Italy’s SARS-CoV-2 Outbreak Brings Out Best in Clinical Labs

NEWSMAKER INTERVIEW

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CEO SUMMARY: Italy was one of the first countries outside of China to experience an explosive outbreak of COVID-19 and its northern provinces were hit hardest by this novel coronavirus. In this exclusive interview with THE DARK REPORT, internationally-known pathologist Mario Plebani, MD, discusses how his clinical laboratory in Padova responded to the pandemic in the Veneto Region.

Second of Two Parts

In italy the COVID-19 outbreak hit early and hard. The nation has large numbers of cases concentrated in the northern regions where death rates have been puzzlingly high. As the first COVID-19 cases were diagnosed, pathologist Mario Plebani, MD, and his team in the Department of Laboratory Medicine at University-Hospital of Padova, responded to patients’ needs in some of thehardest-hit communities in Northern Italy.

A professor of clinical biochemistry and clinical molecular biology at the University of Padova, Plebani explained during an interview with The Dark Report that clinical lab professionals have much to learn about the steps the Italian healthcare system took—and the steps not taken—to address one of the world’s largest clusters of COVID-19.

Serological testing for COVID-19 should provide intriguing data, not for the diagnosis, but for monitoring the outbreak and understanding the epidemiology of the virus.
—Mario Plebani, MD

As was the case in many other nations, Italy’s health system was unprepared, he said. From his lab in the Veneto region, Plebani had a close-up view of the outbreak as it spread through the neighboring region of Lombardy, breaking out rapidly in the towns of Bergamo, Milan, Brescia, and Vó.

We conducted this interview on March 25, shortly after the peak rate of new confirmed cases per day in Italy reached more than 6,000 on March 20. As of April 13, the daily number had dropped to 1,363 new cases, with 103,616 total positive cases. Since the first case of COVID-19 in Italy was reported on Jan. 20, the country reported 181,228 cases and 24,111 deaths by April 19, according to the Johns Hopkins Coronavirus Resource Center.

Third Hardest-Hit Nation

While the daily number of new cases had declined somewhat, the number of deathsdue to the novel coronavirus made Italy the third hardest-hit nation in the world (behind the United States and Spain). On April 10, among regions of Italy, the Lombardy region had the most confirmed cases (56,048) and deaths (10,238), according to data from the World Health Organization.

As the Editor-in-Chief of the American Association for Clinical Chemistry’s journal, Clinical Chemistry and Laboratory Medicine (CCLM) and Co-Editor-in-Chief of the Society to Improve Diagnosis in Medicine’s journal Diagnosis, Plebani is well known to pathologists and clinical laboratory professionals in the United States.

The interview is presented below and edited for clarity:

EDITOR: As you know, pathologists and clinical laboratory scientists in the United States are watching the outbreak of the novel coronavirus closely as it spreads worldwide, and particularly in your home country of Italy. What should lab professionals understand about COVID-19?

PLEBANI: There are many issues to understand, but first, I would say that we were totally unprepared to manage this coronavirus outbreak at the beginning. It was unexpected because we didn’t know where it came from and who was the first case in Italy. There was some talk about some people who came here from China, but that is not true.

EDITOR: Were the first diagnosed cases of COVID-19 in communities near your clinical laboratory?

PLEBANI: Initially, two areas had a lot of cases. One—the area of Vó—is near me, and the other area was Lodi in Lombardia. In both areas, officials ordered a lockdown, but by the time they issued that order, it was too late. From Lombardia, the virus spread to Milan and that vicinity and into Bergamo—which is a big city not far from Milan. Also, we saw a high number of cases in Brescia, which is not far from Bergamo. In these areas, there have been many, many cases, and—unfortunately—there have been severe cases of COVID- 19, with many deaths.

EDITOR: News accounts have reported that a high proportion of cases in those regions of Italy are serious and required hospitalization.

