Post-COVID Syndrome

Background: As defined by the WHO, the term post-COVID syndrome (PCS) embraces a group of symptoms that can occur following the acute phase of a SARS-CoV-2 infection and as a consequence thereof. PCS is found mainly in adults, less frequently in children and adolescents. It can develop both in patients who initially had only mild symptoms or none at all and in those who had a severe course of coronavirus disease 2019 (COVID-19).

Methods: The data presented here were derived from a systematic literature review.

Results: PCS occurs in up to 15% of unvaccinated adults infected with SARS-CoV-2. The prevalence has decreased in the most recent phase of the pandemic and is lower after vaccination. The pathogenesis of PCS has not yet been fully elucidated. Virus-triggered inflammation, autoimmunity, endothelial damage (to blood vessels), and persistence of virus are thought to be causative. Owing to the broad viral tropism, different organs are involved and the symptoms vary. To date, there are hardly any evidence-based recommendations for definitive diagnosis of PCS or its treatment.

Conclusion: The gaps in our knowledge mean that better documentation of the prevalence of PCS is necessary to compile the data on which early detection, diagnosis, and treatment can be based. To ensure the best possible care of patients with PCS, regional PCS centers and networks embracing existing structures from all healthcare system sectors and providers should be set up and structured diagnosis and treatment algorithms should be established. Given the sometimes serious consequences of PCS for those affected, it seems advisable to keep the number of SARS-CoV-2 infections low by protective measures tailored to the prevailing pandemic situation.

While the vast majority of patients recover from acute infection with SARS-CoV-2 without discernible sequelae, a proportion of patients experience long-term effects that can last for months (1, 2, 3, 4, e1). The World Health Organization (WHO) estimates that following the acute phase of infection, 10–20% of SARS-CoV-2-infected individuals complain of persisting or new-onset symptoms in the longer course, which is referred to as post-COVID syndrome (PCS) (e2). PCS affects patients that were asymptomatic or had only mild acute symptoms and who self-isolated at home as well as patients with moderate or severe disease that required hospitalization or care on an intensive care unit. The lack of control group in the numerous studies carries the risk of overestimating the prevalence of PCS (5, e45), since comparable symptoms potentially occurring in a control group are not included in the calculation. In principle, long-term sequelae can develop independently of severity and with or without demonstrable organ pathology. In the case of acute disease requiring intensive care, it may be difficult to differentiate PCS from post-intensive care syndrome (PICS), since the latter can be associated with similar clinical symptoms.

Methods

For the statement (6) on which this review article is based, the literature for the publishing period 2020–2022 was collated and reviewed in a structured, methodological review process (for a detailed description of the literature search, see eMethods, eTables 1–4). Searches were carried out between 19 July 2022 and 22 July 2022. The recommendations are based on these studies.

eTable 1

Guideline search

eTable 2

Evidence syntheses

eTable 3

Randomized controlled studies

eTable 4

Cohort studies

Definition

The terminology and definition of long-COVID and PCS is not standardized. The term “long-COVID” emerged as a hashtag on social media during the early phase of the pandemic and is still used there by the majority of people (7, e3). Since the term PCS has become established in the specialist literature, including the S1 guideline of the the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) (8), it will be used in the following. The WHO has developed the following definition of PCS by a Delphi consensus (9): The symptoms must still be present more than 12 weeks after acute infection and persist for at least 2 months. There can be no other etiological explanation. The clinical course may be persistent, relapsing, or fluctuating (ICD-10 U09.9).

Protracted symptoms in the second and third month following SARS-CoV-2 infection are classified as persistent symptomatic infection and delayed recovery, respectively. In such cases, the ICD-10 code U08.9 may indicate the need for healthcare in the context of COVID-19. The authors of this statement do not consider the exacerbation or aggravation of preexisting diseases as PCS in the narrower sense.

Causes

Although the pathogenesis of PCS is not yet fully understood, there is very good evidence to support diverse general as well as organ-specific causes, which will be presented below (10, 11, e4).

The many and diverse organ manifestations of SARS-CoV-2-related disorders are due, in part, to the broad tropism of the virus, which is defined by the distribution of the viral receptor. Cell entry of SARS-CoV-2 begins with its binding to the angiotensin-converting enzyme-2 (ACE2) receptor (12). The ACE2 receptor is abundantly present in tissues in the human body. It has been demonstrated in the lungs, kidneys, small intestine, olfactory neuroepithelium, heart, testes, muscle cells, and substantia nigra in the brain (13, e5, e6, e7, e8, e9). Accordingly, the number of organs in which the virus or viral components can be found is large. Infection typically begins on the mucous membranes of the mouth, nose, and lungs and can spread in the further course. The presence of ACE2 receptors in the vascular endothelium as well as the development of accompanying inflammatory and immunological processes provide a first possible explanation for the great diversity in the clinical manifestations of COVID-19 (e9).

