This study aims to evaluate the impact of a non-pharmacological treatment (nutritional therapy and pulmonary rehabilitation) on endothelial function, body composition, and physical functionality in recovered COVID-19 patients.

The primary research question is: What is the effect of a non-pharmacological treatment (nutritional therapy and pulmonary rehabilitation) on endothelial function, body composition, and physical capacity in recovered COVID-19 patients, compared to those receiving conventional medical management? A nutritional treatment combined with L-citrulline supplementation (intervention group) will be compared against conventional treatment alone (control group). Both groups will undergo pulmonary rehabilitation for a 3-month follow-up.

Subjects assigned to the intervention group will be required to:

• Take 4 g of L-citrulline daily for 3 months.
• Attend an interim session at 1.5 months for review of the nutritional treatment and supplementation.
• Keep a record of each supplement intake.

Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, represents a global public health crisis that has resulted in severe complications and death in more than 500,000 individuals worldwide.

The risk factors for severe COVID-19 include age over 70 years, hypertension, diabetes mellitus, smoking, coronary artery disease, and obesity, which have been associated with endothelial dysfunction (ED). The coexistence of chronic non-communicable diseases significantly exacerbates the inflammatory response, increasing the risk of adverse events and poor prognosis. Similarly, a high probability of cardiovascular diseases in subjects is at elevated risk of severe COVID-19, due to the overexpression of angiotensin-converting enzyme 2. In addition, in our country, the leading causes of death are related to metabolic diseases: 19% of men and women between the ages of 30 and 69 die from cardiovascular diseases, with diabetes ranking as the second leading cause of death. Furthermore, 76.6% of the population is overweight or obese, and 25.5% has hypertension, factors that render our population particularly susceptible to moderate to severe COVID-19.

Moreover, both pharmacological and non-pharmacological treatments have primarily focused on the acute phase of infection. However, it is essential to implement treatment protocols, including pulmonary rehabilitation and nutritional therapy with citrulline supplementation or immunonutrients with anti-inflammatory properties, to prevent Post-Intensive Care Syndrome, reduce systemic inflammation, and improve endothelial function. These interventions may collectively enhance protein synthesis, attenuate muscle mass loss, and promote patient autonomy, functional recovery, and overall quality of life.

Post-COVID-19 syndrome Post-COVID-19 syndrome has been defined as the persistence of symptoms and/or delayed long-term remission of complications arising from SARS-CoV-2 infection, occurring beyond 4 weeks after initial symptom onset.

Nutritional supplementation L-citrulline L-Citrulline is a non-essential, water-soluble alpha-amino acid and a potent endogenous precursor of L-arginine, which increases the bioavailability of NO. In endothelial cells, NO is synthesized from L-arginine by endothelial nitric oxide synthase, yielding NO and L-citrulline.

Endothelial dysfunction ED is a systemic condition in which the endothelium loses its physiological properties, including vascular permeability, vascular tone regulation, and neutrophil recruitment, thereby promoting a prothrombotic, proinflammatory, and pro-oxidant state.

General objective:

To evaluate the impact of a non-pharmacological intervention (nutritional therapy and pulmonary rehabilitation) on endothelial function, body composition, and physical functionality in recovered COVID-19 patients.

Specific objectives:

To evaluate the impact of a non-pharmacological intervention (nutritional therapy and pulmonary rehabilitation) on endothelial function in recovered COVID-19 patients.

To evaluate the impact of a non-pharmacological intervention (nutritional therapy and pulmonary rehabilitation) on body composition in recovered COVID-19 patients.

To evaluate the impact of a non-pharmacological intervention (nutritional therapy and pulmonary rehabilitation) on physical functionality in recovered COVID-19 patients.

To evaluate the impact of a non-pharmacological intervention (nutritional therapy and pulmonary rehabilitation) on quality of life in recovered COVID-19 patients.

Secondary objectives:

To describe the prevalence of sarcopenia in recovered COVID-19 patients. To describe cardiovascular alterations in recovered COVID-19 patients. To describe alterations in body composition in recovered COVID-19 patients. To describe metabolic alterations in recovered COVID-19 patients. To evaluate the effect of a non-pharmacological intervention (nutritional therapy and pulmonary rehabilitation) on muscle strength in recovered COVID-19 patients.

To evaluate the effect of a non-pharmacological intervention (nutritional therapy and pulmonary rehabilitation) on pulmonary function in recovered COVID-19 patients.

Inclusion Criteria:

• Recovered COVID-19 patients with a negative PCR test for SARS-CoV-2.
• Subjects between 40 and 80 years.
• Subjects who give written informed consent to participate in the study.

Exclusion Criteria:

• Subjects diagnosed with Human Immunodeficiency Virus (HIV).
• Subjects diagnosed with cancer.
• Subjects with a glomerular filtration rate (GFR) <30 ml/min/1.73 m².
• Subjects currently enrolled in another interventional study.