key: cord-0860883-r39ser2c authors: Matricardi, Paolo Maria; Dal Negro, Roberto Walter; Nisini, Roberto title: The first, holistic immunological model of COVID‐19: implications for prevention, diagnosis, and public health measures date: 2020-05-02 journal: Pediatr Allergy Immunol DOI: 10.1111/pai.13271 sha: 782edc699ba9abc492206e67ad9b3bc015a05fd6 doc_id: 860883 cord_uid: r39ser2c The natural history of COVID‐19 caused by SARS‐CoV‐2 is extremely variable, ranging from asymptomatic or mild infection, mainly in children, to multi‐organ failure, eventually fatal, mainly in the eldest. We propose here the first model, explaining how the outcome of first, crucial 10‐15 days after infection, hangs 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 Binding Lectin ). If SARS‐CoV‐2 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 affinity 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‐moderate physical activity can still be recommended. However, extreme physical activity and hyperventilation during the incubation days and early stages of COVID‐19, facilitates early direct penetration of high numbers of virus particles in the lower airways and the alveoli, without impacting on the airway’s mucosae covered by neutralizing antibodies. This allows the virus bypassing the efficient immune barrier of the upper airways mucosa in already infected, young and otherwise healthy athletes. In conclusion, whether the virus or the adaptative immune response reach the lungs first, is a crucial factor deciding the fate of the patient. This “quantitative and time‐sequence dependent” model has several implications for prevention, diagnosis, and therapy of COVID‐19 at all ages. Most serological data currently available in the literature refer to patients examined mostly in the acute phase of the disease. Therefore, they are insufficient to exactly establish durability of the antibody titers of each isotype peak when they eventually disappear. The levels of serum IgG antibodies, however seems to be proportional to the intensity of the viral load and to the symptom severity. [32, 36] The efficacy of specific Ig and their role in limiting viral spread may be indirectly assumed by observations demonstrating that plasma from subjects recovered from COVID-19 showed a therapeutic efficacy if passively transferred to patients.[37,38] Similar effectiveness had been This article is protected by copyright. All rights reserved already demonstrated for plasma from patients having recovered from SARS-CoV and MERS-CoV. [39, 40] Consequently, infusion of plasma from convalescent individuals to critically ill COVID-19 patients is a therapeutic option that is being investigated. Although controlled clinical trials are not yet available, several papers report the efficacy of this treatment and the lack of serious adverse events. [41, 42] Convalescent plasma was administered in patients with a severe disease, and it is unclear whether earlier administration might have been associated with different clinical outcomes [43] and with the prevention of respiratory distress. Only a small proportion of humans younger than 50, among those who get infected by SARS-CoV-2, suffer from moderate and severe COVID-19. [44-46] Among them, hospital doctors frequently exposed to COVID-19 patients are, unfortunately, highly represented. [47] Dr. Li Wenliang, the first man alerting China and the World of the new infection, died from COVID-19 at the age of 33. [48] Similarly, Dr. Carlo Urbani, i.e. the first man alerting the of SARS-CoV, died of SARS at the age of 46. [49] Both doctors cared for weeks patients with severe pneumonia with no personal protection. [48, 49] In Italy, 114 doctors exposed to SARS-CoV-2, have so far (14th April, 2020) died of COVID. [50] The case fatality ratio among doctors working in hospitals and caring patients developing severe COVID-19 has been therefore much higher than among their age and gender matched peers. [50, 51] (Table-1 Observations in previous viral epidemics, further clarify this aspect. The reliability of high viral loads in nasopharyngeal specimens as a prognostic indicator of respiratory failure or mortality, with or without a high viral load in serum, has been previously characterized in SARS. [52] A link has been established between the initial dose and subsequent severity of the disease to the 1918-19 Spanish Flu pandemic. It was demonstrated by simulation models that the number of This article is protected by copyright. All rights reserved simultaneous contacts a susceptible person has with infectious ones are correlated with the infectious dose; that severe cases of influenza result from higher infectious doses of the virus; and that a susceptible person can be easily exposed to very high infectious doses of influenza in over-crowded places. [53] The viral replication is more active and prolonged in patients suffering from severe influenza. Viral clearance is slow when host defenses are weakened, however it is enhanced when antivirals start within the first 4 days of illness. [54] Among over 70 thousand Chinese with COVID-19, most were aged over 30 years (90%), while only 1% were aged 9 years or younger, 1% were aged 10 to 19 years an 8% aged 20 to 29 years. [55] Moreover, most of the relatively few pediatric cases were classified as mild (81%), only 14% severe and 5% critical. [ This article is protected by copyright. All rights reserved COVID-19 mortality has been lower among