Mumbai: COVID-19, caused by the novel coronavirus named SARS-CoV-2--short for severe acute respiratory syndrome coronavirus 2--is also affecting organ systems outside the lungs. “Extrapulmonary manifestations” is the term that describes the effects COVID-19 is having on the body beyond the lungs and the respiratory tract. While these symptoms and conditions have been observed by the doctors we have been speaking to (read here, here and here), perhaps for the first time, we have a comprehensive study on this subject.
This study has been led by Aakirti Gupta, Interventional Cardiology Fellow at the Columbia University Irving Medical Center, New York, Donald Landry, chair of medicine at the Columbia University Vagelos College of Physicians and Surgeons, along with Mahesh Madhavan, fellow and clinical researcher in cardiology at Columbia, and Kartik Sehgal, a haematology and oncology fellow at Beth Israel Deaconess Medical Center/Harvard Medical School in Boston.
We speak to Gupta, Madhavan and Sehgal to find out more.
Aakriti, could you take us through what this project has meant in terms of size and scope before you arrived at the conclusions that you did?
AG: We were at the epicentre of this pandemic in March at Columbia University in New York City, and very quickly, our ICUs [intensive care units] were overflowing with COVID-19 patients. Even though I was a cardiology fellow, taking care of COVID-19 patients became the primary responsibility. Very quickly, we started realising that it is much more than a lung disease. We were experiencing very high rates of kidney failure, high rates of stroke, heart attacks, a lot of blood clots that were forming everywhere. We were changing the catheters very frequently.
All of that was a little surprising, because we had not heard a lot about that in March. And that led us to undertake this massive effort, where we had a lot of different interdisciplinary physicians come together, dig the literature and take insights from our clinical experience at the forefront, to put together this paper so that we could share our experience with the broad audience globally.
Mahesh, could you take us through what the study has found chiefly?
MM: Seeing these patients first-hand in front of us, and having all of us trained in internal medicine, we were all attuned to appreciating how the various organ systems were affected by this virus. And we had collectively done some previous work in this space, prior to doing this specific review. So, we were highly aware of the potential for this virus to have a number of manifestations.
We looked through all the literature available. We went over a thousand articles--published all throughout the world--as a part of this process. We organised them by organ system, from the top down--from the neurologic and nervous system, to the heart, to the lungs, the gastrointestinal system, [and] haematologic abnormality and manifestations [that] are quite prevalent as well.
We grouped the manifestations that were present, and we summarised the purported patho-physiologic mechanisms for these manifestations. And based on our individual experiences along with a number of co-authors with expertise across the gamut of internal medicine and neurology, we were able to summarise our own experiences from a first-hand perspective. And we were able to, in some ways, provide guidance as to how patients should be potentially triaged and treated for these various manifestations. And finally, we were able to show some of the things that are yet to be unanswered in areas that need further exploration, as future research endeavors need to follow.
What would be the highlights--if you were to list the top four symptoms that are different from what we saw in the first month of COVID-19?
MM: The main thing that we are able to say is that the virus has a number of direct and indirect effects. Direct effects: There is some evidence that the viral particles are found in a number of organ systems. That has been shown in biopsy and autopsy specimens in a number of series. But the indirect effects, I think, are the ones that are causing significant consequences as well. In the setting of profound inflammation, and instability in the setting of serious viral infections--and those are ones where patients often require ICU stay, mechanical ventilation and requiring being connected to the ventilator for extended periods of time--this inflammatory milieu and inflammatory response can result in a number of issues.
Firstly, one of the most common things we are seeing--at least anecdotally, and looking at the autopsy series and the clinical series--is the number of clots that patients have. We are seeing clots in large vessels, so if you scan the person’s legs, or if you do a CT scan to evaluate for clots, we are seeing that pulmonary embolism and deep venous thrombosis are very common. There are series that have systematically screened patients, meaning they have scanned at least once or twice upon admission into the ICU; and rates can exceed 60-70% and up to 85% in some series of clots. That is kind of an extremely surprising and elevated number.
As cardiologists, we are attuned to cardio-vascular manifestations. And there are a number of series that demonstrate the rates of myocardial injury that as evidenced by elevated cardiac biomarkers is quite significant, and when patients have that, they are more likely to do poorly. There is evidence out of our hospital, evidence out of Mount Sinai [Hospital], and other institutions across the country that suggest that if you have myocardial injury, you are more likely to require ICU stay, to do poorly, and potentially die from this virus infection.