Endothelial dysfunction

SARS-CoV-2 infection can cause vascular inflammation (11) that leads to impaired microcirculation and endothelial dysfunction (ED) (14). A third of patients with PCS exhibit ED in endothelial dysfunction testing (EndoPAT) as well as elevated levels of the potent vasoconstrictor endothelin-1 (ET-1) 6 months following mild COVID-19 (e10). ED can also cause changes to the retina (e11) and affect reproductive health (e12), for example, through new-onset erectile dysfunction (e13).

Viral persistence

A number of studies show that residual SARS-CoV-2 can persist for more than 6 months after the acute phase of COVID-19 (11), despite the fact that viral replication can no longer be demonstrated. One study showed a persistent spike 1 (S1) protein in CD16 + monocytes of patients with PCS (e14). The gut can be a reservoir for viral persistence—a link to PCS has not been investigated (15, e15). It is possible that persistent viral components cause ongoing inflammation that could ultimately lead to PCS.

Autoimmunity

Autoantibodies (AAB) are detectable not only during acute infection but also in PCS (16). For example, AAB against type-1 interferons as well as G-protein-coupled receptors (GPCR) that have an effect on the control of the autonomic nervous system (e16) have been detected in PCS patients (e16). Antineuronal AAB have been found in the cerebrospinal fluid of patients with neurological manifestations of PCS (e17). It was shown in a large collective that the detection of antinuclear antibodies (ANAs), interferon-alpha AAB, and proinflammatory cytokines in the acute phase correlated with the development of gastrointestinal or respiratory symptoms in the setting of PCS (e18).

Persistent inflammation

Persistent inflammation is an established pathomechanism in PCS (e19), even when SARS-CoV-2 infection and replication can no longer be detected. As long as 8 months following infection, PCS patients still show immunological abnormalities, characterized by an inflammatory cytokine signature, compared to non-infected individuals or patients infected with other viruses. In particular, persistent inflammation was observed in the lungs, heart, and central nervous system (17, e20, e21). A major aspect of persistent inflammation is the defective repair of the sequelae of inflammation (e22). In studies, this inflammatory cytokine signature has a positive predictive value of 79–82% for the development of long-term symptoms such as fatigue, dyspnea, or chest pain, and includes, for example, type I and type III interferons (18). PCS patients also exhibit altered activation patterns of monocytes, granulocytes, and dendritic cells (e21).

Psychosocial factors

In addition to the direct biological sequelae of SARS-CoV-2 infection consistent with a postviral syndrome, one must also consider psychosocial factors, which could either be, for example, the manifestation of separate mental illnesses or the result of measures taken to contain the pandemic. Not only the stressors associated with the effects of COVID-19 infection but also the measures taken against the pandemic can lead many people to develop new-onset mental illness or experience a worsening of existing mental health disorders (19). These stressors may be due to the situation arising from quarantine, loneliness, home office, home schooling, uncertainty about how the pandemic will evolve, threat to economic livelihood, or concern about relatives. This worsening is clearly linked not only to a reduction in the quality of medical care but also to unfavorable health-related behavior, for example, lower levels of physical activity, longer times spent in bed, and increased rumination. Negative effects of the pandemic and the measures for its containment have also been described for other mental illnesses, for example anxiety disorders and eating disorders, as well as for psychosocial stressors such as domestic violence and family conflicts. They result in greater utilization of mental health services (e23, e24). These associations are similar for children and adolescents.

Predisposing factors, risk factors, and protection through vaccination

The currently known risk factors for the development of PCS are summarized in the Box.

Box

Risk factors for post-COVID syndrome (2, 24, 33, 34, 35, 36, e41, e42, e43, e44)

SARS-CoV-2 vaccination appears to significantly reduce the risk of PCS (20, 21, 22). Overall, the presence of vaccination was associated with a lower risk or lower likelihood of PCS. Two vaccine doses appear to be more effective than one (20). Figures from the United Kingdom’s COVID Surveillance Study (as of 27.05.2022) (e25) show that triple vaccination can reduce the prevalence of PCS to below 5% (23). Individual susceptibility in adults for the development of PCS appears to be independent of the severity of the acute pulmonary and systemic disease (e26, e27).

Incidence

The variety and frequency of symptoms that can develop following the acute phase of SARS-CoV-2 infection are not always directly comparable across the various studies, given that the investigated cohorts differ in terms of size, selection process, and symptom recording. In addition, studies without control groups harbor the risk of overestimating PCS. In 10 UK longitudinal studies, the percentage of individuals presumed to have COVID-19 that reported long-term symptoms after more than 12 weeks was between 7.8 and 17% (with a total of 1.2–4.8% reporting debilitating symptoms) (24).

