key: cord-0775331-dlqgj4oc authors: Ballow, Mark; Haga, Christopher L. title: Why do some people develop serious COVID-19 disease after infection, while others only exhibit mild symptoms? date: 2021-01-21 journal: J Allergy Clin Immunol Pract DOI: 10.1016/j.jaip.2021.01.012 sha: fcd58504eb0b5f1b602a6769af903f7ba722a597 doc_id: 775331 cord_uid: dlqgj4oc nan Disclosure: M. Ballow declares that he has no known competing financial interests or personal 27 relationships that could have appeared to influence the work reported in this paper. C. L. Haga 28 has received funding from the Schacknow Family Foundation, Inc; and has previously served as 29 a consultant for the purification of adenovirus-based therapeutics including vaccines for various 30 companies. 31 32 Word count -3522 33 found elsewhere. 6 While clinical disease is usually mild or even asymptomatic in children, a 48 small percentage have serious inflammatory multiorgan disease process, multisystem 49 inflammatory syndrome in children (MIS-C). 7, 8 Most adults also present with asymptomatic or 50 mild to moderate symptoms (reviewed in 9 ) Recent data suggests that approximately 20% have a 51 more progressive disease course with the development of pneumonia and respiratory failure 52 progressing over days to weeks leading to intensive care admission. Approximately 10% of these 53 individuals progress into a hyperinflammatory state, e.g. acute respiratory distress syndrome 54 (ARDS) with respiratory failure and death. 10 In a CDC summary of the New York COVID-19 55 outbreak the fatality rate among confirmed cases was 9.2%, and 32.1% among hospitalized 56 patients. Hospitalization and mortality were elevated among black and Hispanic persons and 57 among residents of high-poverty neighborhoods. 11 In this review we will explore the possible 58 explanations why some individuals have life threatening COVID-19 disease while others have no 59 or mild symptoms. 60 61 Risks factors predisposing to more severe COVID-19 infection -62 a primary immune deficiency known to have autoantibodies to Type I IFNs and other 127 autoantibodies. 28 Males accounted for 94% of the patients who had these autoantibodies and they 128 tended to be older (49.5% were over age 65). IFN dysregulation represents a key part of SARS-129 CoV-2 susceptibility and may lead to new therapeutic modalities. 29 130 131 A international collaborative group of clinical immunologist reported on COVID-19 disease in 132 94 patients with inborn errors of immunity. 30 Fifty-three patients (56%) had primary antibody 133 deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 134 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate 135 immune defect, and 2 (2%) bone marrow failure. Ten had asymptomatic COVID-19 disease, 25 136 were treated as outpatients, 28 required admission, 13 required oxygen administration without 137 invasive ventilation, while 23 patients required more intensive support in the ICU and 9 died. 138 This latter group had predisposing risk factors similar to the general population for greater 139 severity and mortality for COVID-19 disease. Patients with humoral immune deficiency, e.g. x-140 linked agammaglobulinemia, hypogammaglobulinemia, and common variable immune 141 deficiency (CVID) appeared to do better with asymptomatic or mild disease, perhaps by reducing 142 the immune mediated inflammatory response seen in severe COVID-19 disease. 30 At first glance, the humoral immune response against SARS-CoV-2 appears to be strong in 274 patients suffering from severe COVD-19. The antibody response to SAR-CoV-2 is directed 275 against the viral envelope Spike (S) protein, comprised of the S1 subunit that conceals the ACE2 276 receptor-binding domain (RBD) and the S2 subunit, and the Nucleocapsid protein (N). Serum 277 IgG antibody titers directed against S and N correspond with disease severity with elevated titers 278 seen in severe cases throughout disease pathogenesis in contrast to the lower levels found in mild 279 and asymptomatic cases. 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T cells recruited into the lungs appear to be of the 551 CD4+ T h1 phenotype that promote an inflammatory macrophage phenotype via IFN-γ signaling. 552In severe cases of COVID-19, humoral responses are derived from extra-follicular B cells that 553 produce ineffective antibody responses coupled with the production of autoantibodies. This 554 dysregulation and imbalance of the immune response leads to a hyperinflammatory state 555 resulting in a "cytokine storm," ARDS, and, in many cases, death. (Figure created with 556 Biorender.) 557