Long/Post-Covid – An Interdisciplinary Challenge

Abstract

Background

In this overview we summarize the current state of scientific knowledge on the epidemiology, etiology, clinical symptoms and therapy of post-COVID disease.

Methods

The study is based on a search of the scientific literature available on PubMed and on our own clinical experience in the post-COVID outpatient clinic.

Conclusion

The prevalence of post-COVID disease varies greatly depending on the survey method used. The symptoms of post-COVID are manifold, but fatigue, cardiopulmonary complaints, cognitive deficit, and pain syndromes are prominent. There are currently no surefire symptoms or specific markers that prove the presence of the disease. Therefore, diagnosis is often based on an exclusion of other diagnoses, which requires good interdisciplinary cooperation. Therapy for post-COVID disease is also not specific but is always individual and symptom-oriented. There have been various attempts to explain the pathogenesis of post-COVID, but the mechanisms behind the development of the condition have not yet been conclusively clarified. Persistence of the virus or of viral proteins may cause protracted infection or autoimmunity. Infection and inflammation of the endothelium of the small vessels and the hypercoagulation associated with this may lead to local cytokine dysregulation and organ damage. Further clarification of the pathogenesis of post-COVID and the establishment of effective diagnostic tools and therapeutic approaches are urgently needed.

Key Points

• Post-COVID is a commonly reported condition with variable symptoms

• Interdisciplinary exclusion of other diagnoses and therapy planning are important

• Clarification of pathogenesis and establishment of diagnostic markers are urgently needed

Citation Format

• Reisinger EC, Geerdes-Fenge H, Wossidlo C et al. Long/Post-Covid – An Interdisciplinary Challenge. Rofo 2025; DOI 10.1055/a-2578-1363

Keywords

Long-COVID - Post-COVID - SARS CoV-2 - COVID-19 - pathogenesis - diagnosis

Radiology provided initial information about the pathogenesis of long COVID and post-COVID disease. In the spring of 2020, shortly after the start of the pandemic, there were numerous reports around the world of pulmonary artery embolisms (PAE), thereby providing initial information about coagulation defects as a consequence of COVID-19 disease [1] [2]. Deep vein thrombosis, venous thromboembolisms, and pulmonary embolisms were frequently observed. Endotheliitis with microthrombi in various organs, e.g., in the heart or the kidney, was described in histological reports [3].

Long COVID and post-COVID are defined differently by the various international expert committees. The British National Institute for Health and Care Excellence (NICE) defines long COVID as new or ongoing symptoms that last four weeks or more after the acute phase of a SARS-Cov-2 infection [4]. Symptoms lasting more than 12 weeks after the onset of a SARS-CoV-2 infection that cannot be otherwise explained are described as post-COVID syndrome [5]. The German S1 guidelines “Long/Post-COVID” also use this time frame, but the main focus is on post-COVID syndrome [6]. This article uses the more comprehensive term post-COVID.

The frequency of post-COVID is 2–89% in the literature with reports ranging from systematic studies to self-reported patient symptoms [7] [8]. Based on the ICD-10 diagnosis code for “Post-COVID-19 condition” (PCC), the frequency was 2% in a Swedish cohort study [9].

A causality of post-COVID currently cannot be proven. Diagnosis is often based on exclusion. Post-COVID syndrome includes symptom complexes resulting from a COVID-19 infection, or diseases occurring at the same time as or after a COVID-19 infection, or preexisting conditions that may have been exacerbated by the COVID-19 infection. These cases should be differentiated from patients treated for a COVID-19 infection in the ICU experiencing persistent symptoms solely due to their hospitalization in the ICU [10].

The symptoms of post-COVID are diverse, but there are some typical symptoms that indicate the diagnosis. Four main symptoms (clinical phenotype cluster) have been identified: Fatigue, cardiopulmonary symptoms like dyspnea and tachycardia, cognitive impairment, and pain. Other symptoms are typically grouped around these four main symptoms. Many patients report post-exertional malaise (PEM) and persistent loss of smell and taste [11] [12] [13]. The more frequently COVID-19 is contracted, the greater the disease burden in terms of hospitalizations, symptoms, and secondary diseases [14].

