Introduction

Over the last few years, many people have been infected with SARS-CoV-2, and consequently suffered from COVID-19. In many cases, symptoms of the disease or its long-term sequelae lasted much longer than the initial acute phase. For this reason, the terms long COVID-19 and post–COVID-19 have started to circulate in the scientific literature. Different terms are used interchangeably to describe the same group of symptoms, for example, “long-haul COVID-19,” “postacute COVID-19,” “long-term effects of COVID-19,” or “chronic COVID-19.” One of the Polish documents1 also adopted a time census defining long COVID-19 as symptoms of COVID-19 lasting for 4 to 12 weeks and post–COVID-19 as the same symptoms lasting longer than 12 weeks. However, this division is not commonly accepted in international literature. In this paper, we will use the term post–COVID-19.

The official definition of post–COVID-19 syndrome, according to the Delphi Consensus,2 is as follows: “Post–COVID-19 syndrome occurs in people with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months after the onset of COVID-19 with symptoms persisting for at least 2 months and not explained by an alternative diagnosis. Typical symptoms include fatigue, shortness of breath, and cognitive impairment, affecting daily functioning. Symptoms may appear de novo after initial recovery from an acute episode of COVID-19 or persist after illness. Symptoms may also change in intensity or recur over time.”

The number of people with post–COVID-19 globally is estimated to reach at least 65 million.3 The actual number is likely much higher due to many undocumented cases. The prevalence of COVID-19 is estimated at 10%–30% of nonhospitalized cases and 50%–70% of hospitalized cases. Recent observations indicate that the disease affects 10%–12% of vaccinated individuals. Post–COVID-19 syndrome occurs across all age groups, with the highest diagnosis rates between 36 and 50 years. Most post–COVID-19 cases occur in nonhospitalized patients with mild acute illness, as this population represents most COVID-19 cases.

Diagnosis of post–COVID-19 syndrome is challenging, and specific diagnostic tests are lacking. However, a recent study by Klein et al4 showed that the levels of circulating immune cell populations, soluble immune mediators, and hormones differ in patients with post–COVID-19 syndrome, as compared with the general population. This information still waits to be incorporated into general practice. It is yet too early to establish a single biomarker or a diagnostic test capable of properly identifying all post–COVID-19 patients.

Differential diagnosis of complications associated with post–COVID-19 syndrome entails a comprehensive evaluation to discern between sequelae directly stemming from the viral infection and those arising from secondary physiological, psychological, or iatrogenic factors. Clinical manifestations, such as persistent fatigue, dyspnea, cognitive impairment, and musculoskeletal pain present diagnostic challenges, necessitating a thorough exploration of potential etiologies, including but not limited to postviral inflammatory processes, deconditioning, psychological distress, and medication-related side effects. Differential diagnoses further encompass cardiopulmonary complications, including myocardial injury, pulmonary fibrosis, and thromboembolic events, alongside neurologic sequelae, such as peripheral neuropathy, encephalopathy, and neuropsychiatric disorders. Moreover, consideration must be given to cognitive disorders including dementia, cerebrovascular diseases, such as stroke, psychiatric disturbances, and structural brain disorders. The above example underscore the need for a multidisciplinary approach to diagnosis and management to address the multifaceted nature of post–COVID-19 complications. In all cases, post–COVID-19 syndrome should be a diagnosis of exclusion.

The pathology spectrum of post–COVID-19 syndrome is vast and involves various systems and organs.5,6 The most common are cardiovascular symptoms, thrombotic complications, involvement of the nervous system, especially of the cerebral circulation, as well as chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME), dysautonomia, postural orthostatic tachycardia syndrome (POTS), enteritis, and type 2 diabetes.7,8 Symptoms can persist for years, and in the case of newly diagnosed CFS/ME and dysautonomia, they may even become permanent. Persistence of post–COVID-19 syndrome may result in long-term incapacity for work and other socioeconomic consequences. Currently, there are no known effective treatments for post–COVID-19 syndrome. A proposed, systematic approach to conducting research and understanding pathogenesis and management of post–COVID-19 syndrome is presented in Figure 1.8

Figure 1. Multiway approach to COVID-19 and post–COVID-19 syndrome. Modified from Mohamed et al8

Reasons for development of post–COVID-19 syndrome

Pathogenesis of the syndrome is believed to be complex. There are likely to be many potentially overlapping reasons for development of post–COVID-19 syndrome, most of which are not scientifically confirmed. These include survival of SARS-CoV-2 reservoirs in tissues, dysregulation of the immune system, reactivation of latent viruses, such as Epstein–Barr virus and human herpes virus type 6, autoimmune mechanisms, mechanisms of molecular mimicry, intestinal microbiome dysregulation, and excessive coagulation in microvessels with endothelial dysfunction. Attention is also drawn to possible signaling dysfunction in the brainstem and / or the vagus nerve.