Chinese females than males. [59] In Italy, mortality and hospitalization rates have been also more frequent among males than among females. [60] Moreover, patients with blood group 0 and A have slightly lower and a slightly higher risk, The first diagnosis of COVID-19 in Europe has been confirmed in a 38 year-old Italian healthy male who regularly participated in running events and soccer games. One day before starting COVID-19 symptoms, he had been training sport. The time-lapse between the onset of upper airways symptoms and pneumonia was 2 days only. Only 4 days after the onset of COVID-19, the patient was admitted to the intensive care unit of the Policlinico San Matteo in Pavia because of respiratory failure. After weeks of intubation and supportive treatment, the patient luckily recovered and could be discharged in good conditions. The Italian first COVID-19 case is worldwide famous but, surprisingly, no official study on it has been so far published. The example of this physically active, young patient offers room for reasoning with regard to the importance of sport for virus transmission and course of disease. Indeed, other cases of COVID-19 in (semi-) professional athletes have been described. The pattern of breathing during strenuous exercise changes dramatically by a tremendous increase of ventilation (i.e.: inspiratory and expiratory volumes of air), and of alveolar ventilation in particular. Obviously, these changes mostly attain to whatever kind of runners belonging to all sport disciplines, being semi-professional and professional athletes particularly exposed (such as much more than individuals of common population) due to their frequent practice of extreme and long-lasting exercise. Furthermore, the majority of these athletes have their lungs that usually work in perfect physiological conditions, such as very close to those of the "ideal lung". In other words, in the absence of any anatomical or physiological factor causing a significant unevenness in distribution of their alveolar ventilation. Paradoxically, these pre-existing ideal This article is protected by copyright. All rights reserved conditions significantly favor the deep inhalation of several irritants, allergens, infectious agents. Even the SARS-CoV-2 can then spread more easily to the deepest areas of the lungs (alveolar bronchioles and alveoli) during strenuous exercise, and there starts its aggressive action. Not by chance, a great proportion of professional football players claimed the occurrence of fever, dry cough and malaise (and dyspnea in some cases) immediately after, or a few hours following their last official match. In COVID-19, the occurrence of pneumonia requiring oxygen therapy is a critical event discriminating asymptomatic or mild cases, whose infection remains mostly confined to the upper airways, from those with severe disease, who experience massive viral invasion of their lower airways. [19] What makes the difference? What prevents the virus from rapidly reaching the lungs and then causing severe pneumonia? What makes COVID-19 pneumonia a life-threatening disease? 2) Pneumonia may start before adaptive immune response develops; [20] 3) Serious complications begin together with the adaptive immune response. The first two weeks after infection are crucial. [18,20] Innate immunity is the only first-line, early defense against the new SARS-CoV-2 virus. Consequently, the early confrontation between host's innate immunity and SARS-CoV-2, at exposure and during the following two weeks, decides the natural history of the disease. This confrontation also decides whether the infection will be efficiently blocked in upper airways, or how many virus particles reach the lungs, and when. To understand which part of the innate immunity involved in early protection from SARS-CoV-2, we have: 1) Examined which Primary Immune Deficiencies are associated with pneumonia. 2) Examined the patterns of risk factors for COVID-19 severity: dose of exposure to SARS-CoV-2; age, gender, ABO group; 3) Identified the innate immunity components fitting the same patterns of risk factors; This article is protected by copyright. All rights reserved 4) Examined the biological plausibility that the candidate molecules, emerging from the previous reasoning, are really essential in limiting the consequences of SARS-CoV-2 infection to upper airways or to mitigate the course of pneumonia. These data suggest that the lack of natural IgM and IgA in the upper respiratory airways may have contributed to the rapid viral spread to lungs, causing pneumonia. Unexpectedly in immunodeficient individuals, agammaglobulinemic patients, who are unable to develop specific SARS-CoV-2 Igs, did not develop severe pneumonia, suggesting that the serious complications observed in other patients may be related to the development of acquired immunity. Under the circumstances described above, innate immunity become an obvious candidate to act as very first barrier protecting of children, almost all adults and most elders from SARS-CoV-2. Innate immunity is essential to control virus replication early enough, before a very effective adaptive immune response is generated. [77] Accepted Article This article is protected by copyright. All rights reserved We focused on humoral components and, in particular on natural antibodies and MBL, to ascertain whether these players of the innate immunity fit all the epidemiological and clinical pre-conditions