Post-acute infection syndromes (PAIS) with similar symptoms to those described in post-COVID are also seen after other viral diseases. For example, fatigue, neurocognitive impairment, and pain have also been reported in the case of post-Ebola, post-Dengue, post-EBV, and post-Polio. The symptoms last months to years with the number and severity of symptoms decreasing significantly over 1–2 years. In light of the similarity in symptoms, the possibility of similar pathomechanisms among PAISs should be considered [15] [16].

Various attempts have been made to explain the pathogenesis of post-COVID. One controversial hypothesis discusses the role of the persistence of SARS CoV-2 or other viruses (e.g., EBV) or their virus proteins, which can result in protracted infections and possibly autoimmunity. Endotheliitis and hypercoagulation could result in local cytokine dysregulation and organ damage [17]. Dysbiosis in the microbiome of the bowel with an increase in diverse bacteria (e.g., ruminococcus among others) has also been discussed by some authors [18].

Endothelial infection and microthrombi result in the activation of coagulation factors and cytokines (Von Willebrand factor, ICAM1, ADAM TS13, etc.) and activation of a pro- and anti-inflammatory cytokine cascade, causing inflammation and tissue damage around the vessels [19].

Other neurotransmitters are then responsible for organ-specific damage in individual organs. For example, eotaxin (CCL-11), which is elevated in various neurological diseases like in cognitive impairment and neurodegeneration, is produced in the brain by microglia [20]. Secondary damage can occur in the lung due to thromboembolisms or the development of pulmonary fibrosis [21].

Antibodies ranging from ACE-receptor-specific antibodies to prothrombotic anti-phospholipid antibodies can also play a role as a tissue damage trigger [17]. An interesting hypothesis is the formation of neoantigens when virus proteins bind with the body’s own proteins resulting in a new immunologically active protein. These antibodies then attack the body’s own structures. This could play a role in SARS-induced diabetes [22].

Both treatment with the antiviral drug Paxlovid and COVID-19 vaccination can significantly reduce the risk of COVID-19 infections and thus post-COVID [23].

An evaluation of post-COVID condition (PCC) coded as ICD-10 (U09.9) in a Swedish cohort study including 649,071 patients showed a reduction in post-COVID of 21% after one vaccination, 59% after two vaccinations, and 73% after three vaccinations [9]. This reduction has been confirmed by numerous other studies [24].

Various risk factors for post-COVID are being discussed. Female sex, more than five early symptoms, early onset of dyspnea, and prior psychiatric diseases seem to be favorable conditions for the development of post-COVID [25]. The typical sex distribution was also seen in our post-COVID clinic at the university hospital: 72% female, 28% male. The percentage of girls in a study on post-COVID in children was 56% [26].

A specific diagnosis of post-COVID disease is currently not possible since there are no specific markers indicating the disease. Therefore, the diagnosis is often based on exclusion, which requires good interdisciplinary collaboration. [Table 1] shows a summary of organ-related diagnostic techniques in relation to post-COVID-associated symptoms and complications.

Table 1 Various organ systems that can be affected by post-COVID-19 and diagnostic methods for detecting complications (table based on data from [27]).

