Working Paper Hypothesis Version 1 This version is not peer-reviewed

The First, Comprehensive Immunological Model of COVID-19: Implications for Prevention, Diagnosis, and Public Health Measures

Version 1 : Received: 22 April 2020 / Approved: 24 April 2020 / Online: 24 April 2020 (10:25:27 CEST)

A peer-reviewed article of this Preprint also exists.


The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic infection, to pneumonia, and to complications eventually fatal. 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, MBL). 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. Strenuous exercise and high flow air in the incubation days and early stages of COVID-19, facilitates direct penetration of the virus to the lower airways and the alveoli, without impacting on the airway’s mucosae covered by neutralizing antibodies. This allows the virus to bypass the efficient immune barrier of the upper airways mucosa in young and 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.


antibodies; COVID-19; glycans; immunoglobulin M; SARS-CoV-2; pneumonia; prediction; protection


Medicine and Pharmacology, Immunology and Allergy

Comments (4)

Comment 1
Received: 25 April 2020
Commenter: Colli Vignarelli Cesare
The commenter has declared there is no conflict of interests.
Comment: A pagina 9 si afferma che “5.1 The facts: In COVID-19, the occurrence of pneumonia is a critical event discriminating asymptomatic or mild cases, whose infection remains confined to the upper airways, from those with moderate or severe disease, who experience viral invasion of their lower airways.”

Non sono completamente d’accordo su questa affermazione che pare contraddetta dall’articolo citato qui sotto:

Inui S, Fujikawa A, Jitsu M, Kunishima N, Watanabe S, Suzuki Y, Umeda S, Uwabe Y. Chest CT Findings in Cases from the Cruise Ship “Diamond Princess” with Coronavirus Disease 2019 (COVID-19). Radiology: Cardiothoracic Imaging 2020;2(2). doi: 10.1148/ryct.2020200110

Nel quale in breve si conclude che:

Of 104 cases analyzed, 76 (73%) were asymptomatic, 41 (54%) of which had pneumonic changes on CT. Other 28 (27%) cases were symptomatic, 22 (79%) of which had abnormal CT findings.
Asymptomatic cases showed more GGO predominance over consolidation (83%), whilesymptomatic cases were more likely to show a consolidation predominance over GGO (41%).
Asymptomatic cases showed milder CT severity score than symptomatic cases.

(GGO: Ground-glass opacity)

P.S. a questo studio fa riferimento anche l’interessante articolo:

The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society

Geoffrey D. Rubin, M.D, Christopher J. Ryerson, M.D, Linda B. Haramati, M.D, Nicola Sverzellati, M.D, Jeffrey P. Kanne, M.D, Suhail Raoof, M.D, Neil W. Schluger, M.D, Annalisa Volpi, M.D, Jae-Joon Yim, M.D, Ian B.K. Martin, M.D, Deverick J. Anderson, M.D, Christina Kong, M.D, Talissa Altes, M.D, Andrew Bush, M.D, Sujal R. Desai, M.D, Jonathan Goldin, M.D, Jin Mo Goo, M.D, Marc Humbert, M.D, Yoshikazu Inoue, M.D, Hans-Ulrich Kauczor, M.D, Fengming Luo, M.D, Peter J. Mazzone, M.D, Mathias Prokop, M.D, Martine Remy-Jardin, M.D, Luca Richeldi, M.D, Cornelia M. Schaefer-Prokop, M.D, Noriyuki Tomiyama, M.D, Athol U. Wells, M.D, Ann N. Leung, M.D CHEST

Cordiali saluti
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Comment 2
Received: 25 April 2020
Commenter: Riccardo Iuliani
The commenter has declared there is no conflict of interests.
Comment: Buongiorno, non è una domanda sostanziale più che altro una curiosità. nell'articolo del corriere vengono citati i Canottieri. Nel PDF del vostro articolo ma letto velocemente, non trovo questo esempio. (nella bibliografia c'è un articolo sui rowers). Vi é la citazione nell'articolo in italiano? O non c'è? O avendo letto sommariamente non lo ho trovato? Grazie. Buon lavoro. (L'argomento in generale sui carichi eccessi di lavoro in sportivi amatoriali quindi master e già con una certa età è di mio interesse)

Dott. Riccardo iuliani
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Comment 3
Received: 25 April 2020
Commenter: Francesco Venturelli
The commenter has declared there is no conflict of interests.
Comment: Dear authors,

thank you for sharing this comprehensive model that connects the points of knowledge on this new disease and will help the next steps in treatment and control.