PLEBANI: As I mentioned, we saw a lot of deaths in the area of Bergamo where the epidemic has been a nightmare. In addition to having many deaths there, we’ve had large numbers of hospitalizations, including many admitted to intensive care units. I don’t know exactly why the COVID-19 outbreak was so severe in that community. We would like to evaluate why as soon as possible. We do not understand why the mortality rate is so high in those areas, particularly since it seems to be so different from the mortality rate in China.

EDITOR: Have you communicated with pathologists, physicians, or health officials in China about this difference?

PLEBANI: Yes. Recently, I had a conference call with experts in Shanghai and Wuhan and learned that the mortality rate in China is much different from one area to another. In particular, one area had a mortality rate of 5%, but in Shanghai the death rate was only 1%. Those numbers show that the problem of understanding the mortality rate stems from not knowing the denominator.

EDITOR: Will you explain why knowing the denominator is important?

PLEBANI: That’s a very important number because without that number, how can you know how many cases there are and how many patients are asymptomatic? At the beginning of the outbreak, we didn’t know that asymptomatic patients would be contagious—either within their families or in the cities and towns where they lived. That’s the main question clinical laboratory testing can help us to answer.

At the beginning of the outbreak, we didn’t know that asymptomatic patients would be contagious—either within their families or in the cities and towns where they lived.

EDITOR: And what level of infection have you seen in your region of Veneto?

PLEBANI: In my region, the rate of infection has been much better. The mortality rate is not so high, and our intensive care units are not completely full. If we had more COVID-19 testing from the start, we might have been able to tell why the number of deaths was different in those various areas of northern Italy. In response to the outbreak, a lot of testing and a strict quarantine has had an effect on the death rate.

EDITOR: Was lab testing done in tandem with the quarantine?

PLEBANI: In Vó, for example, there was a program to implement a quarantine and to test everyone twice using the molecular test. We gained many insights from COVID-19 testing that was done in Vó, where there are about 3,000 citizens.

After 14 days under the quarantine, all the residents were tested again and there was a decrease in the number of patients testing positive, including no new positive results. That’s what we learned from the second molecular test.

EDITOR: Are there plans to do more testing in these regions?

PLEBANI: Next, we want to use the serological test, which up until now we have not been able to do. Serological testing should provide intriguing data, not for the diagnosis, but for monitoring the outbreak and understanding the epidemiology of the virus. We expect that the serological test could give us more data than the molecular test can give us in terms of epidemiology.

EDITOR: What serological tests for COVID-19 do you plan to use in your clinical laboratory?

PLEBANI: At the moment, of the different assays used to test for SARS-CoV-2 infections, we don’t know which serological test would work best in terms of the specificity and sensitivity. Until now, most serological tests have been developed in China, and we need to know more about the performance of those tests.

Recently, we published a paper in CCLM dealing with the analytical validation of an automated-chemiluminescent assay and the kinetics of COVID-19 IgM and IgG. The main question about serological tests is, in fact, that we need to better understand their analytical quality and clinical usefulness both for qualitative (rapid) and for quantitative assays.

EDITOR: Will you have access to blood specimens from patients diagnosed with COVID-19 that you can use for serological testing?

PLEBANI: In Vó—where we repeated the molecular test after 14 days—it was impossible, unfortunately, to collect blood from those same subjects. That was a pity because we missed the opportunity to have data about how the serological tests might perform versus how the molecular test performs. That comparative data would have been very useful.

EDITOR: While we wait for anything you can tell us about how serological tests perform, we wanted to ask how quickly Italian labs were able to get a COVID-19 molecular test up and running?

PLEBANI: I can speak only about our experiences here in the north of Italy, because that’s where the outbreak started. In our area—that’s the Veneto region—the microbiology and virology department in my University-Hospital immediately developed a home brew or lab-developed test for COVID-19. Once we validated that test, we gave that same test to other microbiology departments around Veneto. So in terms of efficiency, that went rather quickly.

EDITOR: Do you have the supplies to collect specimens and perform the tests you need to run? Here in the United States, there are shortages of swabs, face shields, and other personal protective equipment.