Assuming that approximately 5–15% of adult unvaccinated patients develop PCS, a relatively large number of individuals would be affected by PCS. With 22 million individuals having recovered from COVID-19 (as of August 2022), one can assume that statistically, the number of people with PCS in Germany would be several hundred thousand. One needs to bear in mind that this process is subject to dynamic changes that depend in particular on virus variants and the level of immunization in the population.

Symptoms, diagnosis, and treatment

Since the ACE2 receptor is expressed in many organs and COVID-19 manifests in multiple organs, PCS can also present with diverse clinical symptoms and organ manifestations (e21, e28) (Table). As a general rule, the main symptoms occurring in adults can also be observed in children and adolescents, albeit far more rarely (25). The course of the pandemic thus far has shown that symptoms and organ manifestations can change depending on the prevailing SARS-CoV-2 virus variant and the vaccination status of those infected (20, 21, 22, 23).

Table

Organ-related disorders with a morphological substrate in PCS

Since no specific diagnostic markers (for example, in blood) or characteristic imaging findings are known to date, the diagnosis of PCS needs to be made on the basis of clinical presentation. This can be particularly challenging in children and adolescents due to the limited self-reported patient history. A prerequisite of establishing the diagnosis of PCS is that the relevant symptoms were not already present prior to SARS-CoV-2 infection and that patients experience impairments in everyday life as well as a level of suffering, meaning that previous medical findings as well as the collaboration of the various healthcare providers take on central importance (Figure). Patients suffering from fatigue and exercise intolerance need to be assessed for myalgic encephalomeylitis/chronic fatigue syndrome (ME/CFS) on the basis of clinical diagnostic scores. Differentiation from depression is a common differential diagnostic question due to the 1-year incidence of depression of approximately 8% in the adult population.

Figure 1

Collaboration between the different care providers

A targeted assessment of findings, paying particular attention to new-onset symptom-related limitations, and the basic laboratory work-up are of crucial importance (8), since in many cases PCS represents a diagnosis of exclusion. The S1 guideline of the AWMF provides an overview of the individual organ manifestations and the initial assessment in suspected PCS (8). It is important to accurately record the various symptoms in order to offer patients tailored treatment and rehabilitation concepts aimed at shortening the recovery phase.

There are currently no evidence-based, causal, specific treatment options. Only scant interventional studies are available, and no therapeutic concept has been sufficiently validated to date (26). Therefore, no reliable recommendations can be made for numerous procedures, such as apheresis, vitamin replacement, and other pharmacological interventions. Current treatment concepts are based on an interdisciplinary, pragmatic approach that includes physical rehabilitation measures as well as symptom-oriented treatment of the various organ disorders. There are meta-analyses of randomized controlled studies on the efficacy and effectiveness of physical procedures in PCS that support symptom-oriented physical rehabilitation measures (26, 27, 28, 29, 30, e29). In the case of ME/CFS, all diagnostic and therapeutic measures need to be tailored to the often significantly limited physical capacity of individual patients. Pacing, that is to say, sparing, dosed management of the patient’s energy resources and strict avoidance of overexertion, is recommended.

Thus, it remains essential that targeted treatment approaches be identified in the future. Further studies are required on, for example, the effectiveness of vaccinations or the administration of antibodies against SARS-CoV-2 in PCS (e30). Initial results indicate a lasting improvement in PCS following a second vaccine dose, at least in the median follow-up period of 67 days (31).

Likewise in children and adolescents, treatment has thus far been symptom-oriented (32). In the case of interdisciplinary and, where appropriate, multimodal treatment, somatic and mental health aspects need to be taken into account, and physical capacity must be considered on a case-by-case basis.

Current structures and potential needs regarding PCS treatment and research

The sociomedical and economic impact of PCS cannot be foreseen but is likely to be immense. Since PCS is a multisystem disease, an interdisciplinary (including infectious diseases, internal medicine, neurology, psychiatry and psychotherapy, psychosomatics, pulmonology, cardiology, rheumatology, ENT, physical medicine and rehabilitation, general medicine, pain medicine, pediatrics) and intersectoral collaboration involving cooperation with general practitioners and specialists in pediatric and adolescent medicine seems imperative for the comprehensive care of these patients. Close cooperation is needed between primary care and specialist outpatient healthcare providers and centers in larger hospitals.

Against this backdrop, the following structures are required: For clinical care, specialized PCS centers need to be set up at maximum-care institutions (generally university hospitals), where specialists from a number of disciplines can provide comprehensive care (Figure 2). Structures of this kind already exist at some university hospitals in Germany (e31, e32, e33, e34, e35, e36, e37). These PCS centers should form regional PCS networks with local hospitals and practices or embrace existing networks in order to ensure the provision of care to the large number of primarily adult patients (e38, e39).

