Investigating the Wider Impact of COVID-19 Infection

As the COVID-19 pandemic continues to affect everyone, The Johns Hopkins University in Baltimore, Maryland, US, is collaborating with Canon Medical on a ground-breaking study to investigate the wider clinical effects of the disease. The investigation is utilizing some of the most advanced technologies possible to reveal the impact of the disease on the whole body. Dr. Joao Lima, Director of Cardiovascular Imaging and Professor of Medicine at Johns Hopkins University, who is leading the study, spoke to VISIONS about this ground-breaking work.
Amongst others, Dr. Lima is collaborating closely on the study with Dr. Chia Liu, Senior Clinical Scientist at Canon Medical Systems Corporation, who has worked with Dr. Lima in previous years on a significant study into Atherosclerosis (the Multi-Ethnic Study on Atherosclerosis – MESA).

Longer term implications

Investigations into the clinical effects of novel corona virus of 2019 (COVID-19) have begun, because Dr. Lima’s team wanted to gather some insight into what happens after the acute disease. This study is a morphological and quantitative analysis of COVID-19 sequalae.

“We have done a lot of studies in patients with acute COVID-19 and we wanted to investigate if patients with the disease would have sequalae in the myocardium, because from our studies in the acute cohort, it's clear that there is a process that involves the heart. We are also particularly interested in measuring fibrosis, and particularly, interstitial fibrosis in the heart, as a way to measure healing from an inflammatory insult. And, of course, not only for the heart, we thought also to image the lungs and the brain. We are in collaboration with our Neuro Radiology Department on this study.” remarked Dr. Lima. “In addition, we are acquiring seed data to propose a study to the US National Institutes- plural of Health (NIH) to follow these patients longer term. There are data suggesting that a few months after an insult, the patient can develop a fibrosis in the heart, and we would like to see the consequences of that.”
Left: Dr. Joao Lima, Director of Cardiovascular Imaging and Professor of Medicine at Johns Hopkins University Right: Dr. Chia Liu, Senior Clinical Scientist, Canon Medical Systems Corporation

“The images that we've been acquiring by ultra-short TE from the lungs are really remarkable. Our UTE images are among the best, if not the best.”

Dr. Joao Lima
Director of Cardiovascular Imaging and Professor of Medicine
Johns Hopkins University, USA

Specially developed protocol

A protocol for the investigation was designed and developed through the combined expertise of Dr. Lima and his team and Dr. Liu. Some of the techniques are so cutting edge that many are not yet widely used in clinical practice. Along with imaging of the heart, brain, lungs and liver, there are also specific practical challenges posed by the nature of this particular corona virus. Before the public vaccination campaign began in the US, it was not always possible to carry out scans on patients, because of restrictions. In addition, acute COVID-19 patients often have a great deal of pain and other difficulties.

“With COVID-19, it’s most important to keep the patient in the scan for the shortest possible time,” remarked Dr. Liu. “Our eventual protocol for this study includes T1, T2 mapping on the heart and T1 mapping on the liver, with T2* (ultra-short TE) imaging on the lung. The T2* sequence has such a short TE, less than one millisecond, that we are able to see a lung parenchyma. Diffusion tensor imaging (DTI) is used for brain imaging. We also have lots of parametric mapping techniques that we apply with these patients.”

“The images that we've been acquiring by ultra-short TE from the lungs are really remarkable,” said Dr. Lima. “We are using the Canon platform for other studies as well, one of which is a pulmonary study. As we are part of a network of nine sites in the United States, we can compare images. Our UTE images are among the best, if not the best.”

Basis for a wide range of understanding

The study and its data could provide the basis for further extension, or could provide useful key data for other research groups with an interest in this aspect of COVID-19, such as the longer term clinical effects of different variants of the virus. There is emerging evidence that other conditions, such as Type 2 diabetes, might result from severe or moderate infection cases of COVID-19 1. In addition, cases of COVID-19 that are seen in hospitals tend to be due to the severe pulmonary difficulties caused in some people. This may not be the only long term concern about the disease.

“What brings the patient to the hospital is the pulmonary involvement, but we wonder, for example, if a lot of patients that don't come to the hospital actually do have inflammation in the heart, and perhaps in the liver, but we just don't know about it. They could have maybe very little pulmonary involvement, but more cardiac involvement.” said Dr. Lima.“ We want to use the sample seen in the hospital, but also at one point, include people who are symptomatic, but not ‘pulmonary enough’ to be admitted, and see if there are changes in those as well.”