PLEBANI: Yes, fortunately, we have had the personal safeguards we need, and we have been assured—at least up to now—that all people working in hospitals have the masks, gloves, and other safety gear they need. That’s been true so far in the Veneto region, but we know that problem is increasing in other parts of Italy, and we are worried about the future, the maintenance of future procedures.

The main question about serological tests is, in fact, that we need to better understand their analytical quality and clinical usefulness both for qualitative (rapid) and for quantitative assays.

EDITOR: Has your lab been able to access instruments, reagents, and consumables to increase the number of COVID-19 tests it can perform?

PLEBANI: The need is to test a large number of subjects, and the increasing number of COVID-19 cases puts great demands on all labs in terms of workload and workflow. Not only in the analytical phase, but also in the pre-analytical phase, on our information systems and so on. We are working to address these challenges, but all those steps take time.

Also, we don’t know if we have enough reagents or enough of the instrumentation required for this testing. Italy is like all other European countries, unfortunately, in that we have a rising number of patients to be tested.

EDITOR: Within the European Union, is there a shortage of lab instruments and supplies for COVID-19 testing?

PLEBANI: In Germany, for instance, they want to run these COVID-19 tests on instrumentation produced in Germany. Does that mean labs here in Italy won’t be able to get the instruments we need?

EDITOR: In the United States, the FDA has approved COVID-19 test kits that a growing number of IVD manufacturers have developed under emergency-use rules. One of those IVD companies is Roche Diagnostics, which has manufacturing and distribution plants in Europe. Are you getting access to those kits in Italy?

We need to implement a scheme of proficiency testing or at least a better quality-assurance system as soon as possible. We need a benchmark for quality and a way todo comparisons against that benchmark among different laboratories.

PLEBANI: Oh, yes, Roche offered a lot of cooperation to our government and to our national institute of health. But I know that our government now has the problem of understanding the number of COVID-19 tests that we need. It’s not the offer of assistance. It’s how many tests do we need—not only in Italy, but in other European countries. As you know, Roche is not established in Italy. It’s established in Switzerland and partly in Germany. So, we have problems because it’s not easy to manage the shipment of reagents and instrumentation. It’s much more difficult now than it has been in the past.

EDITOR: Labs in the United States are having similar problems. And that issue raises another question: Is your lab getting the specimen-collection supplies it needs for patients who qualify for COVID-19?

PLEBANI: Yes. Up to now we have enough supplies to allow us to collect the specimens we need. Instead, the problem has been that some IVD companies cannot assure us that we have what we need to produce high-quality testing. It’s not a matter of quantity. It’s a matter of quality.

EDITOR: Are you referring to the data necessary to understand the performance of different COVID-19 assays and what affects the sensitivity and specificity of different assays?

PLEBANI: By quality, I mean that laboratory medicine professionals need to share any information we have, and we need to make that information available to scientists all over the world. I say that because we have to win the fight against this virus.

EDITOR: What would help you and your lab team in regard to quality?

PLEBANI: In order to ensure that we are getting high-quality results with our COVID-19 testing, we need to implement a scheme of proficiency testing or at least a better quality-assurance system as soon as possible. We need a benchmark for quality and then we need a way to do comparisons against that benchmark among different laboratories. That’s the only way to assure patients that labs are producing the same quality results, whether positive or negative, regardless of where that testing is done. If we can’t do that, we can’t be sure that any other diagnostic and therapeutic step is performed correctly. That is our duty right now.

EDITOR: In other words, all medical laboratories should be collecting COVID-19 in the same way and those tests should be run in the same way. Is that correct?

PLEBANI: Yes, that’s it exactly. We need to be sure that the pre-analytical, the analytical, and the post-analytical phases are done correctly. The turnaround time is very important as well and so we have to ensure that we have a fast turnaround time. Otherwise, if a lab notifies a positive patient after five or six days, that doesn’t make sense for the health of the patient.

Our labs would like to use serological testing to better understand this disease and help predict what could happen in the future. More specifically, it is important for us to understand how many asymptomatic subjects have been infected.