Affected organ system	Diagnostic methods
Pulmonary	X-ray of the thorax, high-resolution CT (HRCT), CT pulmonary angiography (CTPA), pulmonary function tests
Cardiovascular	Electrocardiogram (ECG), echocardiogram (ECHO), cardiac MRI, biomarkers (troponin, NT-proBNP), stress echo
Renal (kidneys)	Serum creatinine, glomerular filtration rate (GFR), renal ultrasound, biomarkers for acute kidney injury (AKI), and chronic kidney disease (CKD)
Neurological	Brain MRI, EEG (in case of seizure), neurocognitive tests for memory and attention disorders
Angiological (thrombosis)	D-dimer testing, Doppler ultrasound for deep vein thrombosis (DVT), angio CT for pulmonary embolism, antiphospholipid testing
Gastrointestinal (liver)	Liver function tests, abdominal ultrasound, CT/MRI of the liver
Endocrine (diabetes)	Blood sugar testing, HbA1c, insulin level testing
Musculoskeletal	X-ray, MRI for joint/muscle pain, bone density measurement (for osteoporosis)

As an example of lung imaging, [Fig. 1] shows rapid formation of pronounced post-COVID-associated pulmonary fibrosis with severe dyspnea in a 60-year-old patient after COVID pneumonia seen on primary imaging.

Fig. 1 60-year-old patient; a CT examination with a slice thickness of 3 mm was performed as initial diagnostic imaging due to suspicion of SARS-CoV-2 pneumonia. For further evaluation of post-pneumonia interstitial parenchymal changes, a high-resolution CT examination with a slice thickness of 1 mm was performed. a Chest CT without contrast (slice thickness: 3 mm) showing bilateral partially arcade-like ground-glass infiltrates, located primarily peripheral/subpleural and in the lower field. b 4 weeks later, chest CT with contrast (slice thickness: 1 mm) in the case of severe dyspnea; significant subpleural reticulations and traction bronchiectasis now visible in the areas of formerly present ground-glass infiltrates; thickened interlobular septa also visible in the case of persistent interstitial infiltrates.

[Fig. 2] shows CT images of a 76-year-old patient with COVID pneumonia and the development of mild fibrosis over the course of the disease.

Fig. 2 76-year-old patient with COVID-19 pneumonia and mild fibrosis on follow-up: a Chest CT with contrast (slice thickness: 1 mm) as initial imaging showing bilateral consolidated infiltrates with a peripheral and arcade-like configuration. b Initial follow-up chest CT without contrast (slice thickness: 1 mm) after 2 months showing regression of the consolidations. Persistent ground-glass opacities with subpleural and parapleural reticulations. c Chest CT with contrast (slice thickness: 1 mm) 6 months after initial imaging in the case of persistent dyspnea. Further regression of changes, only fine bands of subpleural reticulations with isolated adjacent areas of traction bronchiectasis are still visible.

As an example of cardiac imaging, [Fig. 3] shows COVID-19-associated acute myocarditis in a 36-year-old patient with visible scarring on the 9-month follow-up MRI scan.

Fig. 3 36-year-old patient with myocarditis after COVID infection: 1.5 Tesla MRI, short-axis sequences with two-chamber view; a T2-TIRM sequence showing edema of the myocardium from the midventricular to the distal third of the left ventricle in the inferoseptal segment (thin arrow) 14 days after positive PCR test. b Follow-up MRI examination after 9 months showing intramural scarring at the junction from the midventricular to the distal third of the left ventricle in the inferoseptal segment (thick arrow) in the PSMDE sequence.

[Fig. 4] shows the practical diagnostic approach.

Fig. 4 Primary care/general medicine approach in accordance with the S1 guidelines of the Association of the Scientific Medical Societies in Germany regarding post-COVID/long COVID.

During the corona virus pandemic, the RACOON project (Radiological Cooperative Network) was initiated by the German Radiological Society and the Federal Ministry of Education and Research to improve the networking of radiology databases. All university radiology departments in Germany are included in this cooperative project. Research institutes outside the university setting are also included in the list of network partners. This network makes it possible to conduct large multicenter studies and detailed image analyses so that the effects of COVID-19 on the lungs and other organs can be systematically evaluated even in later disease stages.

To determine the severity of post-COVID disease, a classification system allowing objective and comprehensive description of post-COVID symptoms, known as the Post-COVID-Syndrome Score (PCS Score) was developed as part of the NAPKON-POP cohort study COVIDOM [28].