More and more data are available in the literature analyzing possible contribution of individual mechanisms to developing post–COVID-19 syndrome.9,10 The presence of viral proteins and / or RNA has been demonstrated in the cardiovascular system, brain, muscles, lymph nodes, appendix, liver tissue, lung tissue, as well as plasma, feces, and urine of patients with symptoms of post–COVID-19 syndrome. Similarly, antibodies against the SARS-CoV-2 receptor, β2-adrenoreceptor, muscarinic receptor, angiotensin II receptor, and several others, as well as autoantibodies against many tissues, such as the endothelium, lung tissue, or connective tissue, have been found. Numerous studies document increased or decreased activation of individual immune system elements. At this stage, it is difficult to unambiguously interpret the meaning of individual results.

SARS-CoV-2 protein interactions with host-specific cellular targets could result in severe human metabolic reprogramming / dysregulation (HMRD). Disturbed metabolism may induce immune dysfunction and redox imbalance. Based on HMRD and organ / system involvement, the post–COVID-19 patients can be categorized into 4 different clusters or subphenotypes, with dominance of cardiac and renal manifestations (subphenotype 1); respiratory, sleep, and anxiety disorders (subphenotype 2); skeletomuscular and nervous disorders (subphenotype 3); and digestive and pulmonary dysfunctions (subphenotype 4). The effects of viral hijack on the host cellular machinery may be responsible for virus-induced HMRD.11

Respiratory symptoms in patients with post–COVID-19 syndrome

Respiratory symptoms occur after COVID-19 at least twice as often as in the general population. Shortness of breath and cough are the most common respiratory examples. Studies show that they persisted for at least 7 months in 40% (shortness of breath) and 20% (cough) of post–COVID-19 patients.6-8 Several imaging studies that included post–COVID-19 patients showed lung abnormalities, including air traps and perfusion abnormalities. The presence of a general inflammatory response during post–COVID-19 syndrome correlated negatively with efficiency of the respiratory system.6-8 The most common respiratory symptoms are shown in Table 1.

Table 1. Respiratory symptoms of post–COVID-19 syndrome

  • Dyspnea
  • Persistent cough
  • Chest pain
  • Decreased exercise tolerance
  • Wheezing or other abnormal auscultation sounds
  • Pulmonary fibrosis

Neurologic and psychiatric aspects of long-COVID-19 and post–COVID-19

COVID-19 is an infectious disease that also harms the nervous system. At least several mechanisms affect not only the cells of the nervous system but also the endothelium; modification of the immune system through the inflammatory reaction and hypoxia have been observed. Therefore, the impact of SARS-CoV-2 infection on the nervous system is multidirectional and can cause or exacerbate a whole spectrum of neurologic and mental diseases.

The basic mechanisms of action of the virus on the nervous system include: 1) damage to the nerve cells by a direct action of the virus; 2) inflammatory reaction resulting from stimulation of the immune system, secondary damage to the cells of the nervous system occurs through antibodies and / or activated lymphocytes; 3) decreased expression of angiotensin-converting enzyme II; 4) damage to the endothelium of endothelial vessels leading to the formation of local thrombi or damage to the vascular wall, resulting in ischemic or hemorrhagic stroke; 5) acute or chronic decrease in hemoglobin oxygen saturation resulting from lung damage and impaired gas exchange, leading to neuron hypoxia.11-13

Previous studies have found that within 6 months of acute COVID-19, one-third of patients would suffer damage to the nervous system manifested as neurologic and mental disorders.14 An increased risk of these diseases is observed even up to 2 years after SARS-CoV-2 infection.15

Several neurologic disorders are common in people with COVID-19 or are directly related to the infection.16,17 These include symptoms shown in Table 2.

