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Speculations abound about how SARS-CoV-2 came to be, but a few studies now raise an important question: Could the coronavirus have been spreading internationally much earlier than December 2019?

Could SARS-CoV-2, the coronavirus that causes COVID-19, bactrim venezuela have been circulating outside of China much earlier than we thought?

New theories and supporting research are gradually emerging as scientists seek to determine exactly when and where the coronavirus emerged.

Recent studies into the spread of the virus have focused on an earlier timeline than initially thought, putting “day zero” as early as late summer 2019.

Previous investigations have raised the possibility of an earlier outbreak. One such investigation is a joint study published by China and the World Health Organization (WHO) at the end of March 2021. The study suggested that there could have been sporadic human infections before the Wuhan outbreak.

Meanwhile, researchers from the University of Kent in the United Kingdom estimate that SARS-CoV-2 emerged on November 17, 2019, and had spread globally by January 2020.

However, some European studies, in particular, have piqued the curiosity of scientists and sparked a debate.

Studies that challenge the current notion

The current timeline of SARS-CoV-2’s spread in Europe dates back to January 2020, weeks after it was first detected in Wuhan, China, on December 8, 2019. This is according to currently available data.

Europe’s first COVID-19 patient was reported on January 24, 2020, in Bordeaux, France. The same day, two more cases were confirmed in Paris. All three had come from China.

A week later, on January 31, 2020, Italy confirmed its first two cases in Rome. The first major cluster emerged a few weeks later, on February 21, 2020, in Codogno, Lombardy. That day also saw the first COVID-19-related deaths in the country and the beginning of the first wave.

However, there have been a few pieces of retrospective research that have suggested that these were not the first cases.

October 2019: Blood samples from cancer screening in Italy

A cancer research center in Italy published research that sparked many debates about the origins and spread of SARS-CoV-2.

The research, which was conducted by scientists from the VisMederi laboratory at the University of Siena and the Milan Cancer Institute, originally appeared in the journal Tumori and later appeared in MedxRiv after a retesting of the samples.

The researchers analyzed blood samples taken from 959 healthy volunteers during a lung cancer screening trial in October 2019. They found that more than 100 people had developed coronavirus-linked immunoglobulin M antibodies, immunoglobulin G antibodies, or both. This led the scientists to believe that the volunteers had recently contracted SARS-CoV-2.

Other scientists, however, have pointed out a few idiosyncrasies about the study.

For example, the researchers took no measures to prevent the detection of other coronavirus antibodies, such as those from the common cold.

The Dutch counterparts of the study — led by virologist Prof. Marion Koopmans, from Erasmus University in Rotterdam, The Netherlands — also expressed that false positives were likely in such low-prevalence situations.

They pointed out that different testing methods could have affected the results, adding that they could not confirm the majority of the positives.

A WHO investigation later revealed that there were not enough antibodies to prove that there were any infections.

Late December 2019: Man with suspected pneumonia in France

A 43-year-old man from Bobigny received treatment at a hospital near Paris on December 27, 2020, with complaints of a dry cough, difficulty breathing, and a fever.

He was suspected of having pneumonia, but his doctor Yves Cohen retested the swab in May 2020. It came back SARS-CoV-2-positive, which ignited discussions about earlier circulation in France.

The man had reportedly not traveled abroad.

Mid-December 2019: Sewage samples from Milan and Turin

Environmental monitoring in three Italian cities revealed the presence of SARS-CoV-2 RNA in sewage samples taken between October 2019 and February 2020.

The study, which was conducted by Rome’s Department of Environment and Health, found that of the 15 positive samples detected, eight dated back to before February 2020. The earliest was found on December 18, 2019, in Milan and Turin, suggesting that the virus was already circulating in mid-December 2019.

In the early days of the pandemic, there was no specific test to look for SARS-CoV-2. Instead, doctors had to rule out other conditions — such as bacterial pneumonia and influenza — in people with coronavirus-like symptoms.

One other way in which scientists have attempted to spot traces of infection has been to analyze sewage systems.

Referring to the Italian study, Dr. Semih Tareen, Ph.D., a virologist and senior director of gene therapy, said that the testing had a predictable outcome.

“Sewer testing is not a new concept. People have used sewage samples to track epidemic diseases for antibiotic resistant bacteria. If you sample sewer outlets from hospitals, you will find a lot of antibiotic resistant bacteria simply because of the [wide] use of antibiotics.”

Dr. Tareen also added that sewer testing is now being used predictively for early intervention.

