While the COVID-19 pandemic, in at least some parts of the world, is slowly shifting towards a potentially more manageable endemic phase, many questions and concerns regarding the consequences of a COVID-19 infection remain.

A particularly burning one relates to long COVID, that puzzling constellation of symptoms that linger long after the actual infection. What do we know at this stage? What are potential implications? And, what lessons can be gleaned regarding the role we, the medical imaging community, can play?

In this article I’ll walk you through what long COVID is, our current understanding of the potential underlying mechanisms and consequences of multi-organ injury, the role of imaging, and conclude with my key takeaways.

Both in our professional and private lives, we have all been confronted with long COVID. Whether it has been patients, friends or maybe even ourselves, we all know someone who months after the COVID-19 infection still hasn’t quite returned to normal, despite not having been very sick or having any prior health issues. It leaves us with many questions regarding the sheer size of the problem and its cause but also motivates us to discover potential ways to better diagnose and treat this condition. In the next paragraphs, we will zoom in on long COVID, the potential pathways of multi-organ injury and update you on how imaging is being used in clinical practice and how research in this field may dramatically change its utilization.

The term post-COVID syndrome, or long COVID or post-acute sequelae of SARS-CoV-2 (PASC) syndrome, is used when a patient presents with signs and symptoms developed during or after an infection consistent with COVID-19 four or more weeks after the acute COVID-19 illness ¹. Basically, it can be considered as a lack of return to the usual state of health following COVID-19 infection ². Approximately 10% to 30% of COVID-19 patients appear to be affected, although estimates vary widely. Importantly, many of these patients were not hospitalized or even experienced only mild symptoms during the acute phase. Nonetheless, months after infection, persons with long COVID are confronted with being limited in their daily activities and experience a range of symptoms such as fatigue, shortness of breath, muscle aches and headaches.

Long term effects from COVID-19. Image reproduced from Lopez-Leon et al. ³, under the Creative Commons Attribution 4.0 International License.

Several pathophysiological mechanisms may drive long COVID. In fact, long COVID may rather be a constellation of several syndromes, which can even overlap in a single patient. Likely contributors are injury to organs during the acute phase and exacerbations of pre-existing conditions. While in the acute phase COVID-19 mostly presents as a respiratory disease, we soon recognized that the disease also impacted other organs. COVID-19 infection has been associated with an increased risk of extrapulmonary complications such as stroke, cardiac damage or renal failure, driving awareness of a far more systemic nature of the disease as well with endothelial damage, thrombo-inflammation, and immune response dysregulation as possible underlying pathways ⁴. The knowledge that an infection can have pro-inflammatory and pro-thrombotic effects throughout the body which are mediated through the immune system is essentially not new ⁵. Influenza for example has been known to cause progression of atherosclerosis and increase risk of cardiovascular complications. Beyond the acute phase, persistent reservoirs of SARS-CoV-2 in certain tissues could also be a potential contributor to lingering symptoms over time as seen with other viruses. However, never has the world been confronted with these effects on such a large scale and affecting so many persons. Certainly, long COVID challenges our predominant focus on short-term COVID-19 infection management strategies as well as corresponding metrics like number of deaths and hospitalizations.

To better understand the natural course of disease and long term implications of COVID-19 infection, imaging nowadays plays a crucial role. Evaluation of the lungs has been central from the start. Advanced imaging techniques, such as CT and MRI, may identify changes that are not evident on standard imaging techniques ^6,7. Such observations could help understanding symptoms like prolonged breathlessness and offer directions for more targeted treatment. Beyond the lungs, researchers worldwide have embarked on multi-organ imaging protocols. Amongst them, Dr. Yoko Kato and colleagues from Johns Hopkins School of Medicine developed a comprehensive state-of-the-art MRI protocol. As she recently explained during an online Canon webinar ⁸, the protocol provides a full characterization of the COVID-19 consequences on brain, lung, heart and liver imaging.

She observed that post-COVID patients even in the absence of symptoms show abnormalities in multiple organs, although their clinical relevance remains unclear. Similar observations are emerging from European studies as well, showing that persistent abnormalities not only in the lungs but also other organs are highly prevalent. One study, performing MRI on patients who had been hospitalized, observed abnormalities in the lungs (60%), heart (26%), liver (10%) and kidneys (29%), while also changes in various brain regions were observed, providing a potential explanation for the high rate of breathlessness, fatigue and limited exercise capacity observed in this cohort ⁹. The extent of abnormalities were linked to the severity of disease during the acute phase. However, even in patients that were mainly at lower risk for severe COVID-19 illness and not hospitalized, abnormalities in multiple organs have been identified through imaging ^10,11. Whether these changes are permanent or whether some will resolve over time remains to be elucidated.