Figure 2

Understanding post-COVID syndrome—dimensions of scientific analysis (from [6]: reprinted with kind permission from the German Medical Association [Bundesärztekammer])

In addition to providing interdisciplinary care, the PCS centers should also collaborate on translational research efforts. The main focus will be to evaluate the concepts of the newly created care structures, to investigate the effects of more interdisciplinary treatment strategies on the course of the disease, and to develop diagnostic guidelines and novel treatments for PCS. Furthermore, the formation of a national PCS network that coordinates the collaboration of all important actors and is also the contact point for both science and policy is proposed.

For housebound or bedridden PCS sufferers, there is an urgent need to strengthen and expand telemedical and outreach care structures (for example, specialized outpatient palliative care [SOPC]).

In addition to providing interdisciplinary care, the PCS centers should collaborate on translational research with the aim of developing scientifically based diagnostic guidelines and novel PCS treatments as rapidly as possible.

The primary focus of this research should be a patient-oriented treatment approach (Figure 2) that will advance translational concepts at an internationally competitive level and within an international network as early on as possible.

Other collaborators

Prof. Dr. med. Reinhard Berner, Prof. Dr. med. Dr. h. c. Manfred Dietel,

Prof. Dr. med. Hans Drexler, Dr. med. Pedram Emami,

Dr. med. Christiana Franke, Dr. med. Johannes Grundmann,

Prof. Dr. med. Ulrich Hegerl, Prof. Dr. med. Karl Hörmann,

Dr. med. Susanne Johna, Univ.-Prof. Dr. med. Florian Klein,

Prof. Dr. med. Thea Koch, Prof. Dr. med. Wilhelm-Bernhard Niebling,

Prof. Dr. med. Johannes Oldenburg, Prof. Dr. med. Klaus Püschel,

Dr. med. Gerald Quitterer, Dr. med. (I) Klaus Reinhardt,

Dr. med. Anett Reißhauer, Prof. Dr. med. Carmen Scheibenbogen,

Prof. Dr. med. Stefan Schreiber, Dr. med. Martina Wenker,

Prof. Dr. med. Fred Zepp

Acknowledgments

The members of the Working Group would like to thank Professor Dr. med. Nicole Skoetz as well as Ana-Mihaela Bora, Caroline Hirsch, Ina Monsef, and Carina Wagner (Working Group on Evidence-Based Medicine, Department of Internal Medicine, University Hospital Cologne, Germany [AöR]) for carrying out the systematic literature search.

The statement (6) on which this review article is based, “Post-COVID-Syndrom (PCS)” (post-COVID syndrome [PCS]) (6), was discussed by the Executive Board and the Plenary Meeting of the Scientific Advisory Board on 23.09.2022 and was discussed and adopted by the Executive Board of the German Medical Association (Bundesärztekammer) on 23 September 2022.

Conflict of interest statement

PD Dr. Adorjan received funding from the Bavarian State Ministry of Health and Care (Bayerisches Staatsministerium für Gesundheit und Pflege) as well as the Bavarian State Office for Health and Food Safety (Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit).

Prof. Behrends received project funding from the Bavarian State Ministry of Science and the Arts (Bayerisches Staatsministerium für Wissenschaft und Kunst), Bavarian State Ministry of Health and Care (Bayerisches Staatsministerium für Gesundheit und Pflege), German University Medicine Network (Netzwerk Universitätsmedizin), German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung), German Federal Ministry of Health (Bundesgesundheitsministerium), as well as from Weidenhammer-Zöbele Foundation (Weidenhammer-Zöbele-Stiftung) and the Lost Voices Foundation (Lost-Voices Stiftung). She received honoraria from the German Alliance for Pediatric and Adolescent Rehabilitation (Bündnis Kinder- und Jugendreha). She is medical advisor to the German Society for ME/CFS and and a founding member of the board of the German Long COVID medical association.

Prof. Ertl received funding from the Bavarian State Ministry of Science and the Arts (Bayerischen Staatsministerium für Wissenschaft und Kunst).

Prof. Suttorp is a member of the advisory board of Biontech.

Prof. Lehmann received funding from the North Rhine-Westphalia Ministry of Culture and Science (Ministerium für Kultur und Wissenschaft NRW), the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung), the German Center for Infection Research (Deutsches Zentrum für Infektionsforschung), the German University Medicine Network (Netzwerk Universitätsmedizin), and the German Federal Joint Committee/Innovation Fund (gemeinsamer Bundesausschuss/Innovationsfonds). She received speaker’s fees from Biontech, Gilead, Novartis, Pfizer, ViiV, and Janssen. She is a founding member of the board of the German Long COVID medical association.

Prof. Hallek declares that no conflict of interest exists.

Manuscript received on 14 November 2022, revised version accepted on 19 December 2022.

Translated from the original German by Christine Rye.