The renal manifestations are very common. We see patients fairly frequently requiring renal replacement therapy. In our hospital, there is a series out of our pulmonary critical care group that demonstrated that if you are in the ICU, the need for renal replacement therapy is pretty common--at least 30% in our internal cohort.
And then there are a number of other manifestations that we have described pretty extensively that suggest that this virus has, unfortunately, systemic consequences.
Karthik, this disease was supposed to be a severe acute respiratory syndrome--a version of that, or a deadlier version of that. Now it is much more and beyond. What do we know more about the behavior of this virus?
KS: One of the first things we have to realise is that we are still early on in the pandemic, though it feels like a lifetime for sure. But in terms of science, scientists are still working at an unprecedented scale to find out what might be special or unique about this virus, which may be bringing on all of its manifestations that we have had the chance to review. We have looked into the literature and based upon experience with other coronaviruses such as the one that caused the SARS epidemic of 2003, and we were able to use the science that was discovered during that time.
We proposed four different ways in which the virus can affect the body and may be responsible for all its systemic effects. Two of them maybe unique to the virus--one of them being its entry into different body parts through the receptor that has ACE2 [an enzyme attached to cell membranes], and there is evidence in the literature that ACE2 and some of the other receptors that are required by the virus to enter and attack the cell can be present in the heart, the kidneys, and the gut, which may cause this. The second way linked to this ACE2 is the RAAS pathway, which is generally responsible for maintaining the blood pressure, fluid and electrolytes in the body and that may be modulated. But again, all of this needs to be investigated a little bit more.
The second part, which may not be unique to this virus, is whenever an infection happens--be it with the virus or bacteria--the immune system gets activated, and it is a normally protective mechanism of the body to fight against the infection. But sometimes, some of the infections--and this virus, particularly--may come up with ways to hijack the system and lead to a very severe inflammatory response, which can then lead to clotting abnormalities as well and dysregulated immune response, which can then go haywire and affect all the body parts.
Aakirti, I am asking since I am sitting in India, are you getting a sense that all these findings you have today will be universally applicable?
AG: Yes, for sure. I have been very closely following the situation in India, and my colleagues in the hospitals in Delhi and Mumbai universally are reporting very similar presentations as what we saw in our ICUs. Particularly, I think any population that has higher proportions of either high blood pressure, diabetes, obesity or metabolic syndrome is going to be much more vulnerable to the serious effects of the virus. And I think India fits that bill, unfortunately.
How has your treatment response changed because of this? We have seen doctors responding to the same question in India as well, that the number of drugs you are administering now to treat is changing, or the cocktail of drugs is evolving constantly. Where does it stand today for you?
AG: During the course of treating these patients in the last three to four months, I think a lot of things have changed. For example, in the beginning, there was a lot of emphasis on pre-emptively intubating these patients, even if they have not reached the threshold we normally would use, because the thought was that it helps. But we realised that it probably does not help to pre-emptively intubate. So now, we actually wait and avoid putting breathing tubes in these patients for as long as we can.
Secondly, when we were putting the tube in, in the beginning we would give very high pressures into the lungs, because the thought was that these lungs are going to benefit more from higher pressure. But then we realised that that is not true, because the lung would burst open sometimes and cause air to accumulate in the chest cavity, which is not good.
There is something that is called ‘awake proning’. Normally, we would prone the patients only when they had a breathing tube in them. And that was thought to be helpful, which it still is. But now even without putting the tube in, we can prone them--that is, they lie on their stomach--and that actually helps them to breathe better. These are all practices that evolved in the first two-three months of taking care of these patients, and we have gotten so much better doing that.
Secondly, there is the steroid study that came out of the UK. Earlier, we were reserving our steroids only for the really last ditch effort, when the patient is really sick and may not survive. But now, it has become a routine practice that these patients are getting steroids when they are going into the ICU and getting critically ill. I think there are also efforts now to think about that as soon as they get hospitalised.
And I am sure you are aware of the hydroxychloroquine studies. In the beginning, everyone would get them when they get hospitalised. We are not doing that anymore, based on a lot of evidence that has come out.
The other thing is, in terms of extra pulmonary manifestations--because now we are more aware of all the systems that can get involved--we have a series of what we call ‘COVID labs’, which are a lot of different laboratory tests that we perform in patients as soon as we know that they are COVID-positive. And that would uniformly screen for injuries to the lungs, the kidneys, the heart--particularly the kidneys, because we check the urine for proteins. So, we have a lot of information now that we act upon with much more anticipation than we did before.
Mahesh, for those doctors who are reading your study, what are the key things that the study would be telling them, which may cause some shift in strategy in response to patients and severe patients?