EDITOR: What type of COVID-19 testing does your lab do now? Is most of thetesting now being done manually or haveyou automated some of this testing?

PLEBANI: It is impossible to work manually because of the heavy workload andhow that volume of tests affects workflow.Also, doing these tests manually increasesthe risk of mistakes. In our University-Hospital, the microbiology department is performing about 2,500 COVID-19 tests aday. By next week, we’ll have new instrumentation and should be able to perform more than 3,500 tests. Up to now, we’ve had good throughput, but in our region, we will need to increase the number of tests because the number of patients who need tests is likely to grow.

EDITOR: Did you apply any lessons from what officials did in China and South Korea to control the spread of the pathogen? As you know, those countries acted quickly to reduce the number of new infections.

PLEBANI: Yes, we did. In particular, South Korea’s approach to using molecular tests for COVID-19 was useful for us. As was done in South Korea, we would like to extend the molecular tests to asymptomatic patients and to understand the vicinities of close friends and associates who would be at risk of infection.

EDITOR: What about new digital approaches to tracking the outbreaks, such as was done in South Korea, Taiwan, and Singapore to track people who may have been exposed to SARS-CoV-2?

PLEBANI: In South Korea, they use some devices—such as mobile phones and other technologies—to track the virus. However, legislation in Italy does not allow us to do that. To safeguard the health of people, we should adopt some strategies that South Korea used in other parts of this province. I’m quite comfortable with the South Korea paradigm.

EDITOR: Have healthcare providers done COVID-19 testing outside of hospitals by, for example, sending out healthcare professionals to collect swabs in people’s homes? Or are you collecting swabs at drive-through locations, rather than having patients go to a hospital or to patient service centers?

PLEBANI: Yes, with the help of the Red Cross, we began to collect specimens in patients at home. In the Treviso area, which is not far from Padua, this has begun, and we would like to follow this strategy to increase the number of subjects tested without moving them to the hospital. Within about a week or so we will probably start doing this in our region with the help of the Red Cross.

EDITOR: Do you have any COVID-19 lab test result data that allows you to predict where the spread of the virus may go in the coming days or weeks?

PLEBANI: Not at the moment. But every day our government reports the data about the number of infected patients and the number of deaths. Our labs would like to use serological testing to better understand this disease and help predict what could happen in the future. More specifically, it is important for us to understand how many asymptomatic subjects have been infected and we can help them to stay healthy.

EDITOR: What are your lab’s plans to bring up a serological test for COVID-19 and test a large number of subjects?

PLEBANI: We don’t know exactly and this is a problem. We don’t know how long it takes for the immunoglobulin M (IgM) antibodies to be produced. These are the first antibodies humans make to fight a new infection. Nor do we know how long the IgM will stay high. Next, we don’t know when we will see the immunoglobulin G (IgG) antibodies in a serological test result or how long the IgG antibodies will remain in the blood. Few papers have been published on serological tests for SARS-CoV-2 tests. Even China doesn’t have much comprehensive and better evidence-based data on antibody testing.

EDITOR: Do you have concerns about how labs will introduce serological tests for COVID-19 throughout the world?

PLEBANI: Good science and good laboratory medicine are always based on quality data. Labs must understand the analytical performance of the serological test. We need to know these tests will perform because some authorities want to introduce a rapid test—whether positive or negative. I worry about this, because our lab community doesn’t know exactly how these tests would work and, lab scientists know, there can be a wide range of variability from one subject to another. All these reasons make it difficult to understand the quality of serological testing for the virus.

EDITOR: You mentioned that if only patients who have symptoms are tested, but patients who are asymptomatic do not get tested, it will be difficult to know the true levels of sensitivity and specificity for a serological test.

