Post-COVID—More than chronic fatigue?

After the first COVID-19 survivors were medically treated in Germany from spring 2020 onwards, various courses of the disease emerged that, in addition to the acute infection, led to prolonged symptoms (long COVID), but also to a symptomatic course beyond 12 weeks, which is referred to as “post-COVID syndrome” (PCS). Currently, the incidence of PCS is estimated to be approximately 15% of all symptomatically infected patients, although over- or underestimations may occur due to the soft definition and lack of control groups. The etiology of PCS is currently unknown. The following pathogenetic processes are discussed in particular: an endothelial dysfunction with microcirculatory disturbances and subsequent organ damage, a residual virus or virus particles, and/or an excessive autoimmune process. Due to the large number of organs that may be affected, PCS presents as a very complex clinical picture with up to 200 described symptoms. An evidence-based causal therapy for PCS has not yet been established. The guideline-based inpatient rehabilitation measures adapted to the individual patient resources have proven to be an effective therapy and should therefore be involved in the therapeutic concept at an early stage. Post-COVID syndrome is a multicomplex disease that can have a considerable impact on the quality of life, but also on the professional performance of the affected patients. Thus, it is clearly more than just a chronic fatigue syndrome. In the interest of our patients, treating physicians should take this disease seriously, clarify the differential diagnoses, and provide sensitive therapeutic care.

After medical treatment of the first COVID-19 survivors in Germany in spring 2020, it became clear that many patients often suffer from persistent symptoms for a very long time after the acute infection. Long-term symptoms include reduced cardiopulmonary resilience, rapid fatigability, shortness of breath, chest pain, headaches, and concentration and memory disorders [1]. These limit the patients in many everyday areas, but also in relation to their occupation, and often result in very long periods of incapacity to work. In addition to physical limitations, patients often also suffer psychologically from the late effects of the disease.

Definition
This longitudinal course of COVID-19 disease is currently classified in different ways. The classification according to NICE (National Institute for Health and Care Excellence), which is frequently used in the clinic, is based on three different terms: -The acute infection phase lasts for 4 weeks, followed by persistently symptomatic COVID-19 disease, which lasts between 4 and 12 weeks. -If symptoms persist or new symptoms appear after 12 weeks, this is called "post-COVID syndrome" (PCS; ICD 10 code U09.9!), whereby the course can be constant, fluctuating, or with symptom-poor intervals (recurrent).
-The term "long COVID" encompasses both terms: the phase of ongoing disease and the PCS and does not include a time limit (. Fig. 1; [2,3]).

Incidence
The current literature suggests that approximately 15% of patients infected with SARS-CoV-2 have a prolonged course of disease [4]. In this study, 20,000 people who tested positive for COVID-19 were screened between 26 April 2020 and 6 March 2021. Overall, 13.7% showed symptoms for longer than 12 weeks. A review paper in Nature Reviews Microbiology [5] describes that at least 65 million individuals around the world have long COVID, based on a conservative estimated incidence of 10% of infected people and more than 651 million documented COVID-19 cases worldwide. The number is likely much higher due to many undocumented cases. The incidence is estimated at 10-30% of non-hospitalized cases, and 50-70% of hospitalized cases [6,7]. Due to the lack of control groups that may have similar symptoms due to the pandemic, there is a risk that the incidence of PCS is overestimated [8].
The incidence of PCS, according to the currently available data, occurs independently of preexisting concomitant diseases [9]. However, a history of comparable somatic or psychosomatic complaints or a high psychosocial burden can favor the manifestation of PCS. Moreover, diagnostic criteria are not well defined and are used differently in various studies, so that the incidence of PCS is influenced by the respective study design, the recruitment strategy, the questionnaires used, and the criteria of recovery [10]. The extent to which the severity of COVID-19 infection causes a post-COVID or long COVID syndrome is the subject of current studies. From our own clinical experience, however, patients with a mild course seem to be just as affected as patients with a severe course. This observation is also in line with the statements of the current S-1 guideline on PCS of the AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften)-Association of Scientific Medical Societies; [3].