Table 2. Neurologic symptoms of post–COVID-19 syndrome

Central nervous system symptoms

  • Chronic fatigue syndrome
  • Brain fog
  • Cognitive impairment
  • Headaches
  • Sleep disorders
  • Mood / emotional disorders
  • Dizziness / balance disorders
  • Extrapyramidal syndromes
  • Stroke
  • Epilepsy

Peripheral nervous system symptoms

  • Myopathies, including muscle weakness or myalgia
  • Smell disorder
  • Taste disturbances
  • Peripheral nerve damage, including Guillain–Barre syndrome or Bell palsy
  • Muscle tremors

Autonomic system disorders

  • Postural orthostatic tachycardia syndrome
  • Hypertension
  • Inappropriate sinus tachycardia

For most of the above complaints, no specific therapy has been established in post–COVID-19 patients. They should be treated following the standards of treatment of individual neurologic and mental diseases. Among specific therapies in patients with post–COVID-19 in the case of vascular diseases, including stroke, additional treatment stabilizing the endothelium, for example, with sulodexide, may be beneficial.18,19

Post–COVID-19 peripheral neuropathies and myopathies are mainly related to inflammation and oxidative stress. Therefore, it is postulated to use substances with antioxidant properties. α-Lipoic acid is effective in treating diabetic neuropathy, which is also associated with oxidative stress.20 Other substances with potential beneficial effects in post–COVID-19 neuropathy include vitamin D, vitamins B, and acetyl-L-carnitine. For all of the above, further research is needed.

Newly diagnosed mental disorders associated with COVID-19 are diagnosed within 30–120 days of the infection. Later, the risk was not shown to be higher than in the general population.21 The most common mental disorders are the ones affecting mood, especially depression and anxiety disorders. In these cases, treatment should also be in line with the standard therapy for the general population.

In the described cases, research focuses on the use of pharmaceuticals, such as coenzyme Q10, D-ribose, tramadol, naltrexone, cannabinoids, α-lipoic acid, low-dose aripiprazole, and honokiol. A combination of coenzyme Q and α-lipoic acid is particularly effective in reducing pain and chronic fatigue symptoms.22

Specific recommendations are shown in the chapter discussing treatment.

Chronic fatigue syndrome and autonomic dysregulation

CFS/ME is a multisystem neuroimmune disease that often begins immediately following a viral infection. The criteria include “a significant reduction or impairment in the ability to engage in occupational, educational, social, or personal activities at a predisease level” for at least 6 months, accompanied by profound fatigue not relieved by rest. In addition, postworkout fatigue, malaise, nonrecovery sleep, and cognitive impairment or orthostatic intolerance may occur. As many as 75% of people with CFS/ME cannot work full-time, and 25% have severe CFS/ME, which often means they are bedridden, suffer from extreme sensory sensitivity, and depend on others for care. Approximately half of people with post–COVID-19 syndrome are estimated to meet the CFS/ME criteria. An even higher percentage reports postexercise malaise.7,8

Dysautonomia, especially POTS, often coexists with CFS/ME. POTS results from autoantibodies against the G protein-coupled adrenergic receptor, muscarinic acetylcholine receptors, and small fiber neuropathy. One study found that up to 67% of patients with post–COVID-19 syndrome may be affected by POTS. Moreover, sensitization of the carotid chemoreflex occurs, which may explain dysregulated breathing and exercise intolerance in these patients, also contributing to inappropriate sinus tachycardia and blood pressure dysregulation.23

In a recent study of 200 consecutive patients with an increased heart rate, a history of mild COVID-19 was confirmed in 83% of cases with no coexisting structural heart disease.24 Inappropriate sinus tachycardia was accompanied by a decrease in most heart rate variability parameters, especially those related to cardiovagal tone. The etiology of inappropriate sinus tachycardia in post–COVID-19 syndrome patients is unknown; however, the proposed mechanisms overlap with those of POTS, including increased sympathetic and / or reduced cardiovagal activity. Even in patients not meeting the diagnostic criteria for inappropriate sinus tachycardia, an increased resting heart rate is so common that a term “post–COVID-19 tachycardia syndrome” has been recently proposed.25

Autonomic dysregulation is one of the mechanisms of frequent blood pressure abnormalities in patients with post–COVID-19 syndrome. Other issues include disturbances of the renin-angiotensin-aldosterone system with autoantibodies against angiotensin II present during COVID-19.26 The presence of these antibodies correlates with lower blood oxygenation, poorer blood pressure control, and overall higher disease severity. Transiently altered blood pressure values are observed in some COVID-19 cases.