presented in the last three months by SARS-CoV-2. Finally, we tentatively describe mechanisms beyond the most severe cases of pneumonia as a possible consequence of the development of adaptive immunity in individuals with an early high viral spread in lungs. Anti-glycan natural antibodies are detected in serum in the absence of previous immunization, are observed also in gnotobiotic animals, and belong mostly to the IgM isotype [79] but also to the IgA and IgG isotype. (B) old patients -viral exposure is probably higher (the source of contagion is also an old person) but the innate immunity is much weaker; a high number of viral particles can reach the alveoli and replicate in type II pneumocytes in coincidence or even much before the This article is protected by copyright. All rights reserved expansion of the specific immune response leading to a more severe and symptomatic pneumonia; (C) young but highly exposed patients -the exposure to an excessive cumulative viral dose (i.e. unprotected health care personnel) will overcome their efficient innate immunity. Viral particles will reach the alveoli in early stages and cause symptomatic pneumonia; This article is protected by copyright. All rights reserved macrophages via Fc-receptors. In addition, Ig binding to the S protein of SARS-CoV-2 may cause its conformational changes that make the binding to the ACE-2 receptor more effective for the viral fusion with the cell membrane. The local high concentration of cytokines and chemokines that contribute to recruitment of inflammatory cells and vasodilatation, permits to serum natural Igs and MBL to maintain a vicious circle of inflammation with complement activation and immunocomplexes deposition. In this light, it cannot be excluded that MBL or IgM mediated immunocomplexes contribute to activation of platelets or tissue factor leading to coagulation and microthrombosis that have been described in COVID-19 patients with acute respiratory failure. In this phase of the disease, natural IgM and MBL that circulate in serum may have no protective role, but, rather may contribute to tissue damage. Moreover, during this second phase of the disease, the adaptive response is also progressively on the increase. This may be one side protective against further virus spread in the lungs,but may also reinforce the immunological and coagulation cascades provoking complications. MBL binds to polymeric IgA and initiates complement cascade, a defense against invading pathogens in mucosal immunity. Polymeric IgA also has a role in activating lectin-mediated complement signaling. The complement cascade links the innate and the adaptive immune system, protecting against invading pathogens during the first phase of the diseases. In this sense, Ab-mediated complement activation flows in parallel between MBL and C1q. Additionally, it can boost proinflammatory effects of IgA deposition with the same mechanism that is supposed to occur in the glomerulus, and results in renal injury. This article is protected by copyright. All rights reserved Evidence-based medicine should also apply for Covid-19 patients, so that "new" or off-label drugs or treatment regimens should only be given in a clinical study context, following approval by relevant national or international agencies. However, we believe that these points are first priorities for intensively and focused clinically oriented research. microarras and other tests aimed at measuring natural antibodies, that might be protective against SARS-CoV-2 and other viruses, should be developed. Individuals with low natural antibody and MBL levels should be identified and specifically protected. Moreover, governments promoting herd immunity must protect individuals, even if young, who may have low levels of natural antibodies. These individuals should be not exposed to the virus, especially if shed at high doses. including strenuous sport activities requiring high respiratory volumes and flows, should be avoided during the early stage of infection. when the adaptive immune response is This article is protected by copyright. All rights reserved still not initiated. Particular precautions should be given to athletes performing fatiguing sports, since a portion of sub-micrometer-size, aerosolized particles, are expired by the runner or eliminated by cough or nasal secretions and may contain viruses if the athlete is an asymptomatic but SARS-CoV2 infected individual. These droplets or aerosol might be re-inhaled and facilitate the spread of the virus from the upper to the lower airways. This article is protected by copyright. All rights reserved moieties flanking SARS-CoV-2 S1-RBS may be useful, among elders, to identify those at higher risk of severe disease. Glycan microarrays will be instrumental for this target. paucisymptomatic individuals could be pursued by measuring SARS-CoV-2 specific serum IgG and IgA that are expected to persist as a memory response to infection. Appropriate and high performing validated tests should be used to retrospectively evaluate the seroconversion status to estimate the herd immunity of a given population. Immunization strategy: innate and adaptive immunity 10.5.1 While effective vaccines are being developed, produced, tested, and validated, a strategy to stimulate innate immunity and natural IgM antibody production in particular, would empower the defences of at-risk elderly population. 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