Etiology
The cause of post-COVID/long COVID syndrome is not yet known. In all probability, the clinical picture is caused by various factors and may not have the same origin in every patient. The diverse symptoms (see below), which can be explained by the involvement of various organs, are due to the multiple occurrences of the angiotensin-converting enzyme 2 (ACE2) receptor, which can be detected not only in the lung and olfactory epithelium but also in various organs (e.g., vascular endothelium, myocardium, substantia nigra, myocytes, testis, kidney, small intestine, etc.; [8,11]).
For the cardiac and endovascular consequences, an analysis of the US Department of Veterans Affairs databases (VA data), which included more than 150,000 individuals 1 year after SARS-CoV-2 infection, should be mentioned as an example. The authors were able to show that these patients developed cardiovascular diseases, including heart failure, dysrhythmias, and stroke, significantly more frequently, independent of the severity of the initial COVID-19 presentation [12].
The following causes are discussed as possible causative factors: a) Virus retention [13][14][15], possibly affecting patients with immunodeficiencies in particular [16], or retention of viral components [17,18]. b) Chronic or even excessive autoimmune phenomena. Several studies have shown increased levels of autoantibodies in patients with long COVID [20]. Examples include autoantibodies against ACE2 ( [19]; the receptor for SARS-CoV-2 entry), β2adrenoceptor, muscarinic M2 receptor, angiotensin II AT1 receptor, and the angiotensin 1-7 MAS receptor [21]. c) Endothelial dysfunction with microcirculatory disturbances, long-lasting tissue damage. Studies have shown a reduction in capillary density 18 months after infection [22]. In addition, it was demonstrated that the detection of angiogenesis markers ANG1 and P-selectin showed high sensitivity and Fatigue syndrome (red) occurred very frequently, in more than half of the patients; symptoms marked in yellow occurred frequently and symptoms marked in green occurred occasionally (with permission from [25]; http:// creativecommons.org/ licenses/by/4.0/) specificity for predicting long COVID status [23].

Symptoms
Post-COVID syndrome is characterized by a variety of symptoms and functional limitations. A recently published paper in Nature Medicine [24] mentions over 200 symptoms. The possible symptoms are illustrated in . Fig. 2.
Persistent symptoms such as fatigue, headache, attention deficit, hair loss, dyspnea, anosmia, ageusia, cough, chest pain or tightness, memory difficulties, and increased anxiety and depression indicate involvement of other organ systems outside the respiratory tract [25].
Similar to Middle East respiratory syndrome (MERS), SARS-CoV-2 has extrapulmonary manifestations of the disease, such as cardiac, renal, gastrointestinal, and neurological disorders. These can be attributed to varying levels of ACE expression depending on the organ system, which form the portal of entry for the virus [26]. In addition, other infectious diseases such as Q fever (20% after 6-12 months; [27]), MERS (46 after 6 months; [28]), or infectious mononucleosis (Epstein-Barr virus infections, 13% after 6 months; [29]) have also been described as frequently having long-lasting post-viral fatigue symptoms, which have an influence on many areas of the affected person's life [29].
By far the most common symptom is fatigue. In our own patient collective, we see fatigue symptoms in 91% of patients, which we assess using two standardized questionnaires (A LQ-11 FS-T, A LQ-11 FS-S).

Therapy
An evidence-based causal therapy for PCS has not yet been established. The current S-1 guideline of the AWMF [3] recommends, since the causality of PCS has not been conclusively clarified, symptomatic therapy with the goal of symptom relief, as well as the prevention of chronification of the complaints. The guideline-based inpatient rehabilitation measures adapted to the individual patient resources have proven to be an effective therapy and should therefore be involved in the therapeutic concept at an early stage [3]. Currently, therapeutic measures include the promotion of sleep, sufficient pain therapy, cardiovascular training, therapies for stress reduction and relaxation, strengthening of personal resources, as well as the support of adequate coping behavior (e.g., neither excessive demands nor avoidance of activities). These therapies are adapted to the individual symptoms of the patients in the sense of pacing.
In our own patient collective, the focus is on instruction in physical activity, psychological support, occupational therapy including training in cognitive performance or olfactory ability, as well as nutritional counseling based on bioelectrical impedance analysis (BIA) measurement. Overstraining on a physical and/or psychological level should be avoided, as this can often be associated with symptom exacerbation. Remedial care should be considered on a case-by-case basis. For this reason, therapies such as physiotherapy or occupational therapy should be planned early on in the therapeutic setting. Since 1 July 2021, PCS (U09.9!) has been recognized as a special healthcare need in Germany, and the budget of practicing physicians is not burdened if physiotherapy and/or occupational therapy is prescribed (https://www.kbv.de/ html/1150_52751.php).
Finally, due to the rapidly growing amount of information, we refer to the S-1 guideline of the AWMF on this topic [3].

Conclusion
Post-COVID (PCS) affects about 15% of symptomatically infected COVID patients. The cause of this disease course is not yet clearly understood, even though various etiologies are being discussed. Owing to the large number of organs that carry ACE-2 receptors, PCS is a very complex disease in the sense of a systemic disorder. Since the etiology of PCS is not yet fully understood, an evidencebased causal therapy has not been established to date. The guideline-based inpatient rehabilitation measures adapted to the individual patient resources have proven to be an effective therapy and should therefore be involved in the therapeutic concept at an early stage. In summary, it can be stated that PCS is a multicomplex systemic disease that can significantly affect the quality of life, but also the occupational performance, of the affected patients and is thus clearly more than just a chronic fatigue syndrome. For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.