Corresponding author
Prof. Dr. med. Michael Hallek
Bundesärztekammer
Herbert-Lewin-Platz 1, 10623 Berlin, Germany

Cite this as:
Hallek M, Adorjan K, Behrends U, Ertl G, Suttorp N, Lehmann C, on behalf of the Long COVID Working Group of the Scientific Advisory Board within the German Medical Association: Post-COVID syndrome. Dtsch Arztebl Int 2023; 120: 48–55. DOI: 10.3238/arztebl.m2022.0409

►Supplementary material

eReferences, eMethods, eTables:
www.aerzteblatt-international.de/m2022.0409

cme plus

This article has been certified by the North Rhine Academy for Continuing Medical Education. Participation in the CME certification program is possible only over the internet: cme.aerzteblatt.de. The deadline for submission is 26.01.2024.

References

1. Augustin M, Schommers P, Stecher M, et al.: Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg Health Eur 2021; 6: 100122

2. Sudre CH, Murray B, Varsavsky T, et al.: Attributes and predictors of long COVID. Nat Med 2021; 27: 626–31

3. Nalbandian A, Sehgal K, Gupta A, et al.: Post-acute COVID-19 syndrome. Nat Med 2021; 27: 601-15

4. Huang L, Yao Q, Gu X, et al.: 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. The Lancet 2021; 398(10302): 747–58

5. Amin-Chowdhury Z, Ladhani SN: Causation or confounding: why controls are critical for characterizing long COVID. Nat Med 2021; 27: 1129–30

6. Bundesärztekammer: Post-COVID-Syndrom (PCS). Deutsch Arztebl DOI: 10.3238/arztebl.2022.Stellungnahme_PCS (last accessed on 4 January 2023).

7. Callard F, Perego E: How and why patients made Long Covid. Soc Sci Med 2021; 268: 113426

8. AWMF online—Das Portal der wissenschaftlichen Medizin: S1-Leitlinie Post-COVID/Long-COVID. www.awmf.org/uploads/tx_szleitlinien/020-027l_S1_Post_COVID_Long_COVID_2021-07.pdf (last accessed on 21 June 2022).

9. World Health Organization: A clinical case definition of post COVID-19 condition by a Delphi consensus. www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1 (last accessed on 22 June 2022).

10. Ackermann M, Verleden SE, Kuehnel M, et al.: Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383: 120–8

11. Castanares-Zapatero D, Chalon P, Kohn L, et al.: Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med 2022; 54: 1473–87

12. Hoffmann M, Kleine-Weber H, Schroeder S, et al.: SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271–280.e8

13. Ziegler CGK, Allon SJ, Nyquist SK, et al.: SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020; 181: 1016–1035.e19.

14. Charfeddine S, Ibn Hadj Amor H, Jdidi J, et al.: Long COVID 19 syndrome: is it related to microcirculation and endothelial dysfunction? Insights from TUN-EndCOV Study. Front Cardiovasc Med 2021; 8: 745758

15. Gaebler C, Wang Z, Lorenzi JCC, et al.: Evolution of antibody immunity to SARS-CoV-2. Nature 2021; 591: 639–44

16. Wang EY, Mao T, Klein J, et al.: Diverse functional autoantibodies in patients with COVID-19. Nature 2021; 595: 283–8

17. Puntmann VO, Martin S, Shchendrygina A, et al.: Long-term cardiac pathology in individuals with mild initial COVID-19 illness. Nat Med 2022; 28: 2117–23

18. Phetsouphanh C, Darley DR, Wilson DB, et al.: Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol 2022; 23: 210–6

19. Czaplicki A, Reich H, Hegerl U: Lockdown measures against the spread of the COVID-19 pandemic: negative effects for people living with depression. Front Psychol 2022; 13: 789173

20. Oyungerel B, Paulina S, Justin C, Kylie A, Paul G: Impact of COVID-19 vaccination on long COVID: a systematic review and meta-analysis. Medrxiv 2022.

21. Notarte KI, Catahay JA, Velasco JV, et al.: Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: a systematic review. EClinicalMedicine 2022; 53: 101624

22. Al-Aly Z, Bowe B, Xie Y: Long COVID after breakthrough SARS-CoV-2 infection. Nat Med 2022; 28: 1461–7

23. Ayoubkhani D, Bosworth M: Self-reported long COVID after infection with the Omicron variant in the UK: 18 July 2022: The likelihood of self-reported long COVID after a first coronavirus (COVID-19) infection compatible with the Omicron BA.1 or BA.2 variants, compared with the Delta variant, using data from the COVID-19 Infection Survey. www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/selfreportedlongcovidafterinfectionwiththeomicronvariant/18july2022#toc (last accessed on 26 August 2022).

