Guest article : Prof. Dr. Bernhard Schieffer

SARS-CoV-2 infections cause post-COVID syndrome (PCS) in approximately 5 percent regardless of the progression. Some patients suffering with the PCS meet diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). With steadily increasing numbers of SARS-CoV-2 (re)infections across Germany, a further increase in the number of cases must also be expected in the winter of 2023/2024. The evidence-based methods for diagnostics and therapy that are missing at present as well as the lack of regional contact points pose a complex challenge for us, i.e. medical professionals and the health care system. The post-COVID syndrome, which affects many organ systems and often limits the ability to work and cope with everyday life, requires effective networking and strengthening of primary care, specialist doctors, inpatient and rehabilitative resources. Such intersectoral integration with the establishment of outpatient specialist practices and university competence centres is only beginning to emerge. Changing this emergency situation due to the lack of adequate care structures and advancing the prevention and treatment of PCS through effective research are likely to be among the most important health policy challenges of the coming years. Even if many of us do not want to hear it, we expect the pandemic after the pandemic.

Which symptoms are in the foreground?

From the clinical aspect, the PCS is extremely heterogeneous with a variety of over one hundred symptoms affecting all organ systems. The most frequent ones are fatigue, stress intolerance, anosmia, dysgeusia, dyspnea, sleep disorders, pain, and cognitive dysfunction. Long COVID (LC) and post-COVID syndrome (PCS) and post-vaccination syndrome (PVS, postVAC, post-COVID symptomatology after vaccination) are defined as persistent or new-onset symptoms that interfere with activities in the daily life and cannot be explained otherwise. While LC is an umbrella term for symptoms persisting 4 weeks after infection, WHO has defined PCS as symptoms that persist even after three months after the onset of COVID-19 disease, that last at least two months, that cannot explained by another diagnosis, and that affect daily life. The often dominant symptom cluster of fatigue, stress intolerance, and cognitive dysfunction is prominent in most patients. This symptom cluster is followed by circulatory dysregulation and the sometimes most severe progressions of ME/CFS. Peripheral nerve damage represents the third major symptom complex, which may resemble polyneuropathy or muscular dystrophy in some cases. Biomarkers for which the various sub-groups of post-COVID syndrome need to be rapidly explored and therapeutic options tested in clinical trials.

Key syndromes of PCS: Fatigue, orthostatic intolerance, stress intolerance, post-exertional malaise.

• Fatigue is one of the most commonly observed symptoms and does not simply denote “tiredness”, but rather exhaustion that is disproportionate to the preceding stresses and that cannot be relieved by sleep, and that may be physical or mental in nature. In some PCS progressions, especially in ME/CFS, fatigue is regularly accompanied by sleep disorders - yet in these cases, there is usually no depressive symptomatology, as evidenced by the usually preserved drive and high motivation to cope with the disease.
• The frequently occurring orthostatic intolerance (OI) is probably due to a dysregulation of the autonomic nervous system (dysautonomia). The core feature of OI is symptom worsening on sitting up and corresponding improvement on lying down. Symptoms include drowsiness, dizziness, syncope, and tachycardia, as well as fatigue, headache, anxiety, cardiac pain, dyspnea, and stress intolerance. 
• The majority of PCS cases with fatigue are also characterized by stress intolerance, an inadequate response (such as increase in fatigue, dyspnea, exaggerated tachycardia, dizziness) to even mild physical or mental stress. The increase in symptoms after light physical or mental exertion is referred to as post-exertional malaise (PEM).  The primary problem with PEM is therefore not the lack of resilience (depending on the initial state of health, those affected can sometimes even exert themselves normally for a short time), but the worsening of their symptoms is triggered by this. The latter often begins after a time delay of several hours or on the following day and is still noticeable hours after exertion and often lasts for several days (up to weeks). Triggers can be physical, cognitive as well as emotional, sensory or orthostatic stress. PEM can occur in milder manifestations in various forms of PCS. However, PEM is the cardinal symptom of ME/CFS (where PEM is one of the mandatory clinical diagnostic criteria) and is often severe and persistent for at least 14 hours.

Is there evidence on the cause of post COVID?

SARS-CoV-2 infection often leads to strong and prolonged immune activation and sustained inflammatory response with increased levels of interferons and cytokines in PCS compared to recovered, as well as activated T cells and myeloid cells (sometimes more than six months after COVID-19) without viral replication. Other studies provide evidence of endothelial dysfunction and impaired micro-circulation in PCS, which in turn may cause circulatory disorders with decreased tissue oxygenation (oxygen supply). At present, it is under investigation as to which role that S1 protein binding to endothelial cells and a proinflammatory imbalance in the renin-angiotensin system (RAS) mediated via the angiotensin II type 1 receptor (AT1R) may play in this process.

Increased levels of the potent vasoconstrictor endothelin-1 (ET-1) have also been detected. Reactivation of certain autoantibodies to herpes viruses, particularly Epstein-Barr virus (EBV), are observed in PCS. Similarly, autoantibodies against cytokines, chemokines, complement components, and neuronal structures have been described in affected individuals with PCS. However, the possible mechanisms of post-vaccination syndrome have not been studied extensively as yet and are still unclear. For this reason, the diagnosis of PCS is challenging due to its clinical and pathogenetic diversity.

