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We propose here the first model explaining how the outcome of first, crucial 10\u201015\u00a0days after infection, depends on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, mannose\u2010binding lectin). If SARS\u2010CoV\u20102 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high\u2010affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm), leading to complications often requiring intensive therapy and being, in some patients, fatal. Low\u2010moderate physical activity can still be recommended. However, extreme physical activity and oral breathing with hyperventilation during the incubation days and early stages of COVID\u201019 facilitates re\u2010inhalation and early direct penetration of high numbers of own virus particles in the lower airways and the alveoli, without impacting on the airway\u2019s mucosae covered by neutralizing antibodies (\"viral auto\u2010inhalation\" phenomenon). This allows the virus to bypass the efficient immune barrier of the upper airway mucosa in already infected, young, and otherwise healthy athletes. In conclusion, whether the virus or the adaptive immune response reaches the lungs first is a crucial factor deciding the fate of the patient. This \u201cquantitative and time\u2010\/sequence\u2010dependent\u201d model has several implications for prevention, diagnosis, and therapy of COVID\u201019 at all ages.<\/jats:p>","DOI":"10.1111\/pai.13271","type":"journal-article","created":{"date-parts":[[2020,5,2]],"date-time":"2020-05-02T16:21:25Z","timestamp":1588436485000},"page":"454-470","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":149,"title":["The first, holistic immunological model of COVID\u201019: Implications for prevention, diagnosis, and public health measures"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5485-0324","authenticated-orcid":false,"given":"Paolo Maria","family":"Matricardi","sequence":"first","affiliation":[{"name":"Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine Charit\u00e9 Universit\u00e4tsmedizin Berlin Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto Walter","family":"Dal Negro","sequence":"additional","affiliation":[{"name":"National Centre of Pharmacoeconomics and Pharmacoepidemiology Verona Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Nisini","sequence":"additional","affiliation":[{"name":"Unit of Immunology Dipartimento di Malattie Infettive Istituto Superiore di Sanit\u00e0 Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,6,5]]},"reference":[{"key":"e_1_2_18_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017"},{"key":"e_1_2_18_3_1","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES.2020.25.3.2000045"},{"key":"e_1_2_18_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa030747"},{"key":"e_1_2_18_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0695-z"},{"key":"e_1_2_18_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30374-3"},{"key":"e_1_2_18_7_1","unstructured":"WHO pandemic statement.http:\/\/www.euro.who.int\/en\/health\u2010topics\/health\u2010emergencies\/coronavirus\u2010covid\u201019\/news\/news\/2020\/3\/who\u2010announces\u2010covid\u201019\u2010outbreak\u2010a\u2010pandemic. 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