24. Thompson EJ, Williams DM, Walker AJ, et al.: Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat Commun 2022; 13: 3528

25. Borch L, Holm M, Knudsen M, Ellermann-Eriksen S, Hagstroem S: Long COVID symptoms and duration in SARS-CoV-2 positive children—a nationwide cohort study. Eur J Pediatr 2022; 181: 1597–607

26. Hawke LD, Nguyen ATP, Ski CF, Thompson DR, Ma C, Castle D: Interventions for mental health, cognition, and psychological wellbeing in long COVID: a systematic review of registered trials. Psychol Med 2022: 1–15

27. Fugazzaro S, Contri A, Esseroukh O, et al.: Rehabilitation interventions for post-acute COVID-19 syndrome: a systematic review. Int J Environ Res Public Health 2022; 19: 5185

28. Halabchi F, Selk-Ghaffari M, Tazesh B, Mahdaviani B: The effect of exercise rehabilitation on COVID-19 outcomes: a systematic review of observational and intervention studies. Sport Sci Health 2022: 1–19

29. Chandan JS, Brown K, Simms-Williams N, et al.: Non-pharmacological therapies for postviral syndromes, including Long COVID: a systematic review and meta-analysis protocol. BMJ Open 2022; 12: e057885

30. Vieira A, Pinto A, Garcia B, Eid RAC, Mol CG, Nawa RK: Telerehabilitation improves physical function and reduces dyspnoea in people with COVID-19 and post-COVID-19 conditions: a systematic review. J Physiother 2022; 68: 90–8

31. Ayoubkhani D, Bermingham C, Pouwels KB, et al.: Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study. BMJ 2022; 377: e069676

32. DGKJ-Konvent-Gesellschaften mA: Einheitliche Basisversorgung von Kindern und Jugendlichen mit Long COVID. https://link.springer.com/content/pdf/10.1007/s00112-021-01408-1.pdf (last accessed on 22 June 2022).

33. Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ: Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet 2022; 399: 2263–4

34. Antonelli M, Penfold RS, Merino J, et al.: Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis 2022; 22: 43–55

35. Crook H, Raza S, Nowell J, Young M, Edison P: Long covid-mechanisms, risk factors, and management. BMJ 2021; 374: n1648

36. Yong SJ: Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond) 2021; 53: 737–54

37. Yong SJ: Persistent brainstem dysfunction in Long-COVID: a hypothesis. ACS Chem Neurosci 2021; 12: 573–80

38. Carfì A, Bernabei R, Landi F: Persistent symptoms in patients after acute COVID-19. JAMA 2020; 324: 603–5

39. Dennis A, Wamil M, Alberts J, et al.: Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study. BMJ Open 2021; 11: e048391

40. Weng J, Li Y, Li J, et al.: Gastrointestinal sequelae 90 days after discharge for COVID-19. Lancet Gastroenterol Hepatol 2021; 6: 344–6

e1. Huang C, Huang L, Wang Y, et al.: 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2021; 397: 220–32

e2. Rajan S, Khunti K, Alwan N, et al.: In the wake of the pandemic: preparing for Long COVID. Copenhagen (Denmark): European Observatory on Health Systems and Policies 2021.

e3. Perego E, Balzarini F, Botteri M, et al.: Emergency treatment in Lombardy: a new methodology for the pre-hospital drugs management on advanced rescue vehicles. Acta Biomed 2020; 91: 111–8.

e4. Nauen DW, Hooper JE, Stewart CM, Solomon IH: Assessing brain capillaries in coronavirus disease 2019. JAMA Neurol 2021; 78: 760–2

e5. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H: Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. Afirst step in understanding SARS pathogenesis. J Pathol 2004; 203: 631–7

e6. Qi J, Zhou Y, Hua J, et al.: The scRNA-seq expression profiling of the receptor ACE2 and the cellular protease TMPRSS2 reveals human organs susceptible to SARS-CoV-2 infection. Int J Environ Res Public Health 2021; 18: 284

e7. Chen M, Shen W, Rowan NR, et al.: Elevated ACE-2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. Eur Respir J 2020; 56:2001948

e8. Baig AM, Khaleeq A, Ali U, Syeda H: Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 2020; 11: 995–8

e9. Salamanna F, Maglio M, Landini MP, Fini M: Body localization of ACE-2: on the trail of the keyhole of SARS-CoV-2. Front Med (Lausanne) 2020; 7: 594495

e10. Haffke M, Freitag H, Rudolf G, et al.: Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). J Transl Med 2022; 20: 138

e11. Hohberger B, Ganslmayer M, Lucio M, et al.: Retinal microcirculation as a correlate of a systemic capillary impairment after severe acute respiratory syndrome Coronavirus 2 Infection. Front Med (Lausanne) 2021; 8: 676554

e12. Kresch E, Achua J, Saltzman R, et al.: COVID-19 endothelial dysfunction can cause erectile dysfunction: histopathological, immunohistochemical, and ultrastructural study of the human penis. World J Mens Health 2021; 39: 466–9

e13. Chu KY, Nackeeran S, Horodyski L, Masterson TA, Ramasamy R: COVID-19 infection is associated with new onset Erectile Dysfunction: insights from a national registry. Sex Med 2022; 10: 100478