“Some researchers in Spain are using sewage PCR [polymerase chain reaction testing] to identify early bursts of local COVID-19 transmissions before people start reporting symptoms. I think that’s quite brilliant because it allows local governments and healthcare workers to act proactively rather than reactively,” he said.

Early December 2019: A boy with measles symptoms in Milan

Researchers from the University of Milan decided to investigate a particular case from early December 2019. It was in a boy from northern Italy who had a measles-like rash.

The researchers analyzed swabs from 39 people, including the boy, taken between September 2019 and February 2020. The only SARS-CoV-2-positive result was the child’s.

The study paper said that the findings suggested that SARS-CoV-2 could have been circulating for about 3 months before the first identified case in Italy.

However, was the laboratory SARS-CoV-2-free, as stated?

Critics of the study say that because the researchers used a control sample from someone who had tested positive for SARS-CoV-2, the possibility of contamination was not zero.

Michael Worobey, an evolutionary biologist at the University of Arizona in Tucson, raised the point in a series of Tweets.

Dr. Tareen added, “[Y]ou can imagine [that] a lab that does SARS-CoV-2 testing today can accidentally contaminate samples with SARS-CoV-2 RNA, or DNA, if they’re not careful.”

November 2019: A woman with a rash from Milan

Dermatologists were among the first medical experts to notice signs of COVID-19 in their patients. One such instance of this happening was in a 25-year-old female patient who presented with a plaque-like skin rash on November 10, 2019.

Raffaele Gianotti ordered a skin biopsy for the patient and conducted a study in hopes of identifying Italy’s patient zero. He detected SARS-CoV-2 molecules in the sample.

However, a subsequent WHO investigation failed, as the patient could not be located. Gianotti also reportedly died in March.

Summer 2019: Surveillance in Lombardy

Italian researchers conducted measles and rubella surveillance in Lombardy, focusing on skin manifestations and measles-like symptomology.

They took 435 samples from 156 people and analyzed them for the presence of SARS-CoV-2.

They found genetic material belonging to the virus in 13 samples, 11 of which were from the pre-pandemic period. However, they found no clear evidence of infection in 281 samples collected between August 2018 and July 2019, ruling out much earlier circulation.

The first case they detected dated back to September 12, 2019, which spurred them to believe that infections emerged between late June and August 2019.

The preprint study appears in the journal The Lancet.

One criticism of the study is about the methodology. The researchers amplified small amounts of SARS-CoV-2 DNA or RNA in the samples they collected, but this method can be susceptible to contamination and can generate false positives.

When reviewing studies or data…

According to Dr. Tareen, as with all studies, it is important to be cautious before coming to any conclusions.

“What’s important is to approach all the data from the perspective of a reviewer. This is something that all scientists do on a regular basis. When we publish our own findings, we know they are going to get peer reviewed. For that reason, we want to ensure accuracy and quality. And similarly, when a journal asks us to review a third party’s findings, you approach it the [same],” he told Medical News Today.

Dr. Tareen continued:

“When I look at studies like that, there are a few questions that pretty much every reviewer would want to ask. What was the sample? How was it treated? What control samples do [the researchers] include, and were there enough?”

Dr. Tareen said that one caveat about the studies could be the lack of samples. Most often, he said, they used single samples.

“But I thought the scientists and the doctors in the team may have worked smarter because they made an observation. Like in the skin example, there’s one where they saw dermatological signs, and in others, they saw other types of COVID-like symptoms. Lucky for them, they had biopsy samples that were preserved. So, they were able to go back to the samples to see if there is any virus, RNA, or virus antigen present in the samples,” he said.

Jonathan Ball, a professor of molecular virology at the University of Nottingham in the U.K., said that for that reason — “the lack of samples that would yield higher quality data” — further studies on these particular findings could not be carried out.

Dr. Tareen also stressed that the tests that the scientists conducted were different than regular PCR tests with nasal swabs.

“Instead,” he said, “some rely on tests that are probably not as accurate as PCR. But still, they were able to detect viral antigens.”

Prof. Ball pointed out two shortcomings of some of the studies’ methodologies.

“The one thing [that almost] all of these early ​case studies have in common is that they use PCR to identify potential cases or clinical symptomology. The former is prone to [error], and the studies I am aware of fail to recover larger fragments of virus or yield sequence that would allow us to date the virus. The latter is not diagnostic, beyond knowing there is a respiratory infection,” he said.

However, Dr. William Schaffner — a professor of medicine in the division of infectious disease at Vanderbilt University Medical Center in Nashville, TN — said that a simple laboratory contamination of specimens could be ruled out, as several different laboratories were involved and the studies were conducted by different investigators in different institutions.