Accordingly, it is also difficult to establish uniform guidelines for therapy. Due to its therapeutic relevance, the AWMF Long-COVID Guideline recommends an orthostasis test (e.g. Schellong test or 10-minute leaning test) both in the presence of post-COVID fatigue and in the presence of OI symptoms. This serves in particular to detect or exclude orthostatic hypotension (OH) (characterized by a drop in blood pressure of systolic > 20 mmHg and/or diastolic > 10 mmHg within 3 minutes after standing up), as well as postural tachycardia syndrome (POTS). In the latter case, there is a sustained pulse increase of > 30/minute (in children and adolescents: > 40/minute) within 10 minutes of standing upright, or, depending on definition, a sustained heart rate of > 120/minute.

The longer fatigue persists within the effect of PCS (e.g., 3 months in children and adolescents, 6 months in adults), and the longer an associated PEM persists after exertion, the more urgently the suspicion of ME/CFS should be investigated. This is coded in ICD-10 as a disorder of the nervous system (G93.3) and it is considered as one of the most serious and complex diagnoses of the PCS spectrum that occurs more frequently without reliable epidemiological data until now. Therefore, the pre-pandemic prevalence of ME/CFS of approximately 0.3% of the population is expected to increase significantly within the next few years.

The therapy of PCS - where will we be in the summer of 2023?

Current "off-label" medicinal drug candidates for experimental treatment of PCS and/or ME/CFS are for example antihistamines, low dose naltrexone (LDN - PCS and low dose aripiprazole. In addition, preliminary studies and case series show that hyperbaric oxygen therapy and ganglion stellate blockade may be effective in PCS and ME/CFS. Immunomodulatory approaches tested so far only in small studies include treatment by immunoadsorption and are currently being tested in clinical trials; immunoglobulins may be used in refractory myocarditis. Concepts that are yet to be tested and for which there are only case reports available until now, include the aptamer BC007, HELP apheresis, plasmapheresis, and perispinal etanercept. Due to the large number of rapidly changing therapeutic approaches, this summary does not claim to be exhaustive, but it must be noted that most therapeutic approaches often lack randomised clinical trials. 

Importance of Post COVID for health care system

The care should focus on intersectoral and/or cross-sectoral and interdisciplinary treatment. Initial examination, planning, and process flow of diagnosis and therapy should be managed by family physicians or paediatricians and adolescent physicians who normally handle primary care. Regional specialised clinics, which are closely associated with the primary care clinics (as has been tested for many years in the district of Marburg-Biedenkopf), are decentralised competence centres on one hand and have direct access to the respective university specialised outpatient clinics on the other. The main task of the university centres of excellence is to conduct research and clinical trials. Through their networking, expertise such as the study platform existing in Marburg or at the Charité would be made available to others and clinical studies could be standardised. 

The circle of care structures is completed with outpatient or inpatient rehabilitation facilities, which, upon referral by the specialised clinics or university specialty outpatient clinics, provide co-treatment in accordance with the latest version of the AWMF S1 guideline. Inter-institutional and inter-specialty digital case conferences can support the indication of rehabilitation measures, especially if the (suspected) diagnosis of ME/CFS has been made. A major focus should be on comprehensive and structured treatment of young people with post-viral ME/CFS.

Telephonic and telemedical follow-up and after-care programs can facilitate the sustained implementation of treatment recommendations close to home after diagnosis or even after inpatient treatment measures. In particularly severe cases, treatment must be exclusively or predominantly outreaching or telephone/telemedicine. According to our own experience, the interdisciplinary competence of specialised outpatient palliative care (SAPV) is extremely helpful here. In this context, it is important to establish classic training formats, webinars, and web app platforms that serve as communication platforms to enable nationwide access to the latest therapy options and thus to ensure the sovereignty of science in therapy management. Sustainable funding for such an intersectoral care concept is the central aspect for all of these tasks and offerings. Specially remunerated university outpatient tariffs are necessary for multidisciplinary care in university outpatient clinics as well as in private clinics. 

Current care problems for PCS, PostVAC and ME/CFS

The established care structures are currently unable to cover effective diagnosis, therapy and care for PCS. The workload of general practitioners is high, waiting times at specialist care centres and university special outpatient clinics are long, and hence diagnosis is often delayed. According to currently plausible models, this situation increases the risk of avoidable chronification and psychosocial consequential damage. However, in addition to contact points for PCS, there is currently a lack of competence centres for people with possible PVS (such as the post-COVID/post-vac outpatient clinic in Marburg). Another unresolved problem is the insufficient remuneration for the complex care of PCS at all levels. At present, many post-COVID facilities are co-financed within the framework of research projects.

Thirdly, there is a lack of adequately specialised, tertiary interdisciplinary care structures, especially in the area of university outpatient clinics, which can guarantee the interface to translational and basic research beyond care research and therapy studies. At least one adequately equipped specialised university post-Covid network should be available in each federal state for children, adolescents and adults with PCS and/or ME/CFS. The establishment of a digital patient record would not only be helpful for continuity in patient care and for research purposes, but would also mean resource optimisation by avoiding duplicate examinations and unnecessary appointment requests.

 

Published 12.07.2023