SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15-20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation. 

/pdf/human-genetic-and-immunological-determinants-of-critical-1zf8ryuv.pdf

Human genetic and immunological determinants of critical COVID-19 pneumonia

Purpose of review The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused extreme concern for patients with inborn errors of immunity (IEIs). In the first 6 months of the pandemic, the case fatality rate among patients with IEIs resembled that of the general population (9%). This review aims at summarizing what we have learned about the course and outcome of coronavirus disease 2019 (COVID-19) in patients with different IEIs and what this can potentially teach us about the immune mechanisms that could confer protection or predisposition to severe disease. Recent findings A total of 649 patients with IEI and COVID-19 have been reported in the last year and a half, spanning all groups of the International Union of Immunological Societies classification of IEIs. For most patients, the underlying IEI does not represent an independent risk factor for severe COVID-19. In fact, some IEI may even be protective against the severe disease due to impaired inflammation resulting in less immune-mediated collateral tissue damage. Summary We review the characteristics of SARS-CoV-2 infection in a large number of patients with IEI. Overall, we found that combined immunodeficiencies, immune dysregulation disorders, and innate immune defects impairing type I interferon responses are associated with severe disease course.

Coronavirus disease 2019 in patients with inborn errors of immunity: lessons learned.

Since the arrival of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, its characterization as a novel human pathogen, and the resulting coronavirus disease 2019 (COVID-19) pandemic, over 6.5 million people have died worldwide-a stark and sobering reminder of the fundamental and nonredundant roles of the innate and adaptive immune systems in host defense against emerging pathogens. Inborn errors of immunity (IEI) are caused by germline variants, typically in single genes. IEI are characterized by defects in development and/or function of cells involved in immunity and host defense, rendering individuals highly susceptible to severe, recurrent, and sometimes fatal infections, as well as immune dysregulatory conditions such as autoinflammation, autoimmunity, and allergy. The study of IEI has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. Indeed, this has been exemplified by assessing the impact of SARS-CoV-2 infection in individuals with previously diagnosed IEI, as well as analyzing rare cases of severe COVID-19 in otherwise healthy individuals. This approach has defined fundamental aspects of mechanisms of disease pathogenesis, immunopathology in the context of infection with a novel pathogen, and therapeutic options to mitigate severe disease. This review summarizes these findings and illustrates how the study of these rare experiments of nature can inform key features of human immunology, which can then be leveraged to improve therapies for treating emerging and established infectious diseases. 

http://www.jacionline.org/article/S0091674922015688/pdf

Impact of SARS-CoV-2 infection and COVID-19 on patients with inborn errors of immunity

Inborn errors of immunity (IEI) are a heterogeneous group of disorders affecting immune host defense and immunoregulation. Considering the predisposition to develop severe and chronic infections, it is crucial to understand the clinical evolution of COVID-19 in IEI patients. This review analyzes clinical outcomes following SARS-CoV-2 infection, as well as response to COVID-19 vaccines in patients with IEI.

COVID-19 and Inborn Errors of Immunity

ObjectiveTo update clinicians on current evidence regarding the immunogenicity and safety of coronavirus disease 2019 (COVID-19) vaccines in patients with inborn errors of immunity (IEI).Data SourcesPeer-reviewed, published studies in PubMed, clinical trials listed on ClinicalTrials.gov, and professional organization and governmental guidelines.Study SelectionsLiterature searches on PubMed and ClinicalTrials.gov were performed using a combination of the following keywords: primary immunodeficiency, COVID-19, SARS-CoV-2, and vaccination.ResultsA total of 26 studies met the criteria and were included in this review. Overall, antibody responses to COVID-19 vaccination were found in 72% of study subjects, with stronger responses observed after messenger RNA vaccination. Neutralizing antibodies were detected in patients with IEI, though consistently at lower levels than healthy controls. Risk factors for poor antibody responses included diagnosis of common variable immunodeficiency, presence of autoimmune comorbidities, and use of rituximab. T cell responses were detectable in most patients with IEI, with poorer responses often found in patients with common variable immunodeficiency. Safety of COVID-19 vaccines in patients with IEI was acceptable with high rates of reactogenicity but very few serious adverse events, including in patients with immune dysregulation.ConclusionCOVID-19 vaccines are safe in patients with IEI and seem to be immunogenic in most individuals, with stronger responses found after messenger RNA vaccinations. 

http://www.annallergy.org/article/S1081120622005294/pdf

Immunizing the imperfect immune system

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged recently and has created a global pandemic. Symptomatic SARS-CoV-2 infection, termed coronavirus disease 2019 (COVID-19), has been associated with a host of symptoms affecting numerous organ systems, including the lungs, cardiovascular system, kidney, central nervous system, gastrointestinal tract, and skin, among others. Objective Although several risk factors have been identified as related to complications from and severity of COVID-19, much about the virus remains unknown. The host immune response appears to affect the outcome of disease. It is not surprising that patients with intrinsic or secondary immune compromise might be particularly susceptible to complications from SARS-CoV-2 infection. Pathogenic loss-of-function or gain-of-function heterozygous variants in nuclear factor-κB2 have been reported to be associated with either a combined immunodeficiency or common variable immunodeficiency phenotype. Methods We evaluated the functional consequence and immunologic phenotype of a novel NFKB2 loss of function variant in a 17-year-old male patient and describe the clinical management of SARS-CoV-2 infection in this context. Results This patient required a 2-week hospitalization for SARS-CoV-2 infection, including 7 days of mechanical ventilation. We used biologic therapies to avert potentially fatal acute respiratory distress syndrome and treat hyperinflammatory responses. The patient had an immunologic phenotype of B-cell dysregulation with decreased switched memory B cells. Despite the underlying immune dysfunction, he recovered from the infection with intense management. Conclusions This clinical case exemplifies some of the practical challenges in management of patients with SARS-CoV-2 infection, especially in the context of underlying immune dysregulation.

Severe SARS-CoV-2 disease in the context of a NF-κB2 loss-of-function pathogenic variant.

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Severe SARS-CoV-2 disease in the context of a NF-κB2 loss-of-function pathogenic variant.