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.

Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Large differences in COVID‐19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage were associated with low death rates in European countries. SARS‐CoV‐2 binds to its receptor, the angiotensin converting enzyme 2 (ACE2). As a result of SARS‐Cov‐2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT 1 R) axis associated with oxidative stress. This leads to insulin resistanceas well as lung and endothelial damage, two severe outcomes of COVID‐19. The nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is the most potent antioxidant in humans and can block the AT 1 R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are given: Kimchi in Korea, westernized foods and the slum paradox. It is proposed that fermented cabbage is a proof‐of‐concept of dietary manipulations that may enhance Nrf2‐associated antioxidant effects helpful in mitigating COVID‐19 severity.

Rapid MPT64-based immunochromatographic tests (MPT64 ICTs) have been developed to detect Mycobacterium tuberculosis complex (MTBC) in culture. We demonstrated the noninferiority of one commercial MTP64 ICT, the MGIT TBc identification (TBcID) test, to GenoType line probe assays for MTBC identification in positive MGIT cultures. Meta-analysis of MPT64 ICT performance for identification of MTBC in liquid culture confirmed similar very high sensitivities and specificities for all three commercial MPT64 assays for which sufficient data were available.Early tuberculosis case detection underpinned by qualityassured bacteriology is a cornerstone of the WHO Stop TB strategy (32). WHO has endorsed wider implementation of liquid mycobacterial culture in high-burden countries to improve diagnostic sensitivity and culture turnaround times (29-31). However, rapid and accurate identification of Mycobacterium tuberculosis in positive cultures is essential for translating these benefits into earlier diagnosis and treatment for patients-particularly as liquid culture is associated with isolation of more nontuberculous mycobacteria (NTM) (2, 31). Conventional biochemical identification methods are slow, requiring subculture onto solid media, and cost and limited laboratory capacity preclude nucleic acid amplification tests (NAAT) in low-resource settings. Rapid immunochromatographic tests (ICT) that detect the M. tuberculosis complex (MTBC) MPT64 protein are cheaper and simpler to use and thus may have an important role in these and other settings. We compared one MPT64 ICT, the MGIT TBc identification test (TBc ID; Becton Dickinson, Sparks, MD), with the GenoType MTBC and Mycobacterium CM/AS line probe assays (LPA; Hain Lifescience Gmbh, Nehren, Germany) and present a meta-analysis of MPT64 assay performance for MTBC identification in liquid culture.Between August 2009 and June 2011, clinical samples from two Kenyan hospitals were processed using the MGIT 960 system (BD Diagnostics, Sparks, MD) and standard protocols (3, 27). Ziehl-Neelsen (ZN)-stained smears from positive cultures were examined for acid-fast bacilli (AFB), and an aliquot was inoculated onto blood agar to detect contamination (defined as growth after 48 h of incubation at 37°C). Further aliquots from AFB-positive cultures were used to perform TBcID and LPA according to manufacturers' instructions. When results were discordant, we repeated both tests, performed the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA) using the original specimen and culture broth, and reviewed the clinical notes. Assuming an LPA sensitivity of 99% (8) and a smallest acceptable true difference (delta) of 5%, a sample size of 83 MTBC isolates was required to demonstrate the noninferiority of TBcID to the LPA with 90% power.TBcID and LPA results were concordant for 208 (83 MTBC and 125 non-MTBC isolates; 99%) of 210 AFB-positive cultures (kappa ϭ 0.98; 95% confidence interval [CI], 0.84 to 1.0),