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Matteo Bassetti, MD, PhD: Hello. I am Dr Matteo Bassetti. I am professor of infectious diseases at the University of Genoa and the chief of the Infectious Disease Clinic in the San Martino University Hospital in Genoa, Italy. Welcome to Medscape's InDiscussion series on COVID-19. Today we'll discuss how we first addressed severe COVID in 2020, what we have learned since then, and how we manage it now. Nowadays, COVID is probably a different disease compared to what we had seen 3 years ago. But I believe it's important to put attention on the different aspects of COVID, particularly the clinical, the radiological, and the treatment aspects.
First, let me introduce my guest, Dr Antoni Torres, who is a friend of mine and a senior consultant of the respiratory intensive care unit. He is also professor of medicine in the department of pulmonology at the University of Barcelona in Spain. Welcome to InDiscussion. Before we begin our discussion today, what was it that sparked your interest in COVID-19? And what keeps you engaged today?
Antoni Torres, MD: As you know, Matteo, my research has been in respiratory infections for my whole career. I am an intensive respiratory critical care physician and pulmonologist. At the very beginning of the pandemic, I had the opportunity to apply for a big grant in Spain to study, in a multi-center way, the COVID patients admitted to the ICU. These were the two main reasons.
Bassetti: Going back through the memory to 2020, what did treatment options for severe COVID look like in February, March, and April 2020?
Torres: At the very beginning, there was nothing. But we were using treatments not completely studied from the scientific perspective, and we tried everything. This is what happened first. Second, what we learned is that corticosteroids were effective despite the recommendations of the initial guidelines from the different societies, and clinicians used them despite that. And third, because the studies from the RECOVERY trial, for example, and meta-analysis from the World Health Organization (WHO) confirmed that corticosteroids were useful and decreased mortality with some caveats (giving them in the inflammatory phase, a short time period from the initiation of the disease to the admission to the ICU, and several other things). But we learned how to use them. After that, and also from RECOVERY, we learned that other anti-inflammatory agents (for example, tocilizumab) were not useful, but you could add them to the corticosteroids to improve mortality.
Bassetti: Going back again to 2020, Italy was the first Western country that was affected by COVID, but Spain was immediately after Italy. Regarding mortality rates for patients with severe COVID back in 2020, what were mortality rates in Spain as compared to China and other countries?
Torres: Specifically in the 6,000 patients included in our study, many of them from the first part of the pandemic, the mortality was exactly 34%, and the majority of these patients were mechanically ventilated patients. So, the mortality rates were very high but lower compared to other countries. For example, I remember from the Argentina perspective, the mortalities were 50% or more.
Bassetti: Yes. I am interested about the severity illness scores and also biomarkers for prognosis. Do you have an idea of what we learned and had used in 2020 that we are still using nowadays?
Torres: At that time and during the first month of the pandemic, we learned that some biomarkers were useful. One of them was the number of lymphocytes. We already knew from our studies in community-acquired pneumonia, that lymphocytes are prognostic markers. On the other hand, other biomarkers, such as procalcitonin, C-reactive protein, ferritin, lactate dehydrogenase (LDH), and D-dimer were those that alone or integrated in some scores were useful to determine the prognosis at that time.
Bassetti: Because you are a big expert on scores and work a lot on CURB-65 and in pneumonia severity index (PSI), you are one of the first Europeans who worked with these scores. Were the severity scores, such as CURB-65 and PSI, helpful during the first wave?
Torres: At the beginning, several investigators tried to validate some specific scores for COVID. But later on, the studies on CURB-65 and PSI showed the prediction of 30-day mortality was not very different, in my opinion, compared to the specific scores developed for COVID.
Bassetti: Yes. And another important point is regarding comorbidities. We've learned since the beginning [of the pandemic] that even at the same age, there were patients who were good and patients who were bad. How do comorbidities indicate whether a patient will have severe COVID-19?
Torres: Comorbidities were very important because they increased mortality overall, and this is logical because if you have a comorbidity — for example, diabetes, chronic heart disease, and COPD — then it's worse. The mortality of COPD patients in our cities was (and is, because we are still finalizing that paper) 50%. Fifty percent for mortality is higher than 34% for the overall population. We don't know exactly why this is, but it seems that these patients with COPD have a lower level of immunity measured by, for example, the level of immunoglobulins. We have seen that very recently in the samples that we collected at that time. With hypertension, the results were controversial depending on the pharmacology that you treated with, but it seems the blocking ACE receptors are something that could be protective for the patients because this is the way that the virus enters the cell host. And, of course, immunosuppressed patients no doubt [have a higher risk of severe COVID]. We are still seeing that severe COVID is now focused mainly in the immunosuppressed with a very high mortality.
Bassetti: Toni, this is a question that I think is peculiar for a pulmonologist like you are, since it's regarding the mechanism of hypoxemia. What is the main mechanism that drives hypoxemia for the patients, at least at the beginning?
Torres: At the beginning, what was described was two phenotypes. One phenotype with a very high hypoxemia and without many pulmonary infiltrates. Another one — and this is probably due to the face of acute respiratory distress syndrome (ARDS) that we saw, although in COVID, the endothelial and vascular dysfunction was very important, too, related to that. The problem is that in non-COVID ARDS, we see these patients later than in COVID. These patients go to the ICU very early in the disease with a very high severity. I think, and this is the speculation of the experts, that we saw that because this was a very early phase of the disease. But I would like to see more studies comparing ARDS COVID, to non-COVID ARDS.
Bassetti: Before discussing vaccine treatment options and oxygenation, the question after 3 years is, what did we start to learn about severe COVID-19 as the pandemic continued on?