MM: Based on the experiences we have had upfront, we can only inform future physicians treating future patients as to how best they might be able to respond to the patient in front of them. So, the hope is that they do not necessarily have to reinvent the wheel from where we were several months ago. The hope is that this can lead to protocols that individual hospitals can put in place for the patients in front of them based on some of the things we saw and based on their own experiences.
So, for example, Aakriti mentioned laboratory assessments. In some ways, this lends to the practice that if you have the patient in front of you, you should regularly check the labs relating to the kidney, [and] potentially relating to the coagulation system in the heart depending on the specific patient.
The hope is that we are able to give strategies for physicians to treat the patient best in front of them. Additionally, as this evolves over the next subsequent weeks and months, the hope is that additional research will be performed. There are a number of ongoing trials that are going to study a number of questions relating to some of the things that we have brought up in the paper, and hopefully, that will also lend towards better treatment. As you suggested, treatments have certainly evolved, even in such a short period of time, in terms of both best practices on the floor in the ICU, and specific targeted medicines for COVID itself.
Karthik, as you look ahead, what are the things that you take encouragement from, and what are the things that you are still concerned about when it comes to the bottom line--which is really saving more lives and keeping people healthy?
KS: What I have been pleasantly surprised with is how the world has come together to fight this virus. Scientists all over the world are collaborating, and we have seen that when we work together, we build together, I think doing randomised clinical trials as a whole nation, as even the whole world, is an idea that we should all strive for--to be able to answer questions more quickly, to be able to help our patients better. And I think that is something which has been pleasantly surprising and really encouraging for all of us.
The thing that I think is still unanswered is how this virus is hijacking the immune system and how can we do better in terms of fighting this. And also a couple of questions about clotting disorders--as I am a haematologist by training. The big question that I think, hopefully, will be answered in the near future is the question about giving these patients full dose blood-thinning medicines, or anti-coagulation. That is an area that I am particularly invested in. And I know Dr Gupta, Dr Madhavan and their colleagues at Columbia are working towards answering that question through a randomised clinical trial.
Mahesh, what are you looking out for or looking ahead to?
MM: I am really hoping that we can come up with treatments that will be effective. We have seen in recent weeks that there are some strategies that seem to have some benefit. Dr Gupta mentioned the steroid story that came out of the Recovery trial, and we are hoping that that will lead to better outcomes. There are some other studies, such as the remdesivir story that might potentially reduce the length of stay of patients in the ICU, although that does not--at least, as far as we can tell--have a mortality benefit. Obviously, shortening the length of stay in an ICU is an important thing that we can hope to achieve, especially as the resources are tight, in the setting of so many patients being admitted.
The thing I am looking forward to, and the thing we all want to see, is obviously a vaccine to prevent further patients from getting sick from this. And I know there are a number of efforts all across the globe including India itself to help with that. And there are also potential strategies, where you can potentially purify antibodies from patients who have recovered from COVID that are also being studied. Hopefully that can potentially be used as either primary or secondary prophylactic strategy to help patients from getting really sick from this virus.
I am really hopeful that ideally over the next several months, we would have made further headway and hopefully, things will start getting better as we approach next year. But this is just hope, and this requires a lot of work and a lot of effort all over the world. So, we are really crossing our fingers that we can continue to make strides.
Akriti, going by the patients that you have seen--and particularly in those difficult months you talked about--what is your advice to people? Yes, we have to mask up, sanitise, and maintain social distance. But I am sure that it goes beyond that, particularly for those who are more vulnerable. Your advice and insights?
AG: My insights for particularly patients who end up getting so sick that they are hospitalised would be to think about this disease as much more than something that finishes at the time of discharge. COVID care does not end at the time of discharge. I think, as society, as physicians across the world and hospital systems, we all have to think about how we facilitate post-COVID care, because a lot of these patients are sustaining multiple organ damage that they may recover enough to get discharged, but are still not at a place where they do not get seen as an outpatient and get follow up.
For example, like Dr Sehgal and Dr Madhavan mentioned, all of these people who get blood clots particularly in their lungs are now going to be on blood thinners for a long time, and that is something that needs to be followed up very closely as an outpatient. There are a lot of people who will suffer damage to the muscle of the heart, or damage to the kidneys, and they would require dialysis for much more prolonged time now.
So, we need to have systems in place to be able to take care of these patients. And I realise we are so overwhelmed right now, just taking care of patients who are hospitalised. But we do need to think of where these patients transition to at the time of discharge. And even if they go home, [we need to think] how are we going to make sure that they can have meaningful healthy lives moving forward.
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