The suggestion of earlier circulation is not far fetched

Probing the origins of a virus can prove challenging, especially when the virus can infect its host and go undetected for a considerable amount of time. This was true for SARS-CoV-2.

In the early days of the pandemic, many countries were unaware of the incubation period of the coronavirus and its ability to cause asymptomatic infection. For this reason, many resisted imposing mask mandates to stifle the spread.

So, when we consider the asymptomatic presentation of COVID-19 in some individuals, latency in reporting, and a more connected world than ever before, it is not unlikely that SARS-CoV-2 could have been circulating internationally before December 2019.

“It only makes sense in a global world where people are constantly traveling. With that, it’s very likely that somebody who was positive traveled to Italy or France, and we started seeing cases as early as November,” Dr. Tareen told MNT.

That would only mean about a month of difference compared with the original estimate.

“[Hence] it’s not that surprising that there were cases as early as November outside of Wuhan. Now, this doesn’t mean the case originated in Italy or France. The papers aren’t claiming that either. It simply says that, even though we started recognizing COVID-19 around December, it is possible that the earliest cases started in November or earlier, and then came over to Italy, most likely through international travel.”

– Dr. Semih Tareen, Ph.D.

Dr. Schaffner said that it was quite likely that COVID-19 was circulating undetected in Wuhan and had already spread to other countries before doctors first diagnosed it.

“There is much transmission of COVID-19 that is without any symptoms or [that produces] only mild symptoms. This permits wide transmission that can go undetected for a long time. Thus, these retrospective studies likely are correct in determining that the […] virus was circulating in Europe considerably earlier than first thought,” he told MNT.

However, Dr. Tareen raised an important point:

“If it went back 6 months or 1 year, that would be quite surprising. Because then we’d really want to ask ourselves, how did we miss this over 6 months to a year?”

Prof. Ball also acknowledged that Italy and other countries around the Alps may have served as a major focus for onward spread. However, he said that he was not convinced that there was any good evidence suggesting that it occurred before late January or early February 2020.

Prof. Ball and a team of researchers carried out their own retrospective study on the early introduction of SARS-CoV-2 into the U.K. They retrieved good sequence data and found that the virus was present in the country in early or mid-February 2020, but not earlier than that.

COVID-19 will not be the last pandemic

Dr. Tareen underlined that COVID-19 will not be the last zoonotic disease that humans will have to face in years to come.

“Zoonotic events happen all the time. This doesn’t mean that every single time they’re going to cause disease and a human is going to be case zero and spread it. But there are an estimated 400,000 new coronavirus transmissions from animals to humans every year.”

Dr. Tareen went on to explain that having interactions with other humans, some of whom have been in contact with animals and wildlife that harbor many viruses, increases the likelihood of having exposure to new pathogens.

“[Again], it does not mean with every exposure, you’ll have a pandemic. But to date, there have been at least seven human coronaviruses that we are aware of. Five of these are pandemics, and COVID-19 is the fifth. The previous four happened, to our knowledge, over the [past] 200 to 300 years, but they are now permanently with us, and they circulate every year. They don’t cause as serious disease as COVID-19, but they still cause flu-like symptoms.”

Briefly touching on laboratory leak claims, Prof. Ball said that the theory of the infection spreading from animals to humans is much more likely to be true than a laboratory accident.

“Coronaviruses have twice previously made the leap from animals to humans. That was SARS and MERS, so I think that is the most likely way COVID-19 came to humans.”

Takeaways

It is natural for weeks and months to go by before a new outbreak — especially one like COVID-19, which can present without any symptoms — gets noticed.

In that sense, the studies covered in this article — particularly those that focused on Italy — make good points that require further analysis.

“Certainly, further studies would be useful to document the early arrival and spread of the […] virus in Europe,” said Dr. Schaffner.

SARS-CoV-2 could have been circulating in countries such as Italy and France earlier than first detected, but it would be incorrect to conclude that they were the “ground zero” instead of China. Studies so far also do not suggest that.

It may be worth testing samples from 2019 and seeing if there is more evidence of earlier transmission through retrospective surveillance studies. However, not all countries and laboratories will have the means or motive to do this.

“If hospitals — not just in Europe, but all over the world — have biopsy samples, and if they have any reason to […] suspect COVID-19 earlier than they thought, by all means, they should test because all of us want to get closer to that answer,” said Dr. Tareen.

When we take timing and logistics together, the findings may not be completely impossible, he added.

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