“There is also a syndrome called the ‘long haulers’,” he continued. “A percentage of people that had the disease appear to be limited afterwards. Those limitations are not yet understood. The patients are generally fatigued and can't perform anymore to the same level they used to perform. We are very interested in this group as well. It is also an important to find out if the disease limits exercise capacity, particularly in people who are top level athletes. In our institution, this relates to our lacrosse team. Several of the lacrosse players at Johns Hopkins have had COVID-19. There is a discussion to begin a study to look at those. And we may be involved at this center - the MRI center.”
Figure 1. Post hospitalized COVID-19 research participant with ultrashort TE image (A) which demonstrates subtle ground glass opacification and confirmed with CT images (B).

Accessible data

To maximize the ‘usefulness’ of the study, it is Dr. Lima and Dr. Liu’s aim to ensure that the data is as accessible to other research groups as possible.

“We have already had interest from other researchers, for example, Dr. David Bluemke, from the University of Wisconsin, who is studying
COVID-19 in athletes and football players. University of Wisconsin is part of the Big 10. Has a very large sports program, and they have over 100 people, for example, in the football team that had COVID-19. Two of them had clear-cut changes, and that's been published2. So, David will review particularly our lung images as well, but will be collaborating with us very closely on this. There are other groups that are very interested. Our aim is to publish data, put it out there, and have it as accessible as possible to everyone.”

“In addition, the NIH is launching a program to image everybody who has been imaged before in one of their significant studies, including the Multi-Ethnic Study on Atherosclerosis (MESA) and The Coronary Artery Risk Development in Young Adults (CARDIA) study. They call this the cross cohort study, and we're the MRI group for that cross cohort study. So we're going to see participants from other areas of the United States being imaged in the study, so we hope that we're going to have samples from several other parts of the country.”

Key collaboration

Canon Medical Systems has a long history of collaboration with Dr. Lima. This began in 2002 at an American Heart Association meeting, when Dr Lima and his team saw images of a CT-guided arterial stent being placed. The team was so impressed that they began to invest in various Canon equipment, which have served the team’s research needs very well.

“A few years ago, Canon Medical Systems decided to take space in our biotech park. That was a very important moment, because there was then a decision to site an MR – a Vantage Galan 3T - and we became, therefore, part of the Canon MRI users group. This has been wonderful, and then we had Dr. Liu relocate to work with us, which has been yet another big step in the relationship with Canon Medical Systems.”

“We have to adopt a global view of the fact that this is a systemic infection, and we must look for possible consequences outside the lungs, and even outside the heart, and be open to chronic sequela that are not/were not obvious at the time of the acute infection,”

Dr. Joao Lima, Director of Cardiovascular Imaging and Professor of Medicine
Johns Hopkins University, USA

Acting as a system

The Johns Hopkins Hospital has always been the center of a large network of hospitals in Maryland. Currently, there are five hospitals - two in Washington DC, one midway between Baltimore and DC, and the other two in Baltimore. Johns Hopkins Hospital is well-known as a place where more novel procedures or more challenging therapies happen or are attempted.

“COVID-19 is actually a very good opportunity to demonstrate that we are connected as a system, because we acted as a system,” said Dr. Lima. “We tried to bring the more severe patients to the central hospital and now most of the technology is quite distributed, so all the hospitals function at all levels. However, during the first wave of the pandemic, the most severe cases in Baltimore, or even in Maryland, were brought to Johns Hopkins. So we have a lot of records on the most severe cases. We have a very large network of physicians that are affiliated to Johns Hopkins, and so a lot of asymptomatic patients were taken care of outside the hospital, but they were tested in our system and they had information in our IT system, so that we can use that to leverage the ability to study individuals, who were symptomatic, but not admitted. That's what we hope to leverage in the future.”

Continuing challenge

While the challenges of the COVID-19 pandemic continue, research with such a strongly collaborative basis is contributing to fighting the world’s current health crisis. //

References
1 Thirunavukkarasu Sathish PhD, Nitin Kapoor MD, Yingting Cao PhD, Robyn J. Tapp PhD, Paul Zimmet PhD. 2020. “Proportion of newly diagnosed diabetes in COVID-19 patients: A systematic review and meta-analysis“. Diabetes, Obesity and Metabolism 23(3):870-874.
2 Saurabh Rajpal, Matthew S Tong, James Borchers, Karolina M Zareba, Timothy P Obarski, Orlando P Simonetti, Curt J Daniels. “Cardiovascular Magnetic Resonance Findings in Competitive Athletes Recovering From COVID-19 Infection”. JAMA Cardiol. 2021;6(1):116-118.

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