Guest article: Prof. Dr. Clara Lehmann and Prof. Dr. Michael Hallek

Post-COVID syndrome (Long COVID): severe somatic disease with biological causes

The post-COVID syndrome (PCS) can be compared to similar "post-acute infection syndromes" (PAIS) caused by viruses such as Ebola, dengue, Epstein-Barr virus (EBV), MERS-CoV, SARS-CoV-1 or influenza. Thanks to research on these post-acute infection syndromes, synergistic insights into the pathomechanisms of PCS can be gained. SARS-CoV-2 and the PCS now offer the opportunity to learn more about the underlying mechanisms of PAIS, since these are still poorly understood and they are like a kind of "black box" in the medicine field.

Which symptoms are actually attributed to infection with SARS-CoV-2?

In the strict sense, clearly distinguishing PCS from other medical problems, such as persistent symptoms of COVID-19 infection, biological correlations or psychosocial stress caused by the pandemic, is fundamentally important for researchers as well as patients. However, distinguishing PCS from other diseases is complicated by the lack of specific biomarkers for PCS.

Symptoms of the post-COVID syndrome (PCS)

The disease condition is defined by a confirmed or probable history of SARS-CoV-2 infection, wherein symptoms usually arise three months after the onset of COVID-19 infection and last for at least two months. Symptoms include fatigue, shortness of breath, cognitive impairment and many other symptoms that have been shown to affect the quality of life.

Symptoms may be new or persist since COVID-19 infection and cannot be attributed to another diagnosis. PCS can affect all organ systems, including the heart, lungs, kidneys, spleen, liver, pancreas, immune system, gastrointestinal tract, neurological system, blood vessels, and male and female reproductive systems. This multi-systemic impact complicates research significantly. The prevalence of PCS in the European population is influenced by several individual and environmental factors. As regards individual factors, prevalence is highest in women, in the 25-69 age group and in people hospitalised for SARS-CoV-2 infection. Socioeconomic factors also play a role, with residents of disadvantaged areas, economically inactive people and people with health limitations seem to be more affected. On the other hand, vaccination seems to reduce the risk of PCS disease by 15-50%.

Post-COVID syndrome - a problem even in mild or asymptomatic progressions

The PCS also observed in people in whom the original symptoms were mild during the acute phase: Thus, only mild symptoms such as cough, fatigue or mild respiratory problems may appear during the acute phase of the infection, but long-term effects such as persistent fatigue, memory problems, muscle weakness or respiratory problems may still arise. This highlights the complexity and diverse presentation of the PCS, which is further researched to enable better understanding and appropriate support for all those affected.

Current knowledge about the disease

Currently, numerous different causes of the PCS are known, including: Persistence of the virus in the body, overreaction (hyper inflammation) of the immune system, mitochondrial dysfunction, dysfunctional neurological signalling, autonomic nervous system involvement, endothelial dysfunction, clotting disorders or vascular damage. A better understanding of the causes of the PCS is crucial for developing optimal treatment and care for patients.

Care and treatment of patients

People affected by the PCS often face scepticism in their family and work environment. In addition, the PCS is often not recognised by doctors. Since there are no clear diagnostic biomarkers for routine diagnosis so far, the diagnosis of the PCS currently relies mainly on clinical examinations (Hallek et al., DÄB (German Medical Women’s Association) Int 2023; 120: 48-55; DOI: 10.3238/arztebl.m2022.0409). The treatment of the PCS is often costly and complex. Therapeutic management of the PCS is currently individualised and symptom-oriented. Unfortunately, due to limited medical knowledge, patients with the PCS sometimes receive inappropriate, and sometimes even harmful, treatments.

Review of different therapeutic approaches in clinical trials

The PCS is a complex condition for which there are no specific treatment options as present. There are no clear molecular or non-molecular diagnosis markers. Therefore, clinical criteria are used to diagnose the (https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1), which are not always separable. Patients with the PCS do often suffer to a great deal. In this situation, it is all the more important that the diagnosis as well as the resulting therapy recommendations are made in a reflective and critical manner, and that they are well documented and scientifically verified. At the same time, this means that every new therapeutic approach should be tested within the scope of clinical trials. This is the only way to assess whether an improvement in symptoms is achieved. Ultimately, a range of effective treatment options for patients with the PCS can be developed only with a solid scientific knowledge base. This requires the cooperation of all physicians.

Conclusions and recommendations

• The PCS is a severe somatic disease with biological causes. It is not a psychosomatic disease.
• In case of the PCS, various causes can in principle affect all organ systems of patients. The most common symptoms are extreme fatigue, insomnia, shortness of breath, cardiovascular problems and difficulties in concentrating. The PCS is also characterised by stress intolerance, which means that physical or mental exertion or stress worsens the symptoms.
• The PCS is a chronic disease that lasts for several months or years, where convalescence are characterised by fluctuations with periods of relapse.
• The most important prevalence factors for the PCS are female gender, age range (25-69 years) and hospitalisation after an infection with SARS-CoV-2. It is undisputed that vaccines can also cause complications. However, it is very well documented that vaccination against COVID-19 protects against the development of the PCS.
• The causes of the PCS are manifold. The main causes are thought to be damage to the vascular endothelium, over-activation of the immune system and/or viral persistence. Further research is urgently needed to understand the respective causes and their interaction in a better manner.
• Current treatment of the PCS is not curative, but symptom-oriented (individual multi-modal rehabilitative treatments). A number of medicines are undergoing clinical trials.