I'm a public health physician from the Epidemiology unit of the Azienda USL-IRCCS of Reggio Emilia and I would like to share with you evidence on the timing of viral shedding we assesses in our cohort, providing strong evidence that we cannot find in other publication but we think are essential for the phase 2 planning of control measures.
We followed up 1162 subjects for ate least 30 days, and tested the median time also in the whole cohort of SARS-CoV-2 positive subjects resident in our province.

We find median time to first negative swabs of 30 days from diagnosis and 36 from symptoms onset, with different confirmation probability to the second test, highlighting the potential one in five false negative test, deacresing with the time from diagnosis.

We also observer wery long duration with 75 percentile of negativization up to 45 days from diagnosis.

You can find the pre print in the attached link.

I hope this could be useful for you and for the public health, and I will be happy to receive your comments on our work.

Best regards.

Francesco Venturelli
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Comment 4
Received: 25 April 2020
Commenter: Donato Toppeta
The commenter has declared there is no conflict of interests.
Comment: I have found your paper very interesting,
have you investigated (or are you planning to add in a future revision of your model) the potential impact of environmental pollution, like particulate (Becchetti et al.) PM 2.5 (Harward Dominici), PM 10 (SIMA), or other components (NOx) both for long term historical exposure or near term (Particulate matter combined with droplets as a more effective/dangerous vector)?

Some references to pre-prints research papers that I collected:

Becchetti, Leonardo and Conzo, Gianluigi and Conzo, Pierluigi and Salustri, Francesco, Understanding the Heterogeneity of Adverse COVID-19 Outcomes: the Role of Poor Quality of Air and Lockdown Decisions (April 10, 2020). Available at SSRN: or

"Abstract: The uneven geographical distribution of the novel coronavirus epidemic (COVID-19) in Italy is a puzzle given the intense flow of movements among the different geographical areas before lockdown decisions. To shed light on it we test the effect of five potential correlates of daily adverse COVID-19 outcomes at province level, that is lockdown decisions, demographic structure, economic activity, temperature and particulate matter. We find that poor quality of air is significantly and negatively correlated with adverse outcomes of the epidemic, while lockdown and social distancing seem to be effective for contagions, but not yet for deceases. [omissis]"

Updated April 5, 2020: Exposure to air pollution and COVID-19 mortality in the United States. Xiao Wu, Rachel C. Nethery, Benjamin M. Sabath, Danielle Braun, Francesca Dominici. medRxiv 2020.04.05.20054502; doi:
All authors are part of the Department of Biostatistics, Harvard T.H. Chan School of Public
Heath, Boston, MA, 02115, USA
Results: We found that an increase of only 1 g/m3 in PM2.5 is associated with a 15% increase in the COVID-19 death rate, 95% confidence interval (CI) (5%, 25%). Results are statistically significant and robust to secondary and sensitivity analyses. Conclusions: A small increase in long-term exposure to PM2.5 leads to a large increase in COVID-19 death rate, with the magnitude of increase 20 times that observed for PM2.5 and all cause mortality. The study results underscore the importance of continuing to enforce existing air pollution regulations to protect human health both during and after the COVID-19 crisis. The data and code are publicly available.

SIMA POSITION PAPER Relazione circa l’effetto dell’inquinamento da particolato atmosferico e la diffusione di
virus nella popolazione
A query to identify other paper on this topic that I have used:
From the press or other sources, but interesting

Francesca Dominici, Harvard University and Gianluigi De Gennaro, Università di Bari online webinar “Inquinamento dell’aria e Covid-19” organizzato da Ecologia Politica di Pisa (re: )

Coronavirus threat greater for polluted cities
by European Public Health Alliance | Mar 16, 2020 | Clean Air | Latest Developments, COVID-19
Zoltan Massay-Kosubek, EPHA Policy Manager for Clean Air and Sustainable Mobility, +32 499 430 468.
Dr Sara De Matteis PhD Associate Professor in Occupational and Environmental Medicine at the University of Cagliari, Italy.
I'm an only an ICT expert (past Microsoft employee), with a degree from Politecnico di Milano in bio-engineering, but I'm attempting to help a friend in addressing some decisions at municipal level. I hope that a few of the referred sources might be useful for your work, too.
You obviously can contact me also in Italian.