Metabolic disturbances are some of the less-discussed, but potentially long-lasting features of post–COVID-19 syndrome. It is observed that systemic COVID-19 may trigger new-onset type 1 or 2 diabetes mellitus, dyslipidemia and hypertension.27-29 The exact epidemiology of this phenomenon is not known, and it is hard to establish which new-onset cases are attributable to the infection. Nevertheless, after the pandemic, an increase in the total number of the aforementioned conditions was noted. Moreover, there are pathophysiological indications that SARS-CoV-2 infection directly and indirectly affects β-cells, glucose, and lipid metabolism as well as the renin-angiotensin-aldosterone system.

Another metabolic consideration in post–COVID-19 syndrome is associated with thyroid gland pathologies. New-onset and relapsed Graves’ disease has been reported in several patients with acute COVID-19, post–COVID-19 syndrome, and rarely after COVID-19 vaccination.30,31 It was reported to be associated with autoimmunization and in most cases resolved after several weeks.

Abdominal symptoms after SARS-CoV-2 infection and post–COVID-19 irritable bowel syndrome

SARS-CoV-2 infection may also affect the gastrointestinal tract. Abdominal symptoms, after pulmonary ones, are the most common symptoms of infection; according to some publications,32 they occur in more than half of patients. The most common abdominal symptoms are shown in Table 3. The virus exerts its pathogenic effect by binding to the angiotensin II receptor; significant amounts of these receptors are found in the lung tissue and the gastrointestinal tract, including the intestines. In the pathogenesis of abdominal symptoms, the so-called cytokine storm, that is, a significant increase in the secretion of proinflammatory cytokines and, above all, disturbance of the intestinal microbiome play a substantial role.33-35 Due to dysbiosis during hospitalization of patients with SARS-CoV-2 infection, a significantly higher infection rate with Clostridioides difficile was observed, as compared with a similar population hospitalized for other reasons.36

Table 3. Gastrointestinal symptoms of post–COVID-19 syndrome

  • Abdominal pain
  • Nausea
  • Diarrhea
  • Loss of appetite
  • Impaired smell and taste

Another problem associated with persistent abdominal symptoms after SARS-CoV-2 infection is postinfectious irritable bowel syndrome (IBS). IBS is a functional disease of the gastrointestinal tract characterized by recurrent pain in the abdominal cavity with accompanying bowel movements in the absence of an organic etiology. It is understood mainly as a disorder of the gut-brain axis performance, most often resulting from a disorder of the intestinal microbiome. Among many potential causes of intestinal function disorders in IBS mentioned in the literature, postinfectious disturbances in the composition of the intestinal microbiome (dysbiosis), leading to postinfectious IBS, seem very important. A significant increase in the number of patients experiencing various types of food poisoning or even in the number of cases of travelers’ diarrhea has been known for a long time and reported in the literature.37-39 Risk factors for postinfectious IBS include genetic factors, intestinal microinflammation, earlier change in the intestinal barrier permeability, motility disorders, severity of the infection, psychological / psychiatric disorders, infectious factors (more often after bacterial infection), younger age, and female sex.

An infection with SARS-CoV-2, including the gastrointestinal tract infection, is also a risk factor for postinfectious IBS. Abdominal symptoms, such as abdominal pain and bowel rhythm disorders (following the Rome IV diagnostic criteria), occur 3 and 6 months after the infection, also in people who have not previously reported such symptoms. The frequency of IBS symptoms varies, according to different studies, depending on the examined population, from several to even several dozen percent of patients, which, considering the prevalence of COVID-19, constitutes a significant group of patients with new symptoms, such as abdominal pain, diarrhea, or flatulence significantly impairing the quality of life.40 A recently published meta-analysis of 50 studies41 shows that IBS symptoms were observed in about 12% of patients immediately after the infection, and in up to 22% as persistent long COVID-19 symptoms. The incidence of diarrhea in this group was approximately 10%. One of the studies considered in this meta-analysis42 reported as many as 39% of patients showing symptoms of IBS after SARS-CoV-2 infection. Thus, abdominal symptoms meeting the post–COVID-19 criteria are described in almost one-third of patients after 6 months of observation, and postinfectious IBS has become one of the components of post–COVID-19 syndrome.