Primary care is the starting point for the diagnosis and treatment of the diverse post-COVID symptoms. If further workup or treatment is needed, patients can be referred to the post-COVID outpatient clinics that have been established at many centers. Additional disciplines should be included in a coordinated manner.

The treatment of post-COVID disease is always individualized and symptom-based, in accordance with the S1 guidelines of the Association of the Scientific Medical Societies in Germany [6]. In the case of fatigue and respiratory symptoms, pacing strategies as well as relaxation and breathing exercises have proven helpful. Mild cognitive impairment can be treated with ergotherapy and cognitive performance therapy, possibly using a digital app. In the case of a loss of smell, olfactory training with defined scents is available. Pain is treated in accordance with the S1 guidelines “Chronic non-cancer pain” [29]. Medical rehabilitation under consideration of the individual capabilities is often useful [30] [31].

Informing patients of the pathophysiological connections can improve understanding among patients and reduce symptoms.

More than 450 clinical trials studying immunoadsorption, immunosuppression, and COVID-19 vaccinations and drugs can be found on the platform ClinicalTrials.gov (https://www.clinicaltrials.gov). The effect of all of these therapeutic measures against post-COVID has not yet been proven. The use of medications being tested for post-COVID outside of clinical studies is considered “off label” use. These medications can only be prescribed on an individual basis and should not be advertised.

Mecklenburg-Vorpommern approved research funding for the creation of outpatient clinics for cross-sector networking, treatment research, and basic research. Post-COVID outpatient clinics were able to be successfully established at the two university sites and multiple research projects were able to be initiated. Many national and international projects on long COVID and post-COVID have been conducted in recent years thanks to funding from the German Research Society, Federal Ministry of Education and Research, the Federal Joint Committee, and the EU. A funding announcement was also published by the Federal Ministry of Health in March 2024 to improve the care of those patients affected by post-COVID in Germany.

In summary, post-COVID is a heterogeneous disease and its causality is very difficult to prove. The frequency of post-COVID varies greatly depending on the type of data collection and is expected to decrease if herd immunity is maintained through infection and vaccination. The most common symptoms are fatigue, dyspnea, cognitive dysfunction, and pain. These can currently be treated on a symptomatic basis. Since the disease must be treated in an interdisciplinary manner, effective cross-discipline patient care is essential.

At present, the pathogenesis can most likely be attributed to endothelial damage and autoimmunity. Clinical and experimental research approaches are very broad and are currently searching relatively unsystematically for “multiple needles in a haystack”.