e14. Patterson BK, Francisco EB, Yogendra R, et al.: Persistence of SARS CoV-2 S1 protein in CD16+ monocytes in post-acute sequelae of COVID-19 (PASC) up to 15 months post-infection. Front Immunol 2021; 12: 746021

e15. Zollner A, Koch R, Jukic A, et al.: Postacute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases. Gastroenterology 2022; 2: 495–506.e8

e16. Wallukat G, Hohberger B, Wenzel K, et al.: Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms. J Transl Autoimmun 2021; 4: 100100

e17. Franke C, Ferse C, Kreye J, et al.: High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms. Brain Behav Immun 2021; 93: 415–9

e18. Su Y, Yuan D, Chen DG, et al.: Multiple early factors anticipate post-acute COVID-19 sequelae. Cell 2022; 185: 881–895.e20.

e19. Pierce JD, Shen Q, Cintron SA, Hiebert JB: Post-COVID-19 syndrome. Nurs Res 2022; 71: 164–74

e20. Meinhardt J, Radke J, Dittmayer C, et al.: Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 2021; 24: 168–75

e21. Mehandru S, Merad M: Pathological sequelae of long-haul COVID. Nat Immunol 2022; 23: 194–202

e22. Melms JC, Biermann J, Huang H, et al.: A molecular single-cell lung atlas of lethal COVID-19. Nature 2021; 595: 114–9

e23. Witte J, Zeitler A, Batram M, Diekmannshemke J, Hasemann L: Kinder- und Jugendreport 2022: Kinder- und Jugendgesundheit in Zeiten der Pandemie. Eine Studie im Auftrag der DAK Gesundheit. www.dak.de/dak/download/wissenschaftlicher-text-von-dr--witte-2572496.pdf (last accessed on 2 September 2022).

e24. Universitätsklinikum Hamburg-Eppendorf: COPSY-Längsschnittstudie. www.uke.de/kliniken-institute/kliniken/kinder-und-jugendpsychiatrie-psychotherapie-und-psychosomatik/forschung/arbeitsgruppen/child-public-health/forschung/copsy-studie.html (last accessed on 2 September 2022).

e25. Office for National Statistics (ONS) UK: Coronavirus (COVID-19) infection survey, UK 27 May 2022: percentage of people testing positive for coronavirus (COVID-19) in private residential households in England, Wales, Northern Ireland and Scotland, including regional and age breakdowns. /www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/coronaviruscovid19infectionsurveypilot/27may2022 (last accessed on 2 September 2022).

e26. Amalakanti S, Arepalli KVR, Jillella JP: Cognitive assessment in asymptomatic COVID-19 subjects. Virusdisease 2021; 32: 146–9

e27. Nakamura ZM, Nash RP, Laughon SL, Rosenstein DL: Neuropsychiatric complications of COVID-19. Curr Psychiatry Rep 2021; 23: 25

e28. Nalbandian A, Desai AD, Wan EY: Post-COVID-19 condition. Annu Rev Med 2022

e29. Ahmadi Hekmatikar AH, Ferreira Junior JB, Shahrbanian S, Suzuki K: Functional and psychological changes after exercise training in Post-COVID-19 patients discharged from the hospital: a PRISMA-compliant systematic review. Int J Environ Res Public Health 2022; 19: 17

e30. Arnold DT, Milne A, Samms E, Stadon L, Maskell NA, Hamilton FW: Are vaccines safe in patients with Long COVID? A prospective observational study. Medrxiv 2021

e31. Uniklinik Köln: Post-COVID-Sprechstunde. www.uk-koeln.de/patienten-besucher/post-covid-zentrum/klinische-versorgung-und-ambulanzen/#c9474 (last accessed 02 January 2023).

e32. LMU Klinikum: Ein Jahr Corona-Pandemie in Deutschland. www.lmu-klinikum.de/aktuelles/pressemitteilungen/ein-jahr-corona-pandemie-in-deutschland/3dad60a0892ab5a5 (last accessed on 22 June 2022).

e33. Universität Regensburg: Anlaufstelle für junge Menschen mit Long Covid & Pädiatrischem Multiorgan Immunsyndrom (PMIS). www.kiss-regensburg.de/nc/aktuelles/detailseite/news/anlaufstelle-fuer-junge-menschen-mit-long-covid-paediatrischem-multiorgan-immunsyndrom-pmis/ (last accessed on 2 September 2022).

e34. München Klinik Schwabing: Post-Covid-Syndrom (Long Covid): Long Covid Ambulanz: Hilfe bei Covid-Spätfolgen für Kinder, Jugendliche und junge Erwachsene bis 18 Jahre. www.muenchen-klinik.de/krankenhaus/schwabing/kinderkliniken/kinderheilkunde-jugendmedizin/spezialgebiete-kinder-klinik/kinder-immunologie-immunschwaeche-immundefekt/therapie-kinder-immunologie-immundysregulation/long-covid-kinder-jugendliche/ (last accessed on 2 September 2022).