Torres: Let me summarize with three or four points what we learned and what we see now. We learned how to use rapid diagnostic techniques for COVID. For ventilator-associated pneumonia that was very prevalent, we confirmed that corticosteroids were useful. This is very important. And we learned a lot about how to manage ARDS — so, protective ventilation, markers of severity. And now we finalized one study comparing ARDS to non-ARDS. and we saw that for non-COVID ARDS, we ventilated these patients more, and the mortality was higher. This difference in ventilation had lower driving pressure, which is one of the measures that is easy to perform, and ventilatory ratio, which is another bedside parameter that we can use at intensive care to measure the prognosis. So, we probably did better with COVID. I don't know whether the reason for that is because we started from the very beginning of the disease.
Bassetti: I have a provocative question regarding the oxygenation we did with our patients. If we go back to 2020, did you change anything about your behavior in terms of using oxygenation — not only the classical oxygenation but also non-invasive ventilation? Sometimes the question is do we intubate more patients than needed, or have we used more non-invasive ventilation than they needed?
Torres: This is a very good question and extremely important. From our database and other studies, I have personally learned two things. A late intubation worsens the prognosis of the patient, and this is probably due to the self-induced lung injury because of the rapid, shallow breathing pattern of the patient. On the other hand, you have high-flow, nasal cannula, or you have non-invasive ventilation, often used in Italy. Our studies and other studies reveal that it is better to use a high-flow nasal cannula than non-invasive ventilation. This is probably because the injury to the lung is worse with the latter. So, do not delay more than 24 hours to stabilize the patient. Second, there are better outcomes in the inflammatory markers, even now in the sequela in long COVID, when using high-flow nasal cannula.
Bassetti: There is a big debate in my country, and I believe in your country as well, regarding the impact of vaccines. How has the vaccine helped the response in patients with severe COVID? Is it mainly related to the effects of the vaccine, or is it also related to the progression of the different variants? Omicron is not exactly the same as Delta, is not exactly the same as Alpha. Do you think it's more the effect of the vaccination or of the natural progression of the different variants?
Torres: I think it's both. On one hand, there is clear data about the decrease of the severity of the disease and the rates of hospitalization with the vaccines. On the second hand, we know that the Omicron variant is not causing so much severe COVID. I think this is a mix of the two factors, indeed. We are not observing a lot of cases admitted to the ICU except for immunosuppressed and non-vaccinated patients. Although the latter group is decreasing as well, and this is probably because of herd immunity. [In the ICU], we now mainly observe immunosuppressed patients with COVID.
Bassetti: In 2023, what are the treatment options for severe COVID? What did we maintain from 2020, and what do we have in terms of new treatment options and possibilities for patients with severe COVID?
Torres: I think that corticosteroids, particularly dexamethasone, because the studies that were performed with dexamethasone are the standard of care during the inflammatory phase. Tocilizumab and baricitinib are the other options. We also confirmed that the antivirals now for severe COVID, such as remdesivir, were not useful in our database, and perhaps we need more information. We recently published a paper in the Lancet Microbe that showed that measuring antigenemia in the blood in patients with severe COVID, depending on the viral load, was associated with the prognosis.
Bassetti: Yes, but actually the European guidelines and American guidelines recommend the use of remdesivir in hospitalized patients based on several randomized clinical trials and even in real-life experiences. Do you believe that remdesivir should be recommended in hospitalized patients in the general ward and in the emergency room?
Torres: I think so. The answer is yes, because all these observational studies showed benefits. It is more unlikely that it works when the COVID is very severe. At least in our data in a research letter that we published in the Journal of Infection, we didn't see any effect of remdesivir in those patients admitted to the ICU, even when we stratify patients for the viral load.
Bassetti: In patients in the ICU, it is actually not recommended, and I fully agree with you.
Torres: But in the others, yes.
Bassetti: The second question is regarding antiviral treatment. Do you believe there is a role in severe patients for other antivirals? Maybe to combine antivirals together in patients who present with longer viral shedding or in very immunocompromised patients?
Torres: I think so. One example — and I didn't know a lot about this antiviral, but I learned a lot recently — is Paxlovid showed very good results in decreasing the rates of hospitalization, although the indication is for less than 5 days. I think that the combination of antivirals is going to be useful in some particular patients admitted to the ward who are immunocompromised.
Bassetti: Yes. We recently published our experience in Clinical Infectious Diseases with a triple combination with monoclonal antibodies, antivirals, particularly in hematological patients and in immunocompromised patients. We have very good data, but these were patients not admitted into the ICU, and I fully agree with you, these are all probably in a normal ward. So, what do we know now about severe COVID-19 that you wish we would have known at the start of the pandemic? This is a very intriguing question.
Torres: Well, a better use of the anti-inflammatory treatments and how to treat immunosuppressed patients. At that time, we didn't fix our attention to immunosuppressed patients because we had so high a level of patients between brackets that we focused our attention on that, and now we are seeing immunosuppression in patients — so transplant patients, hematological patients — and we need to know more about that. And we didn't know almost anything about that at the very beginning of the pandemic. There are not a lot of publications about immunocompromised patients and severe COVID.
Bassetti: I would like to close this episode by asking you what advice you would share with a clinician treating COVID.
Torres: In short, my advice is to choose the right phenotypes for anti-inflammatory treatments and to know — and this is very important because this is often disregarded — the time period from initiation of the symptoms to the first visit to the emergency department. This is crucial, and sometimes this is not recorded.
Bassetti: Thank you very much. Today, we have talked with Dr Antoni Torres about severe COVID, and we compared 2020 to 2023. We know that we have learned a lot, and we know now how to manage these patients in terms of oxygenation, using antivirals, using corticosteroids, and using immunomodulators. Thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this series on COVID-19. This is Dr Matteo Bassetti for InDiscussion.