These observations raise the question whether individuals even after mild COVID-19 should undergo full assessment, including to some extent systematic organ screening. However, imaging is presently not frequently used except in severe cases or special situations like athletes. Patients with long COVID often face a lack of understanding and adequate response when seeking medical help. Moreover, our fragmented healthcare, with single organ specialties still mostly operating in silos, clashes with their need for a more holistic approach to managing their condition. Improving patient-centered models of care in long COVID ideally requires to set-up multidisciplinary teams and enabling them with appropriate resources and technological support.
Developing first-line management strategies also necessitates to translate observations from high-end imaging into practical solutions. Take for example the observation of subclinical reduction of cardiac function observed in patients with long COVID. Advanced high-end imaging technologies such as MRI may represent the most accurate techniques to assess cardiac contractility and play a crucial role in COVID-19 research. However, their use on a wide scale may not be pragmatic, as Professor Leopoldo Pérez de Isla from the Complutense University of Madrid pointed out during Canon’s webinar on long COVID ⁸. Alternatively, echocardiography could present a more accessible approach to identify subclinical cardiac dysfunction in large numbers of patients. Moreover, he continues, a system that is automated and easy to use will enable also non-expert users to perform sophisticated analyses. Indeed, it is exciting to see the rapid developments in AI, ranging from automation of workflows to improved image quality and diagnosis.

1. A constellation of syndromes
Long COVID appears to be a constellation of several syndromes which can even overlap in single patient.

2. Multi-organ imaging
In patients with long-COVID, not only the lungs are affected. Multi-organ imaging may play a crucial role in identifying changes throughout the body.

3. Integrated multidisciplinary approaches
The systemic impact of COVID-19 will require us to develop integrated approaches if we want to develop effective diagnostic and management strategies for patients with long COVID. Possible the lessons learnt will serve as examples to extend such integrated approaches to other conditions as well in order to further advance patient-centric care models.

4. Translation into practical solutions
Given the sheer number of individuals affected in combination with a healthcare system that is already under enormous pressure, our accumulating understanding of long COVID should be translated into solutions that are easily accessible and easy to use as part of first-line diagnostic strategies.

5. Collaboration
The pandemic has shown us how rapidly collaborative efforts can be initiated on a global scale. Also the importance of partnering between industry, academia, healthcare providers and governments has been put to the forefront. Innovative technologies such as AI and data analytics have great potential, but will fall short if they are developed without understanding of the daily clinical workflows and pressures or how the digital/human interaction should be configured. Ultimately, only by working together we can make clinically effective solutions a reality.


Listen to a full discussion on imaging and post-COVID conditions here.

References

1. IDSA. Post COVID Conditions (e.g. Long COVID) | Accessed Jan 24, 2022 https://www.idsociety.org/covid-19-real-time-learning-network/disease-manifestations--complications/post-covid-syndrome/#MOS
2. CDC. Post-COVID Conditions: Information for Healthcare Providers. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html
3. Lopez-Leon S et al. | More than 50 long-term effects of COVID-19: a systematic review and meta-analysis | Scientific reports (2021)
4. Gupta A et al. | Extrapulmonary manifestations of COVID-19. | Nat Med. (2020)
5. Libby P. et al. | Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week | Journal of the American College of Cardiology (2018)
6. Ohno Y et al. | Comparison of Xenon-Enhanced Area-Detector CT and Krypton Ventilation SPECT/CT for Assessment of Pulmonary Functional Loss and Disease Severity in Smokers | AJR American journal of roentgenology (2018)
7. Wild JM et al. | Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID) | BMJ Open Respir Res. (2021)
8. CANON MEDICAL WEBINAR| Post-COVID Conditions. https://eu.medical.canon/events_calendar/webinars/post-covid-conditions-webinar
9. Raman B et al. | Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge |EClinicalMedicine (2021)
10. Dennis A et al. | Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study | BMJ open (2021)
11. Petersen EL et al. | Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme | Eur Heart J. (2022)

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