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 Geerdes-Fenge H, Reisinger EC, Arndt H. Pulmonary Artery Embolism in COVID-19 Despite Thrombosis Prophylaxis. Dtsch Ärztebl Int 2020; 117: 297
• 2 Sedlaczek O, Wagner W, Dempfle CE. Koagulopathien und thromboembolische Manifestationen. Radiologe 2021; 61: 909-914
• 3 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395: 1417-1418
• 4 Venkatesan P. NICE guideline on long COVID. Lancet Respir Med 2021; 9: 129
• 5 WHO. A clinical case definition of post COVID-19 condition by a Delphi consensus. 2021 https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1
• 6 Koczulla AR, Ankermann T, Behrends U. et al. AWMF S1-Leitlinie Long/Post-COVID. Registernummer 020 – 027: Version 4.1. 2024
• 7 Nittas V, Gao M, West EA. et al. Long COVID Through a Public Health Lens: An Umbrella Review. Public Health Rev 2022; 43: 1604501
• 8 Lopez-Leon S, Wegmann-Ostrosky T, Perelman C. et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep 2021; 11: 16144
• 9 Lundberg-Morris L, Leach S, Xu Y. et al. Covid-19 vaccine effectiveness against post-covid-19 condition among 589722 individuals in Sweden: population based cohort study. BMJ 2023; 383: e076990
• 10 Rasulo FA, Piva S, Latronico N. Long-term complications of COVID-19 in ICU survivors: what do we know?. Minerva Anestesiologica 2022; 88: 72-9
• 11 Gentilotti E, Górska A, Tami A. et al. Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort. EClinicalMedicine 2023; 62: 102-107
• 12 Jennings G, Monaghan A, Xue F. et al. A systematic review of Persistent Symptoms and Residual Abnormal Functioning Following Acute COVID-19: Ongoing Symptomatic Phase vs- Post-COVID 19 Syndrome. J Clin Med 2021; 10: 5913
• 13 Vernon SD, Hartle M, Sullivan K. Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Work 2023; 74: 1179-1186
• 14 Bowe B, Xie Y, Al Aly Z. Postacute sequelae of COVID-19 at 2 years. Nat Med 2023; 29: 2347-2357
• 15 Choutka J, Jansari V, Hornig M. et al. Unexplained post-acute infection syndromes. Nat Med 2022; 28: 911-923
• 16 Leung AKC, Lam JM, Barankin B. Infectious Mononucleosis: An Updated Review. Curr Pediatr Rev 2024; 20: 305-322
• 17 Altmann DM, Whettlock EM, Liu S. et al. The immunity of long COVID. Nature Reviews Immunology 2023; 23: 618-634
• 18 Vojdani A, Vojdani E, Saidara E. et al. Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID. Viruses 2023; 15: 400
• 19 Reisinger EC, Fritzsche C, Krause R. et al. Diarrhea caused by primarily non-gastrointestinal infections. Nature Clin Pract Gastroenterol Hepatol 2005; 2: 216-22
• 20 Ivanovska M, Abdi Z, Murdjeva M. et al. CCL11 or EO. An immune marker for ageing in neuro-psychiatric disorders. Pharmaceuticals (Basel) 2020; 13: 230
• 21 Singh SJ, Baldwin MM, Daynes E. et al. Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation. Lancet Respir Med 2023; 11: 709-725
• 22 Sharma C, Hamza A, Boyle E. et al. Post-Translational Modifications and Diabetes. Biomolecules 2024; 14: 310
• 23 Xie Y, Choi T, Al-Aly Z. Association of treatment with nirmatrelvir and the risk of post-COVID-19 condition. JAMA Intern Med 2023; 183: 554-564
• 24 Byambasuren O, Stehlik P, Clark J. et al. Effect of covid-19 vaccination on long covid: systematic review. BMJMED 2023; 2: e000385
• 25 Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond) 2021; 53: 737-754
• 26 Buonsenso D, Espuny Pujol F, Munblit D. et al. Clinical characteristics, activity levels and mental health problems in children with long coronavirus disease: a survey of 510 children. Future Microbiol 2022; 17: 577-588
• 27 Mohan A, Mittal S. , ed. Post COVID-19 Complications and Management. Singapore: Springer; 2022
• 28 Bahmer T, Borzikowsky C, Lieb W. et al. Severity, predictors and clinical correlates of Post-COVID syndrome (PCS) in Germany: A prospective, multi-centre, population-based cohorty study. EClinicalMedicine 2022; 51: 101549
• 29 Becker A, Straßner C. AWMF S1-Leitlinie Chronischer nicht-tumorbedingter Schmerz. Registernummer 053 – 036: Version 2.0. Stand 30.11.2023.
• 30 Daynes E, Gerlis C, Chaplin E. et al. Early experiences of rehabilitation for individuals post-COVID to improve fatigue, breathlessness exercise capacity and cognition – A cohort study. Chron Respir Dis 2021; 18: 14799731211015691
• 31 Hayden MC, Limbach M, Schuler M. et al. Effectiveness of a Three-Week Inpatient Pulmonary Rehabilitation Program for Patients after COVID-19: A Prospective Observational Study. Int J Environ Res Public Health 2021; 18: 9001

Publication History

Received: 18 July 2024

Accepted after revision: 31 March 2025

Article published online:
23 May 2025