e35. Universitätsklinikum Carl Gustav Carus Dresden: Long-/Post-COVID-Ambulanz für Kinder und Jugendliche. www.uniklinikum-dresden.de/de/das-klinikum/kliniken-polikliniken-institute/kik/bereiche/ambulanzen/anmeldung-postcovid (last accessed on 14 November 2022).

e36. Universitätsklinikum Jena: Post-/ Long-Covid 19 Ambulanz für Kinder und Jugendliche./www.uniklinikum-jena.de/cscc/Post_COVID_Zentrum/Post_COVID+Ambulanzen/Long_+_+Post_COVID+Ambulanz+Kinder+und+Jugendliche-p-1420.html (last accessed on 9 Januar 2023).

e37. Charité – Universitätsmedizin Berlin: Post-COVID-Netzwerk der Charité – Universitätsmedizin Berlin. https://pcn.charite.de/ (last accessed on 7 September 2022).

e38. Bayerisches Staatsministerium für Gesundheit und Pflege: Modellprojekt „Post-COVID-Kids Bavaria“: Teilprojekt 2 „Post-COVID-Kids Bavaria—PCFC“ (Post-COVID Fatigue Center). www.stmgp.bayern.de/wp-content/uploads/2021/10/2021_post-covid-kids-bavaria-2.pdf (last accessed on 22 June 2022).

e39. Bayerisches Staatsministerium für Gesundheit und Pflege: Modellprojekt „Post-COVID-Kids Bararia“: Teilprojekt 1, „Post-COVID Kids Bavaria. Langzeitefeffekte von Coronavirusinfektionen bei Kindern und Jugendlichen in Bayern: Erkennung und frühzeitige Behandlung von Folgeerkrankungen“. www.stmgp.bayern.de/wp-content/uploads/2021/10/2021_post-covid-kids-bavaria-1.pdf (last accessed on 22 June 2022).

e40. Page MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. J Clin Epidemiol 2021; 134: 178–89

e41. Taquet M, Dercon Q, Harrison PJ: Six-month sequelae of post-vaccination SARS-CoV-2 infection: a retrospective cohort study of 10,024 breakthrough infections. Brain Behav Immun 2022; 103: 154–62

e42. Whitaker M, Elliott J, Chadeau-Hyam M, et al.: Persistent COVID-19 symptoms in a community study of 606,434 people in England. Nat Commun 2022; 13: 1957

e43. Anaya J-M, Rojas M, Salinas ML, et al.: Post-COVID syndrome. A case series and comprehensive review. Autoimmun Rev 2021; 20: 102947

e44. Ceban F, Ling S, Lui LMW, et al.: Fatigue and cognitive impairment in Post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun 2022; 101: 93–135

e45. Office for National Statistics (ONS) UK: Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK 2021, 1 April 2021. www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/1april2021.

e46. Kandemirli SG, Altundag A, Yildirim D, Tekcan Sanli DE, Saatci O: Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia. Acad Radiol 2021; 28: 28–35

e47. Konopka KE, Perry W, Huang T, Farver CF, Myers JL: Usual interstitial pneumonia is the most common finding in surgical lung biopsies from patients with persistent interstitial lung disease following infection with SARS-CoV-2. EClinicalMedicine 2021; 42: 101209

e48. Maccio U, Zinkernagel AS, Schuepbach R, et al.: Long-term persisting SARS-CoV-2 RNA and pathological findings: lessons learnt from a series of 35 COVID-19 autopsies. Front Med (Lausanne) 2022; 9: 778489

e49. Yang J-K, Lin S-S, Ji X-J, Guo L-M: Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010; 47: 193–9

e50. Wendisch D, Dietrich O, Mari T, et al.: SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell 2021; 184: 6243–6261.e27

e51. Puntmann VO, Carerj ML, Wieters I, et al.: Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from Coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; 5: 1265–73

e52. Guedj E, Campion JY, Dudouet P, et al.: 18F-FDG brain PET hypometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging 2012; 48: 2823–33

e53. Stefanou MI, Palaiodimou L, Bakola E, et al.: Neurological manifestations of long-COVID syndrome: a narrative review. Ther Adv Chronic Dis 2022; 13: 20406223221076890

e54. Moldofsky H, Patcai J: Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol 2011; 11: 37

e55. Wu Y, Guo C, Tang L, et al.: Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol 2020; 5: 434–5

e56. Sansone A, Mollaioli D, Limoncin E, et al.: The sexual long COVID (SLC): erectile dysfunction as a biomarker of systemic complications for COVID-19 long haulers. Sex Med Rev 2022; 10: 271–85

e57. Rathmann W, Kuss O, Kostev K: Incidence of newly diagnosed diabetes after Covid-19. Diabetologia 2022; 65: 949–54