts had herpes zoster (non-serious) and 3 pts had serious infections (SIs). In Part 2, SIs occurred in 1 tofacitinib pt and 1 PBO pt. No pts died. Conclusion: In pcJIA pts, tofacitinib vs PBO resulted in significantly fewer disease flares, and improved time to flare, disease activity and physical functioning. Tofacitinib safety was consistent with that in RA pts. Table. Safety in all pts Part 1 Part 2 Tofacitinib a N=225 Tofacitinib a N=88 PBO N=85 Pts with events, n (%) AEs 153 (68.0) 68 (77.3) 63 (74.1) SAEs 7 (3.1) 1 (1.1) 2 (2.4) Permanent discontinuations due to AEs 26 (11.6) 16 (18.2) 29 (34.1) AEs of special interest  Death 0 0 0  Gastrointestinal perforation b 0 0 0  Hepatic event b 3 (1.3) 0 0  Herpes zoster (non-serious and serious) 2 (0.9) c 0 0  Interstitial lung disease b 0 0 0  Major adverse cardiovascular events b 0 0 0  Malignancy (including non-melanoma skin cancer) b 0 0 0  Macrophage activation syndrome b 0 0 0  Opportunistic infection b 0 0 0  SI 3 (1.3) 1 (1.1) d 1 (1.2)  Thrombotic event (deep vein thrombosis, pulmonary embolism b or arterial thromboembolism) 0 0 0  Tuberculosis b 0 0 0 a 5 mg BID or equivalent weight-based lower dose in pts 〈 40 kg b Adjudicated events c Both non-serious d One SAE of pilonidal cyst repair was coded to surgical procedures instead of infections, and was inadvertently not identified as an SI. Following adjudication, the SAE did not meet opportunistic infection criteria; it is also included in the table as an SI AE, adverse event; BID, twice daily; PBO, placebo; pts, patients; SAE, serious AE; SI, serious infection Acknowledgments: Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc. Disclosure of Interests: Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Olga Synoverska Speakers bureau: Sanofi, Tracy Ting: None declared, Carlos Abud-Mendoza Speakers bureau: Eli Lilly, Pfizer Inc, Alberto Spindler Speakers bureau: Eli Lilly, Yulia Vyzhga Grant/research support from: Pfizer Inc, Katherine Marzan Grant/research support from: Novartis, Vladimir Keltsev: None declared, Irit Tirosh: None declared, Lisa Imundo: None declared, Rita Jerath: None declared, Daniel Kingsbury: None declared, Betül Sözeri: None declared, Sheetal Vora: None declared, Sampath Prahalad Grant/research support from: Novartis, Elena Zholobova Grant/research support from: Novartis and Pfizer Inc, Speakers bureau: AbbVie, Novartis, Pfizer Inc and Roche, Yonatan Butbul Aviel: None declared, Vyacheslav Chasnyk: None declared, Melissa Lerman Grant/research support from: Amgen, Kabita Nanda Grant/research support from: Abbott, AbbVie, Amgen and Roche, Heinrike Schmeling Grant/research support from: Janssen, Pfizer Inc, Roche and USB Bioscience, Heather Tory: None declared, Yosef Uziel Speakers bureau: Pfizer Inc, Diego O Viola Grant/research support from: Bristol-Myers Squibb, GSK, Janssen and Pfizer Inc, Speakers bureau: AbbVie and Bristol-Myers Squibb, Holly Posner Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Keith Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ann Wouters Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cheng Chang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Richard Zhang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Irina Lazariciu Consultant of: Pfizer Inc, Employee of: IQVIA, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ricardo Suehiro Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Alberto Martini Consultant of: AbbVie, Eli Lily, EMD Serono, Janssen, Novartis, Pfizer, UCB, Daniel J Lovell Consultant of: Abbott (consulting and PI), AbbVie (PI), Amgen (consultant and DSMC Chairperson), AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb (PI), Celgene, Forest Research (DSMB Chairman), GlaxoSmithKline, Hoffman-La Roche, Janssen (co-PI), Novartis (consultant and PI), Pfizer (consultant and PI), Roche (PI), Takeda, UBC (consultant and PI), Wyeth, Employee of: Cincinnati Children’s Hospital Medical Center, Speakers bureau: Wyeth, Hermine Brunner Consultant of: Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Merck Serono, AbbVie, Amgen, Alter, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, EMD Serono, Janssen, MedImmune, Novartis, Pfizer, and UCB Biosciences, Speakers bureau: GSK, Roche, and Novartis