Dr. John Marshall
In the wake of the COVID-19 pandemic, a group of critical care physicians around the world are calling for a broader definition of critical care, one that goes beyond syndromes and the consequences of disease and addresses biological composition. which determines how one the person responds to the disease and its treatments.
“Regardless of its many causes, life-threatening acute illness is just the beginning of a process,” says Dr. John Marshall, a critical care surgeon in St. Louis. Michael’s and scientist at the Keenan Research Center for Biomedical Science. “A lot of things happen that can change their course. These are less a consequence of the initial illness, than of its treatment and the way a person responds to it. They are all part of a process, which can be modified. “
With a team of critical care experts, including Dr. David Maslove, clinical scientist at Queen’s University in Canada; Dr. Benjamin Tang, a physician and scientist at the University of Sydney in Australia; Dr. Manu Shankar-Hari, clinical scientist at the University of Edinburgh in the United Kingdom; and Dr. Patrick Lawler, a cardiologist and intensivist at the University Health Network in Canada, Dr. Marshall co-authored a perspective paper on the subject that was published in Nature Medicine.
We spoke with Dr. Marshall to learn more about why now is the time to redefine intensive care and what led to this call to action.
How do we currently define disease in intensive care and where does this approach come from?
Traditionally, we have defined diseases based on their clinical manifestations, that is, the physical outcome of these diseases or their common symptoms. Two hundred years ago, pneumonia caused a patient to have a fever and cough expectation; it was unknown why this happened. With the identification of bacteria as the cause of these symptoms and the discovery that antibiotics could kill bacteria, pneumonia was redefined as an infectious disease of the lungs.
But even with effective antibiotics, some patients continue to deteriorate, and before the arrival of intensive care units (ICUs), the deterioration was followed by death. The ICU had an impact on the nature of the disease: if you had pneumonia and got very sick, we could support you with a ventilator. This support led to new complications and we created new terms for these complications. If you were with a ventilator and there wasn’t that much oxygen in your blood and your chest x-ray looked poor, but you weren’t with heart failure, we said it was an acute respiratory distress syndrome (ARDS). Patients with pneumonia could develop ARDS, but so could any patient with a ventilator.
Why are you proposing a change in the way critical illness is defined?
There are three key features of syndromes such as ARDS that develop due to ICU care. First, they result from the consequences of ICU support: only if you survive to put on a fan, do you develop SDRA.
Second, they are not unique to a particular initial cause, such as trauma or pneumonia, but are a final common pathway for a number of acute illnesses. Both the body’s response and the treatment offered by the ICU team contribute to its evolution.
Finally, and most importantly, these complications arise through the body’s complex biological response to infection and injury, a response that is biologically variable from patient to patient. As we learn more about biology, we are opening the door to a new treatment strategy: targeting the host response, rather than just the trigger that triggered that response. This can be done if we know which treatment is most likely to help which individual patient, but to do so, we need to think beyond the bacteria and beyond the syndromes we support and describe patients based on treatable processes. who are responsible for the seriously ill patient.
What we propose is to take a step back and say, how do we find common biological traits in multiple physiological processes and diseases and therefore orient the biological process, not the doctor’s image of what the common outcome is?
Why is it now time to think differently about critical illness?
We have seen this in other fields. In the 1940s, oncologists realized that ovarian cancer behaves differently from skin cancer, although we use the word cancer to describe them both. We were asked to stage the cancers based on cell type and advanced. In doing so, they paved the way for effective chemotherapy and, more recently, effective immunotherapy.
Breast cancer studies showed that some breast cancers respond to estrogen and others respond to a protein called vascular endothelial growth factor. It was possible to identify patients who had these sensitive cancers and, therefore, it was possible to target the specific biological pathway and improve their outcomes. This was one of the first examples of what we have come to call “precision medicine.”
In critical illness, we have conducted more than 100 clinical trials studying treatments targeted at biological processes that we know are involved in critical illness; none of them have resulted in effective treatments. Our perspective is that the inherent biological heterogeneity of these patients, or the differences between patients, means that we are not targeting the right patient with the right drug. Our goal is to change that.
How can we learn from COVID-19 in this area?
COVID-19 became the testing ground for the hypothesis that resolving heterogeneity may help find effective treatment. COVID-19 is a disease caused by a single virus but which has variable effects on those infected. We still have this problem of variability, not everyone responds in the same way to treatments, but the fact that we are analyzing a single cause makes it easier for us to understand this variability. For example, we have been able to identify inherited genetic factors that make a patient more susceptible to serious illness. Knowing what they are suggests that there are ways to identify those patients in whom they are present and to specifically target the abnormality.
We have also learned through COVID-19 that we can work together and set aside competition to respond to a common threat. We have learned that doing so costs nothing: progress is much faster and everyone benefits, especially patients.
What should we do now and what are the next steps?
We have brought together many people who have been doing studies and created models to differentiate more homogeneous subpopulations within a larger ICU patient population. The long-term aspirational goal is to merge this group into a global collaboration to share data and study them on a large scale needed to address the inherent complexity. Complexity in critical illness will be much more difficult than complexity in cancer because it includes how we treat patients, as well as economic factors, such as the ability of our healthcare system to support patients and train doctors.
It’s easy to have aspirations and say that’s what we need to do, but the important thing is that we really do. One of the strategic decisions we made was that the people who realize this aspiration are those who are younger and have academic deadlines that are measured in many decades. This will be a process of many decades. But we hope to have taken the first step.
By: Ana Gajic