What is long COVID?

The pathogen responsible for the coronavirus pandemic of 2019 (COVID-19) is severe acute respiratory syndrome coronavirus (SARS-CoV-2). It is known that SARS-CoV-2 attacks multiple organs, which introduces a variety of symptoms to infected patients. As the pandemic has progressed, patients who have recovered from acute COVID-19 are reporting prolonged effects, which have been grouped together under the term post-acute sequel COVID-19 – or “long COVID”. The United Kingdom National Institute for Heath and Care Excellence (NICE) has categorized long COVID as chronic symptoms, also known as sequelae, lasting from four to 12 weeks after recovery from acute COVID-19.¹ Considering the wide variety of symptoms experienced by patients with long COVID, including symptoms related to the patient’s hematology and pulmonary system, there has been discussion regarding the potential risk of pulmonary embolism (PE) associated with long COVID.

Diagnosis of long COVID

Due to the recent emergence of the condition, there are only general criteria for diagnosing long COVID. Most people with long COVID tend to be PCR-negative for the virus, indicating a complete microbiological recovery.¹ However, if symptoms continue three weeks after microbiological recovery from acute COVID-19, the patient has not “clinically recovered”.¹ Thus, a patient can be diagnosed with long COVID if the patient was once infected with the SARS-Cov-2 virus and symptoms are present after the expected period of clinical recovery.¹

Pulmonary and hematologic sequalae of long COVID

Long COVID’s most prominent pulmonary sequelae include persistent breathlessness (also known as dyspnea), lower oxygen saturation in arterial blood (hypoxia), and decreased exercise tolerance.² Analysis of the lung tissue of patients who experienced severe acute COVID-19-associated pneumonia suggest that patients with post-acute COVID-19 may have accelerated lung fibrosis.³ Another study found that fibrotic radiographic abnormalities were present on CT scans performed four months after hospitalization in 72% of previously mechanically ventilated individuals, but in only around 20% of CT scans of patients who had not been mechanically ventilated.⁴

Regarding hematologic sequelae, the risk of thrombotic complications seems to be linked to the severity and the duration of a hyperinflammatory state during acute COVID-19.⁵ Markers of dysregulated inflammation, namely, damaged erythrocytes, hyperactivated platelets, and large anomalous amyloid deposits – also known as micro-clots, are commonly found in the lungs of acute COVID-19 patients. This may lead to thrombosis as well as thrombocytopenia which can be associated with disseminated intravascular coagulation (DIC), a serious condition that causes diffuse blood clotting in blood vessels. However, it is not currently known whether these changes persist in patients with long COVID.

The hematologic consequences of acute COVID-19 have led some to ask whether long-COVID may also be associated with an increased risk of PE. Long COVID-19 patients exhibit evidence of hypercoagulation and platelet hyperactivation.⁶ Plasma samples from patients with prolonged COVID-19 also display micro clots.⁴ Researchers have also observed enhanced thrombin generation and elevated levels of plasma FVIII:C (a clotting protein important in thrombin formation) in convalescent COVID-19 patients compared to healthy controls.⁷ Further evidence for hypercoagulability comes from reports of persistently elevated levels of D-dimer (a protein a byproduct of clot degradation) in about 25% of recovered COVID-19 patients up to four months after recuperation from acute infection, regardless of whether the patient was hospitalized.¹² In a separate study, researchers in the UK studied COVID-19 patients who had abnormal laboratory tests on discharge from the hospital. In this analysis, 30.1% of 229 patients had elevated D-dimer and 9.5% of 190 patients had elevated C-reactive protein on follow up testing (median 54 days post-discharge).⁷ It is important to note, however, that changes in biomarkers does not necessarily mean that patients with long-COVID have an increased risk of thrombotic complications. D-dimer is frequently elevated in otherwise healthy individuals, so it remains unclear whether increased levels of D-dimer in patients with long-COVID experience an increased frequency of clot formation, such as PE.

