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Long COVID: What is it?
Also referred to as post-acute sequelae of COVID-19 (PASC), “long COVID” is a commonly-used term that is deployed to describe the multisystemic symptoms and complications that some sufferers of COVID-19 experience after a severe infection with the SARS-CoV-2 virus.
Some people continue to experience symptoms of COVID-19 for months or even longer, even though most recover within a few weeks. The current estimate is that around 10% of infected individuals suffer from long COVID, equivalent to at least 65 million individuals worldwide.
The incidences of long COVID are higher in hospitalized people (totaling approximately 50-70% of the cases). There is no cure or treatment for long COVID, and the exact causes of the condition are still not fully understood. This article explores the pathophysiology of long COVID alongside the preclinical animal models that can be used to test candidate treatments and better understand this condition.
Long COVID: Symptoms and underlying causes
Multiple organ systems can be affected by long COVID, including the cardiovascular, respiratory, gastrointestinal, and neurological systems. Long COVID includes a range of common symptoms, including chest pain, nausea, memory loss, tinnitus, reproductive system dysfunction, fatigue, shortness of breath, palpitations, abdominal pain, and cognitive impairment.
The causes of these and other symptoms are still being investigated, but from preliminary analysis, there are suspected to be multiple and potentially overlapping. Contributors to the pathogenesis, it has been suggested, may include:
- Maintenance of long-term SARS-CoV-2 reservoirs in the tissues, such as the brain or heart
- Immune system dysregulation, such as autoimmunity
- Impact on the microbiota
- Dysregulation of coagulation
Persistent infection may damage tissues and chronic inflammation and result in long-term symptoms.
There are specific difficulties in the long-term monitoring of such “mild COVID-19” patients, such as that most long COVID patients were not hospitalized for their initial SARS-CoV-2 infection.
Diagnosing and testing for long COVID raises many challenges, such as gaps in the identification and follow-up of this specific group of patients and a certain lack of knowledge of the non-respiratory sequelae of COVID-19 among health professionals.
Preclinical models: Long COVID
Experimental exploration of the pathophysiology of long COVID is vital, considering the current partial understanding of this complex disease. Therefore, the preclinical development of effective therapeutic interventions requires better mimicking of the symptoms in laboratory models.
Major efforts were initiated to provide access to various laboratory animal models soon after the onset of the SARS-CoV-2 pandemic. These efforts were based on previous work done during the SARS-CoV outbreak and included golden Syrian hamster models, (genetically modified) mouse models, ferrets and non-human primates.
It must be stated that neither of these models are able to replicate all of the aspects of the human disease, given that each species tends to grow a fixed severity of symptoms. The heterogeneity in symptoms and severity of disease observed in humans, in other words, cannot be observed in its totality within one given animal model. Despite this drawback, these animal models typically show a viral presence in tissues outside the airways, such as the heart, kidneys, gastrointestinal tract, and central nervous system.
Moreover, in animals such as hamsters, long-term damage has been reported in lungs and other tissues, particularly the brain, heart, and kidneys. This damage could result from excessive local immune responses or local viral replication. Based on this long-term and multi-organ disease profile, such experimental models are attractive for studying long COVID. Only certain aspects of long COVID (Figure 1) may be suitably replicated by each available species model.
Figure 1. Animals models for specific aspects of long COVID. Image Credit: Oncodesign Services
A complex multisystem condition still poorly understood, long COVID significantly impacts the quality of life of affected individuals. Developing successful treatments for this condition is crucial, and deciphering long COVID pathophysiology is an enormous part of this research. We know that preclinical models are vital tools in understanding the mechanisms underpinning long COVID and testing potential treatments, so careful selection of the optimal model is needed depending on the research in question.
References and further reading
Davis HE et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. (2023), 21:133. https://pubmed.ncbi.nlm.nih.gov/36639608/
Frere JJ et al. SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations after recovery. Sci Transl Med. (2022), 14:eabq3059. https://pubmed.ncbi.nlm.nih.gov/35857629/
Jansen EB et al. After the virus has cleared – Can preclinical models be employed for long COVID research? PLoS Pathog. (2022), 18:e1010741. https://pubmed.ncbi.nlm.nih.gov/36070309/
Käufer C et al. Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model. EBioMedicine (2022), 79:103999. https://pubmed.ncbi.nlm.nih.gov/35439679/
Munoz-Fontela C. et al. Animals models for COVID-19. Nature (2020), 586:509. https://pubmed.ncbi.nlm.nih.gov/32967005/
Part of Figure 1 was created with BioRender.com
About Oncodesign Services
Oncodesign Services is a Contract research organization (CRO) specializing in drug discovery and preclinical services. From target identification to IND filing, the company contributes to the development of innovative therapies in oncology, inflammation and infectious diseases, with high medical needs.
Through integrated capabilities in medicinal chemistry, DMPK, pharmaco-imaging, bioanalysis, in vivo/In vitro pharmacology, Oncodesign Services support the R&D programs of customers with a global footprint.
Based in Dijon, France, in the heart of the university and hospital cluster and within the Paris-Saclay cluster, Oncodesign Services has 230 employees in France, Canada and the United States.
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