Did COVID-19 come to Italy months before the pandemic was declared? [duplicate]

Question

A November 2020 Reuters article suggests that COVID-19 reached Italy earlier than the official first case, based on a study done by the Italian National Cancer Institute.

The new coronavirus was circulating in Italy in September 2019, a study by the National Cancer Institute (INT) of the Italian city of Milan shows, signaling that it might have spread beyond China earlier than thought.

I have family friends who recently moved from Italy where they were living for the past 5 years. According to the father, the family caught a very bad respiratory virus during October 2019, with flu-like symptoms, including sore throat, fever, dry cough, runny nose, and shortness of breath. (It wasn't diagnosed as flu), In fact, several families in the neighbourhood caught the same cold/flu. After that, they never caught it again, and they also never contracted COVID-19.

Is it possible that COVID-19 spread to Italy before the first official case in Italy?

Answer 1

Probably not. The research that Reuters story was based on was later cited as using a potentially unreliable test that could have been affected by all of the subjects being older smokers.

As noted by Hilmar, Tumori Journal in Italy published Unexpected detection of SARS-CoV-2 antibodies in the prepandemic period in Italy, placing the earliest cases in Italy in September 2019. (Tumori Journal focuses on cancer, not epidemiology.)

This would be three months before the generally accepted first reports of the outbreak in China in December 2019 and four months before the first official reported case of Covid-19 in Italy from Jan. 3, 2020. There are some stories that talk about a Chinese patient who was sick in November 2019 who was later determined to have Covid-19, but the timing isn't clear, so it would be significant for Covid to be spreading in Italy months before it was noticed in China.

There is a comment on the original study from a group of Italian rheumatologists arguing that the method used by these cancer researchers to infer the presence of Covid-19 in earlier patients was flawed. They note that the data came from a study of 959 healthy smokers ages 55-65 across Italy who were enrolled in a cancer screening study. The serological tests detected the "presence of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to SARS-CoV-2." The rheumatologists note that, in short, smoking leads to an immunological reaction that generates false positives in this sort of testing and that the results should have been directly verified with molecular testing for the presence of Covid:

"Although serologic surveys are valuable tools for understanding public health, they can still suffer from some problems: they are indirect measures of the presence of the infection and do not have complete diagnostic reliability. The gold standard for diagnosing coronavirus disease 2019 (COVID-19) is molecular testing."

Addressing the criticisms and at the request of the World Health Organization, the original authors later had 29 original samples independently retested and published a followup in December 2021: Timeline of SARS-CoV-2 Spread in Italy: Results from an Independent Serological Retesting. That testing confirmed the earliest IGM-positive test as having been collected on Oct. 10, 2019. After some hypothesizing that a progenitor of Covid-19 may have spread in China much earlier than known and been carried to the industrial regions of Italy as early as June 2019, the authors acknowledge about their research: "the findings of these studies are only partially confirmed due to the heterogeneity of methods utilized and the risk of non-specific signals in serological assays."

In short, the evidence was suggestive, but the testing method was not conclusive.

Another study, A serological investigation in Southern Italy: was SARS-CoV-2 circulating in late 2019?, also says "these findings may indicate early circulation of SARS-CoV-2 in Apulia region in the autumn of 2019. However, it cannot be completely ruled out that the observed sero-reactivity could be an unknown antigen specificity in another virus to which subjects were exposed containing an epitope adventitiously cross-reactive with an epitope of SARS-CoV-2."

The possibility there being that a related SARS virus -- of which there may have been many -- or some Covid-19 precursor was in the environment, generating the same serological response without actually being Covid-19. (Which raises the question: If there was a virus like Covid-19 in the environment that wasn't spreading like Covid-19 and wasn't as lethal as Covid-19, can you say it was Covid-19?)

Answer 2

The relevant study is easily available at for example: Giovanni Apolone et al., Unexpected detection of SARS-CoV-2 antibodies in the prepandemic period in Italy // Tumori Journal 107(5), 2021.

The study seems well executed and there don't seem to be any obvious flaws in it. It also cites a few other studies that report "Covid before the official start date", namely wastewater test in Italy and a patient in France.

Is it possible that Covid-19 came to Europe months before the pandemic was declared?

Yes, this is not only possible, but there is clear data to confirm it

1. The WHO declared the Pandemic on Mar 11, 2020 source
2. The first cases in Europe were confirmed on Jan 24, 2020 source

Your question is probably more about: was there Covid in Europe before we officially knew about Covid?