Treatment, management, and outlook

Unfortunately, due to insufficient understanding of long COVID’s pathology, there are a limited number of treatment options available. Despite the uncertainty about the optimal management of patients afflicted with long COVID, numerous countries have developed clinical guidelines to assist clinicians in monitoring patients and providing multidisciplinary care. This care may involve long-term monitoring of symptoms, physical rehabilitation, mental health and social services support.⁷ Furthermore, the use of digital technologies as part of the public health response to the COVID-19 pandemic has allowed clinicians to survey the population, identify cases, trace contracts, and evaluate the need for clinical intervention. Applying technology to manage patients is also allowing clinicians to monitor patients with long COVID. The use of digital technologies has also allowed the collection of electronic patient-reported outcome data and other measures important for potentially identifying at-risk patients.

Thus, handling and managing convalescent COVID-19 patients that have been discharged from the hospital has become an important priority for professional organizations, and as a result, is constantly evolving. As we increase our knowledge of the prolonged effects of COVID-19, we may identify suitable treatments for patients suffering from post-acute COVID-19 and prevent complications like PE.

References

1. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome [Internet]. Nature News. Nature Publishing Group; 2021. Available from: https://www.nature.com/articles/s41591-021-01283-z
2. Aiyegbusi OL, Hughes SE, Turner G, Rivera SC, McMullan C, Chandan JS, et al. Symptoms, complications and management of Long Covid: A Review [Internet]. Journal of the Royal Society of Medicine. SAGE Publications; 2021. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450986/
3. Luger AK, Sonnweber T, Gruber L, Schwabl C, Cima K, Tymoszuk P, et al. Chest CT of Lung Injury 1 Year after COVID-19 Pneumonia: The CovILD Study. Radiology. 2022.
4. Aiyegbusi OL, Hughes SE, Turner G, Rivera SC, McMullan C, Chandan JS, et al. Symptoms, complications and management of Long Covid: A Review [Internet]. Journal of the Royal Society of Medicine. SAGE Publications; 2021. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450986/
5. Grist JT, Author AffiliationsFrom the Department of Physiology, SJ H, Et Al, A C, VO P, et al. Hyperpolarized 129xe MRI abnormalities in DYSPNEIC patients 3 months after COVID-19 pneumonia: Preliminary results [Internet]. Radiology. 2021. Available from: https://pubs.rsna.org/doi/10.1148/radiol.2021210033
6. Mandal, S., Barnett, J., Brill, S.E., Brown, J.S., Denneny, E.K., Hare, S.S., Heightman, M., Hillman, T.E., Jacob, J., Jarvis, H.C., Lipman, M.C.I., Naidu, S.B., Nair, A., Porter, J.C., Tomlinson, G.S. and Hurst, J.R. ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax, p.thoraxjnl-2020-215818. doi:10.1136/thoraxjnl-2020-215818.
7. Pretorius E, Vlok M, Venter C, Bezuidenhout JA, Laubscher GJ, Steenkamp J, et al. Persistent clotting protein pathology in long COVID/post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin – cardiovascular diabetology [Internet]. BioMed Central. BioMed Central; 2021. Available from: https://cardiab.biomedcentral.com/articles/10.1186/s12933-021-01359-7
8. Late‐onset hematological complications post Covid‐19: An emerging medical problem for the hematologist [Internet]. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajh.26384
9. Proal AD, VanElzakker MB. Long Covid or post-acute sequelae of COVID-19 (PASC): An overview of biological factors that may contribute to persistent symptoms [Internet]. Frontiers. Available from: https://www.frontiersin.org/articles/10.3389/fmicb.2021.698169/full
10. Raveendran AV, Jayadevan R, Sashidharan S. Long COVID: An overview [Internet]. Diabetes & metabolic syndrome. Diabetes India. Published by Elsevier Ltd.; 2021. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056514/
11. McGroder CF, Zhang D, Choudhury MA, Salvatore MM, D’Souza BM, Hoffman EA, et al. Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length. Thorax. 2021; thoraxjnl-2021-217031.
12. Townsend L, Fogarty H, Dyer A, Martin‐Loeches I, Bannan C, Nadarajan P, et al. Prolonged elevation of D‐dimer levels in convalescent COVID‐19 patients is independent of the acute phase response. Journal of Thrombosis and Haemostasis. 2021; 19(4):1064–70.