PLEBANI: That’s correct. As the Editor-in- Chief of CCLM, I reviewed a paper that researchers from China submitted about a serological test for SARS-CoV-2. In that paper, they said their experience was better in terms of sensitivity and specificity than the molecular test. But that conclusion raised a lot of questions because the gold standard for diagnosis has been the molecular test. So, how is it possible that these researchers would conclude that a serological test should be considered the gold standard? When we were unable to get satisfactory answers to these questions, we had no choice but to reject the paper. Having said that, you are correct in that we need a better understanding about how antibodies work in our population, and then we need to know how well serological tests work in comparison to molecular tests. We also need to understand if we can test using a serological assay alone or do we need a molecular test too? Right now, these are open questions.

…we need to know how well serological tests work in comparison to molecular tests. We also need to understand if we can test using a serological assay alone, or do we need a molecular test too?

EDITOR: What is your thinking about how the typical influenza season in the northern hemisphere might have a role in containing the outbreak of COVID-19? Historically, cases of influenza, coronaviruses, and other respiratory viruses tend to fall off as the weather warms and summer arrives.

PLEBANI: Well, I don’t know. There are expectations that it could disappear with warmer weather. Past experience says that should be the case, but nobody really knows. This is a new strain of the coronavirus that we do not understand. Here in Italy we still have cold weather here in the northern regions, and so I believe some flu is still coming to our population.

EDITOR: Do you have any lessons to share with pathologists and lab directors about how to manage testing in the midst of this outbreak? What steps should U.S. labs take now, for example?

PLEBANI: If at all possible, clinical laboratories in the United States should be prepared to monitor patients in any way they can, even with some traditional testing, particularly hematology. There is a new methodological index to assess the severity of the disease by testing for an increase or decrease of lymphocytes, an increase in neutrophils, and a decrease in platelets. Also, D-dimer is interesting, because an increase in D-dimer could be useful in testing the severity of the COVID-19 disease.

EDITOR: The news media has not publicized these methods of using standard clinical laboratory tests to aid in diagnosing COVID-19 patients here in the United States.

PLEBANI: I also have another recommendation for labs in the United States, which is to be prepared to establish and perform tests that are not commonly requested. For example, in Italy, there are clinical trials—including at my university—on the use of a new drug for coronavirus patients that has been used to treat patients with rheumatoid arthritis. That drug is monitored with a molecular test. That is why labs need to be ready to perform tests that are not commonly requested.

EDITOR: What other insights would you suggest to your laboratory colleagues in the United States?

PLEBANI: From what we’ve learned here, I would make a number of points. First, for those working in laboratories, it is very important to ensure safety for your lab staff as they work with closed tubes in the lab. And, as point-of-care testing becomes available, those working in the lab, and those collecting specimens, need to be careful in how they handle the SARS-CoV-2 pathogen.

Second, I would add that this outbreak provides an opportunity to increase the visibility of laboratory medicine and the work of pathologists and clinical laboratories to save lives, to make the correct diagnosis, and to monitor patients accurately.

We need make the work we do in the laboratory more visible by getting this information out to the general public in the United States and throughout Europe and Italy.

Third, I hope you can manage this outbreak more effectively than we did when the infection was beginning here in Italy. And I would stress the point that the infection rate is high, not only in patients who are older (meaning in their 70s and 80s). We know that people with existing health conditions are at risk of severe disease. We also have seen that even young patients suffer from severe disease from COVID-19.

Fourth, be careful. Pass along the message to all people that what we’ve learned in Italy is that we have to stay home. We have to discourage people from going out to visit or stay with other people. The lockdown we’ve had here has been very effective, at least up to now, and a lockdown probably should be activated at least in some parts of the United States as soon as possible. That’s the only way we know to block the outbreak. And we learned that you need to start from the beginning. Do not start late.

EDITOR: Dr. Plebani, thank you for taking the time to tell us about your experiences with the COVID-19 outbreak in Italy. Your insights and recommendations for clinical lab scientists in the United States are appreciated.

PLEBANI: Thank you. I’ve welcomed this opportunity to share the experiences of our lab team. I hope our lessons learned can help clinical laboratories everywhere to meet the challenges of this COVID-19 pandemic.

Contact Mario Plebani, MD, at mario.plebani-@unipd.it.

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