There is credible data that supports a hypothesis that Covid was in Europe before the first "official" outbreak in China. This type of research is difficult since you gave to go "back in time" and work with whatever existing samples from that time period you can get your hands on.

None of the studies that I found show a well defined onset, i.e. a period of time where there is no Covid followed by a period of time where there is using the exact same methods for both time periods.

This may very well be because that's what actually happened. The virus (and/or variants of it) may have been around for an unknown period but never in enough concentration to spike. The study shows a small spike in Sep/Oct 2019 around Bergamo but it appears to have fizzled out there. One difference here is that Bergamo has a population of 120,000 whereas Wuhan has 11 million.

Let's clear up a few misconceptions while we are it:

After that, they never caught it again, and they also never contracted Covid.

That's impossible to know without doing either an antibody test or rigorous Covid testing at least once a week with at least two different tests.

A fair amount of Covid cases are asymptomatic. In a recent study in Australia they did antibody tests and found that about half of the patients who claimed to never had Covid actually had Covid: they just didn't notice.

Answer 3

It is almost certainly untrue that there was COVID-19 transmission in Italy in September 2019

The paper in question is Unexpected detection of SARS-CoV-2 antibodies in the prepandemic period in Italy, which is using an assay the authors published in Comparative analyses of SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibodies from human serum samples.

The serologic assay used in this study is an in-house designed RBD-based ELISA, namely, VM-IgG-RBD and VM-IgM-RBD, and is a proprietary assay developed by using spike glycoprotein (S-protein) [...] In our preliminary study, an excellent correlation between the neutralization titer and the IgG, IgM, and immunoglobulin A ELISA response against the RBD of the S-protein was observed, confirming that the RBD-based ELISA can be used as a valid surrogate for neutralization.

The assay published is explicitly an academic test, performed by academics in a non-clinical lab. The authors note this in the discussion.

The next step will be to completely validate these ELISAs according to the criteria established by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (Q 2 (R1), 2006), and to analyze the performance and specificity of these tests with a panel human serum samples that are highly positive towards different HCoVs.

Validating an ELISA is difficult - it requires careful validation of the reagents (so that they are absolutely consistent from assay to assay) and selection of a specific threshold to consider a response positive. Setting the threshold too high means that there will be many Type II errors (false negatives) and setting the threshold too low means that there will be many Type I errors (false positives). The false positive error rate and fall negative error rate of the assay are determined during validation.

No validation ever occurred for this assay and the false positive rate is unknown.

Clinical ELISA tests generally have a false positive rate in the single-digit percents. As an example, here is one Hepatitis B Surface Antigen Reactivity test that is commonly performed. The validation clinical trials demonstrated that this FDA-approved clinical assay has a false positive rate of approximately 2%:

Table 24: Positive and Negative Percent Agreements Between ADVIA 


              Positive  Percent Agreement 
Total, N=1595 (434/443) 98.0% 96.2-98.9% 

The COVID-19 study had a positive rate of 12%. That is a reasonably possible false positive rate for a poorly calibrated ELISA assay.

The timeline for COVID-19 emergence was also well established early in the pandemic. Based on sequencing early viral samples, the virus began transmitting through humans in November or December 2019.

Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made with current sequence data point to emergence of the virus in late November 2019 to early December 2019, compatible with the earliest retrospectively confirmed cases.

Additional evidence has supported this estimate of when COVID-19 emerged.

These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans before November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events.

It is possible, but unlikely, that individuals before December 2019 outside of China were individually infected, but high quality evidence is strongly opposed to any sustained transmission outside of China before late December 2019.

Answer 4

I believe there were probably millions of people who had been infected by November 2019 (in multiple countries and at least 9 U.S. states).

Just look at the American study Serologic Testing of US Blood Donations to Identify Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)–Reactive Antibodies: December 2019–January 2020 that ran ELISA tests on routine blood samples.

Of the 7389 samples, 106 were reactive by pan-Ig. Of these 106 specimens, 90 were available for further testing. Eighty-four of 90 had neutralizing activity, 1 had S1 binding activity, and 1 had receptor-binding domain/ACE2 blocking activity >50%, suggesting the presence of anti–SARS-CoV-2–reactive antibodies.

A big study in France, Evidence of early circulation of SARS-CoV-2 in France: findings from the population-based “CONSTANCES” cohort reaches the same conclusion.

I have found many people who had symptoms in November 2019 or earlier who later received positive antibody tests (some multiple positive tests). This article from my Substack gives examples of at least 153 people who have antibody evidence of infection by November 2019.

The incidence of Influenza-like Illnesses (ILI) was much higher in 2019-2020 than the previous 10 flu seasons.