Following the current recommendations,43 postinfectious IBS, including post–COVID-19 IBS, is treated according to the same schemes as in the general population. Polish guidelines for the management of this group of patients were published in 2018,44 and included step-up treatment based on dietary modifications, antispasmodics, probiotics, and in subsequent stages, rifaximin-α or psychotropic drugs. As in the case of postinfectious IBS, the mechanisms behind the symptoms are well known, a rapid response strategy should be implemented, and therapies targeted at the intestinal microbiota should be used, that is, the gold standard of treatment in the form of rifaximin-α, soluble fiber, microencapsulated butyric acid preparations, and probiotics. We need to remember that the effect of probiotics is strain-dependent, so the recommended strains in this case are primarily Lactiplantibacillus plantarum 299v, Bacillus coagulans, Saccharomyces boulardi, and Saccharomyces cerevisiae.45 Lactobacillus paracasei DG is also highly recommended, especially in postinfectious IBS.46 Rifaximin-α should be used, according to well-documented clinical trials, at a dose of 1600 mg daily (in 4 divided doses) for 14 days.47 In the case of relapse in patients responding to rifaximin-α, the treatment may be repeated after 4 weeks.

It seems that due to high frequency of symptoms and a significant number of patients who have experienced SARS-CoV-2 infections, postinfectious IBS is a new challenge for modern gastroenterology and primary care physicians, so it is worth remembering how to take care of these patients.

In the described cases, research focuses on the use of pharmaceuticals, such as coenzyme probiotics, rifaximin-α, and metformin. Specific recommendations are listed in the chapter discussing treatment.

Cardiovascular symptoms in patients with post–COVID-19 syndrome

Cardiovascular complications are an essential aspect of post–COVID-19 syndrome, affecting a significant percentage of people who have recovered from the acute phase of the disease. These symptoms can be associated with direct cell damage by viruses, hypercoagulable state caused by systemic inflammation, or myocardial damage due to excessive immune response to the virus.48 The most common cardiovascular symptoms are listed in Table 4.

Table 4. Cardiovascular symptoms of post–COVID-19 syndrome

  • Chest pain
  • Reduced exercise tolerance
  • Dyspnea
  • Increased resting heart rate
  • Arrhythmias
  • Myocarditis
  • Thromboembolism
  • Hypertension

The mechanisms underlying these symptoms are multifaceted, with some reports linking them to endothelial dysfunction that triggers thrombosis and leads to myocardial damage. The most common cardiovascular sequelae include myocarditis, heart failure (HF), arrhythmias, and coagulopathy, including deep vein thrombosis and pulmonary embolism.48

Myocarditis has been observed even in mild cases of acute COVID-19, suggesting that myocardial damage can occur regardless of the infection severity.49 Myocarditis occurs not only in the acute phase of COVID-19. Due to its often long-term nature, it also affects patients diagnosed with post–COVID-19 syndrome. It can be manifested by reduced exercise tolerance, chest pain, or cardiac arrhythmias. Markers of myocardial necrosis, such as elevated troponin levels, and results of imaging tests point to changes in the heart structures that may persist for a long time after recovering from COVID-19.50 Moreover, the impact of COVID-19 on the cardiovascular system seems to be long-lasting in some cases, and may be perceived for up to several months after the acute infection has resolved.

It is worth noting that in the context of post–COVID-19 syndrome, HF has been reported to occur de novo or due to deterioration of a previous health condition.51 Symptoms of post–COVID-19 HF, such as shortness of breath, fatigue, and fluid retention, can significantly impact patient quality of life, potentially hindering their full recovery. There are currently no dedicated treatment regimens for post–COVID-19 HF, which should be treated as any other HF cases.

Cardiac arrhythmias, including atrial fibrillation, are other significant cardiovascular pathologies and may result from myocarditis, ischemia, or neurohormonal stress associated with severe disease.52 Arrhythmias in COVID-19 patients are associated with hypoxia, myocardial ischemia, the presence of proinflammatory cytokines, inflammation, electrolyte disturbances, proarrhythmic or QT-prolonging drugs, and cardiovascular diseases, such as severe congestive HF. Arrhythmias and episodes of cardiac arrest are the most common in the population of COVID-19 patients in intensive care units.52 Nevertheless, some cardiac arrhythmias, especially in patients with a history of myocarditis, may persist for a long time and constitute a part of post–COVID-19 syndrome. In patients with post–COVID-19 syndrome, the most common abnormality is resting tachycardia, but all kinds of ventricular and supraventricular arrhythmias may occur.

