**2.6 Post-COVID-19 fatigue**

Fatigue is a typical feature of coronavirus disease 2019 (COVID-19) in both the acute and chronic phases. In a meta-analysis, the prevalence of fatigue was 23% in acute COVID-19 infection [171]. Persistence for weeks or months beyond the acute phase of infection is common [172]. Up to 46% of patients report fatigue lasting weeks to months post-COVID-19 infection [173]. The degree of fatigue can be subjective, or it can be objectively quantified as a reduction in muscle strength on physical examination [173]. Fatigue is reported both in its "physical" (loss of energy and feeling of heaviness) and "mental" (a feeling of brain fog). Fatigue is often perceived as more intense and persistent in the presence of reduced physical or cognitive activity [174], and complete anamnestic evaluation is crucial to clarify the nature of the symptoms, mechanisms of onset, and impact in patient's quality of life. Cardiorespiratory physical examination with laboratory tests with the values of hemoglobin, glycemia, C-reactive protein, troponin, D-dimer and BNP, and arterial oxygen saturation are of crucial importance. ECG and echocardiography represent the first-level tests for cardiovascular assessment. Chest X-ray and spirometry, on the other hand, represent the first step in analyzing the respiratory system. Cardiopulmonary exercise test (CPET) allows to quantify exercise limitation through the direct measurement of oxygen consumption values (VO2), thereby allowing to discriminate between a

*Perspective Chapter: Cardiovascular Post-Acute COVID-19 Syndrome – Definition, Clinical... DOI: http://dx.doi.org/10.5772/intechopen.109292*

cardiac or ventilatory or peripheral cause such as dys-autonomic deconditioning or muscle inefficiency. Finally, a correct evaluation of the neuro-phycological and cognitive functions is also important, to exclude possible other causes of fatigue such as anxious, depressive syndrome, or post-traumatic stress disorder. Further examinations will be considered based on the findings observed during the diagnostic process.

#### **3. PACS therapy**

Since, nowadays, no specific therapy for cardiovascular diseases associated with COVID-19 or PACS (e.g., myocarditis, acute coronary syndrome, pericarditis, Takotsubo syndrome, atrial or ventricular arrhythmias, and heart failure) are available, the standard of care reported by international cardiac guidelines represents the recommended therapeutic strategy for each specific vascular sequela of the PACS. Although current evidence for of long COVID treatment is lacking, many clinical trials on therapy for CV sequelae treatment of long COVID and are currently underway. Moreover, both SARS-Cov2 acute infection specific therapy and vaccinations are opening up promising scenarios in the prevention and treatment of COVID-19 sequelae. In fact, more than 700 studies related to COVID-19 and more than 100 on long term are ongoing (see International Clinical Trials Registry Platform (ICTRP) (who.int) and see Search of: COVID-19—List Results—ClinicalTrials.gov), thereby suggesting the hope for a "new era" in the treatment of this, in many respects, unknown pathology. Studies include a wide range of therapy such as: rehabilitation programs (for the treatment of fatigue, dyspnea, inappropriate tachycardia, POTS, and cognitive decline), immunomodulatory therapies (e.g. steroids, laranilubmab, tocilizumab, atorvastatin, and colchicine), anti-thrombotic (e.g. aspirin), or anticoagulation (e.g. apixaban). Although a large amount of evidence confirms a lack of benefit of aspirin in reducing mortality among hospitalized [175] and non-hospitalized outpatients [176], promising results were produced in support of anticoagulation [177]. The multiplatform adaptive randomized controlled clinical trial [178] reported an improved survival in moderately ill patients treated with therapeutic dose of heparin, but not in critical illness. In contrast, other studies [179–181] reported no difference in primary outcome measures among patients receiving therapeutic vs. prophylactic dose anticoagulation. Therefore, further research is therefore needed to better understand the long-term benefits of anticoagulation in patients. Although anti-inflammatory drugs such as dexamethasone [182] and tocilizumab [183] or antivirals such as remdesivir [184] represent the most used and effective therapeutic armamentarium in patients with severe COVID-19, whether they are able to prevent cardiovascular sequelae or to reduce the impact of long-COVID-19 after the acute phase is still unclear. In conclusion, nowadays, the most effective way of preventing serious complications from SARS-CoV-2 infection is represented by SARS-Co2 vaccination [185–191]. Early data [192] have recently suggested the possibility that of long COVID symptoms could be alleviated through vaccination. More specifically, of 900 people with long COVID, only 18.7% of patients reported a deterioration on clinical status, while 56.7% of vaccinated showed an overall improvement in clinical sequelae.

Finally, since the acute phase of COVID-19 is complicated by several multisystem sequelae in a vast majority of subjects, rather than a single drug, subjects with PACS need a multidisciplinary approach aimed at managing each single PACS sequela. This multidisciplinary approach, including clinical, cardiological, pneumological, neurological psychological, and physiotherapeutic evaluation, is generally provided

**Figure 8.** *PACS evaluation and therapy.*

by the rehabilitation program of chronic diseases (e.g. cardiac or pulmonary rehabilitation) [193]. For these reasons, on top of the aforementioned therapies, a specific post-COVID-19 rehabilitation approach represents new hope in fighting against the sequelae of PACS (**Figure 8**). In fact, results from early post-COVID-19 rehabilitation registry and trials showed an improvement in dyspnea, anxiety, muscle strength, walking capacity, sit-to-stand performance, and quality of life; on the other hand, results on pulmonary function are still inconsistent [194].