Donato Toppeta
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Comment 5
Received: 28 April 2020
Commenter: Stefano corato
The commenter has declared there is no conflict of interests.
Comment: Thanks so much for this helpful document.
Sorry if I dare such question below.
Once admtitted that the DOSE is a basic factor, I cannot refrain from wondering whether there is a kind of minimum dose under which someone might be contacted by the virus without any symptom.
In very much simple words, I'm thinking that there might a certain minimum dose could acting itself as a kind of vaccine.
In other words, all the people defined as healthy carrier must have contacted before the virus.
Maybe a very small dose leave enough time to the body to react.
Therefore my question would be: "how long does the virus take to duplicate itself inside the mouth and nose and throat?".
Question: "what is the duplication time constant of the virus?"
Thank you very much for your kind attention.
Best Regards.
Stefano Corato.
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Comment 6
Received: 28 April 2020
Commenter: Stefano Corato
The commenter has declared there is no conflict of interests.
Comment: Thanks for the helpful article.
Once admitted that the cumulative DOSE is a fundamental factor, I cannot refrain from wondering whether there might be a kind of minimal DOSE under which the body has enough time to react before any symptom might even appear.
In other words, should a very small dose contact the human body, would it take too long to be dangerous possibly ?
In other words again, the virus might act as a vaccine itself if contacted in very small q.ty. This is my thought.
What I miss here, is the understanding of the duplication time constant of the RNA.
Any clue about that ? minutes ? hours ?
This question is asked by a non medical person but I think that the problem is well posed.
Thank you very much for your precious job.
Best Regards.
Stefano Corato.
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Comment 7
Received: 29 April 2020
Commenter: Giuseppe Tambussi
The commenter has declared there is no conflict of interests.
Comment: Very interesting and exhaustive paper.
We have some data on IgM and IgG made on both healthy exposed healthworkers and COVID-19 patients and we would like to write a brief report. We would like to use the figure 1 that depicts very clearly the kinetic of different phases of infection. So I am asking for the permission to use the figure.
Thank you
Warmest regards.
G. Tambussi
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Comment 8
Received: 2 May 2020
Commenter: SANTO ARENA
The commenter has declared there is no conflict of interests.
Comment: buongiorno
finalmente un articolo con delle osservazioni a tutto campo, che non si aggrappa alle restrittive teoriedella "storia clinica del paziente", " patologie pregresse" , "familiarita' alle patologie polmonari" ecc.
spero di offrirle (offrirvi) uno spunto per un diverso angolo di visuale
perche' francia e germania (nazioni mitteleuropee) hanno percentuali cosi' diverse?
perche' italia e grecia? (penisole mediterranee)
perche' spagna e portogallo? (la stessa penisola)
perche' belgio e olanda?

la ringrazio per il lavoro che state facendo per tutti noi (e quindi anche per me)
spero di averla incuriosita

buona giornata

santo arena

good morning
finally an article with observations in all fields, which does not cling to the restrictive theorem "clinical history of the patient", "previous pathologies", "familiarity' to lung diseases" etc.
I hope to offer you an idea for a different angle of view
Why do France and Germany (Central European nations) have such different percentages?
Why Italy and Greece? (Mediterranean peninsulas)
Why Spain and Portugal? (the same peninsula)
Why Belgium and the Netherlands?

thank you for the work you are doing for all of us (and therefore also for me) :-)
I hope I’ve intrigued you

good day

santo arena
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Comment 9
Received: 2 May 2020
Commenter: santo arena
The commenter has declared there is no conflict of interests.
Comment: Is it possible that the newborns who developed the infection, cried a lot?
santo arena

e' possibile che i neonati che hanno sviluppato l'infezione, piangessero molto?
santo arena
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Comment 10
Received: 27 May 2020
Commenter: Alhussein El-Shennawy
The commenter has declared there is no conflict of interests.
Comment: My input would be the following:
-Can the ingestion of glutathione rich food with/without whey protein improve outcome of covid-19 high risk population? Even when used as a protective and preventive measure?
-Increasing/modifying glutathione intake should stop or minimize cytokine storm, beside the antioxidant properties of glutathione!
I guess it is worth a try! We have nothing to loose!
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