Thromboembolic events have proven to be a severe problem in both the acute phase of COVID-19 and post–COVID-19 syndrome. The underlying pathophysiology appears to be multifactorial, involving a combination of endothelial dysfunction, systemic inflammation, and hypercoagulable conditions.53 Studies have shown an increased incidence of deep vein thrombosis and pulmonary embolism in patients recovering from COVID-19, highlighting the need for vigilant monitoring and prophylaxis, especially among high-risk patients.54 Management of thromboembolic events may include the use of anticoagulants, close observation, and personalized therapeutic strategies, depending on individual risk factors.55 Long-term studies are needed to further evaluate the impact, optimal prevention strategies, and therapeutic interventions for thromboembolic complications in COVID-19 patients.56 There are no established principles of thromboprophylaxis in high-risk patients with post–COVID-19 syndrome; however, some drugs, such as sulodexide, are being researched for their usefulness in this group of patients. Sulodexide is recommended as per the International Society on Thrombosis and Haemostasis guidelines,57 in nonhospitalized COVID-19 patients at a higher risk of disease progression, within 3 days of the onset of symptoms, due to a reduced risk of hospitalization and a need for oxygen therapy. In long COVID-19 patients, the use of sulodexide is associated with abolition of endothelial dysfunction and relief of chest pain and palpitations, which, together with anticoagulant effect of the drug, may indicate its significant usefulness in patients with post–COVID-19 syndrome.58 It should be noted that sulodexide has an established position in prolonged, secondary antithrombotic prophylaxis and is recommended for this indication by many scientific societies.59-60

Managing these complications requires a patient-centered approach, including pharmacotherapy, lifestyle modification, and rehabilitation. A multidisciplinary team of cardiologists, physiotherapists, dietitians, and primary care physicians is often required to provide comprehensive care. Despite growing knowledge on the symptoms mentioned above, many issues regarding their long-term impact on prognosis and optimal treatment strategies remain unresolved.

Research focuses on the use of pharmaceuticals, such as angiotensin-converting enzyme inhibitors, statins, β-blockers, ezetimibe, fibrates, ω-3 fatty acids, ranolazine, magnesium salts, potassium, sulodexide, and anticoagulants. Specific recommendations are provided in the chapter on treatment.

Impact of vaccination and reinfection on the incidence of post–COVID-19 syndrome

Results of studies on the effect of vaccination on post–COVID-19 syndrome vary between publications, partly due to different research methods, time since vaccination, and definition of post–COVID-19 syndrome. Most studies indicate that vaccines provide partial protection and reduce the risk of long-term consequences of COVID-19 by 15% to 41%.61 There are also consistent observations regarding an increasing risk of long-term consequences of COVID-19 after the second and third infection. Research literature suggests that multiple infections may cause additional medical problems or susceptibility to CFS symptoms.

Education on the long-term consequences of COVID-19 is essential. There is a widespread belief that COVID-19 causes only respiratory sequelae, making it difficult to properly diagnose the neurologic, cardiovascular, and other multisystem effects of the disease. There is still a disproportionate dominance of pulmonary rehabilitation activities. For obvious reasons, monitoring of people hospitalized for COVID-19 is more accessible and better documented than of those not hospitalized. Proper diagnosis and linking, for example, neurologic or CFS/ME symptoms with a history of COVID-19 seems problematic.

These so-called mild cases that develop into post–COVID-19 syndrome often have a different biological basis than acute severe cases and require appropriate diagnostic tools. Commonly used tests, based on the levels of D-dimer, C-reactive protein, and complete blood count yield unremarkable results. For example, in patients with CFS/ME and dysautonomia, it is necessary to use total immunoglobulin tests, measure cortisol in saliva, or study brain perfusion. Symptoms such as postexercise malaise are not widely known and are rarely included in research panels.62,63

Treatment of patients with post–COVID-19 syndrome

The management of post–COVID-19 syndrome poses unique challenges due to a lack of official guidelines and a complex nature of the disease. Unfortunately, in many cases, the management is focused solely on relieving the symptoms and waiting for spontaneous resolution. It should be stressed that treatment of post–COVID-19 patients should focus on patient education, providing reassurance and offering holistic support. Patients with post–COVID-19 syndrome most of all need rehabilitative care, including well-established symptom management techniques, physical rehabilitation programs, and addressing mental health and well-being. However, in many cases, pharmacotherapy is crucial in symptom relief. A step-by-step approach is summarized in Figure 2.

Figure 2. Step-by-step approach to diagnosis, management, and treatment of post–COVID-19 syndrome

Pharmacotherapy of long COVID-19 must assume individualization of the patient situation and symptoms. The most important factors regarding the assumptions of appropriate pharmacotherapy in this group of patients are summarized in Table 5.64-67 In all cases, pharmacotherapy must follow the current guidelines for specific chronic diseases.

Table 5. Factors to be considered when using pharmacotherapy in a patient with post–COVID-19 syndrome

Factors affecting the course of post–COVID-19 syndrome

Practical conclusions

Patient characteristics

Both residual characteristics of the patient and the most optimal therapeutic management concerning post–COVID-19 symptoms should be considered.

Multimorbidity

Multimorbidity may modify the course of post–COVID-19 syndrome due to common determinants with comorbidities.

Effectiveness of post–COVID-19 symptom control

It depends on the course of SARS-CoV-2 infection and the severity of post–COVID-19 symptoms.

Optimal drug combinations

Treatment should involve optimal polypharmacotherapy based both on a clinical picture of the symptoms and specific mechanisms of action of the used drugs.

Stable effect of pharmacotherapy

Optimal choice of drugs and their combinations are one of the most critical elements of rationalizing pharmacotherapy in patients with post–COVID-19.

Benefit-to-risk ratio of pharmacotherapy

It should be remembered that drugs may have side effects, the clinical picture of which may be consistent with disorders that are part of the post–COVID-19 clinical picture.

Contextuality of pharmacotherapy

Effectiveness and safety of pharmacotherapy are not an absolute concept. The choice of drugs and their dosage must always be contextual, which in practice means that it must take into account essential characteristics of the patient, which are unmodifiable and significantly affect the choice of the drug and the way it is used. Before deciding on pharmacotherapy in individual patients, both residual factors and an impact of comorbidities and other concomitant medications on the efficacy and safety of pharmacotherapy should be considered.

Changes in pharmacokinetic profile of drugs

Inflammation is the most critical element modifying pharmacokinetics of drugs, which should be taken into account when choosing pharmacotherapy.

Moreover, a summary of current knowledge on drugs used to treat individual symptoms of post–COVID-19 syndrome is presented in Table 6.67-70 It should be noted that the knowledge regarding COVID-19 and its long-term consequences is constantly expanding, and the presented indications may be updated soon. None of the listed substances are currently registered for post–COVID-19 syndrome treatment, and this summary should be considered as a list of emerging future therapies.

Table 6. Post–COVID-19 symptoms and the currently investigated pharmacotherapy and supplementation options

Symptoms

Pharmacotherapy / supplementation

Cardiovascular disorders

Renin-angiotensin-aldosterone system inhibitors, statins, β-blockers, ezetimibe, fibrates, ω-3 fatty acids, ranolazine, magnesium salts, potassium

Feeling tired, exhausted

Coenzyme Q10, D-ribose, metformin, α-lipoic acid

Nociplastic pain

Tramadol, naltrexone, cannabinoids, α-lipoic acid, coenzyme Q10

Coagulation disorders

Anticoagulants

Vascular endothelial dysfunction

Sulodexide, statins, renin-angiotensin-aldosterone system inhibitors

Gastrointestinal disorders

Probiotics, rifaximin-α, metformin

Microcirculation disorders

Pycnogenol, sulodexide

Mast cell activation syndrome

Bilastine, famotidine

Brain fog

Low-dose aripiprazole, coenzyme Q10, honokiol

New-onset type 2 diabetes

Metformin

Summary

It should be emphasized that post–COVID-19 syndrome, which refers to several symptoms that may persist after SARS-CoV-2 infection, is a complex, interdisciplinary clinical problem. Studies show that a significant percentage of COVID-19 survivors experience long-term effects, such as fatigue, shortness of breath, arthralgia, and neurologic symptoms, but the clinical presentation can be highly variable and significantly affect patient quality of life. Extensive and long-term research is paramount in understanding the full range of long-term effects that COVID-19 may have on human health. It should also be emphasized that a coordinated, multidisciplinary approach to treatment and rehabilitation is essential to effectively help patients suffering from post–COVID-19 syndrome. To this end, it is also essential to disseminate knowledge about this disease among the general public and doctors, which will allow for more effective diagnosis and treatment of post–COVID-19 syndrome.