Sarcopenia is a progressive and generalized condition that causes loss of muscle mass and function ^[1]. This disorder determines strength reduction, skeletal muscle failure, or insufficiency. The diagnosis is formulated with a stepwise approach. The first step consists in the measurement of the muscle strength by using the handgrip test. As a result of this test, sarcopenia can be excluded or suspected. Suspected sarcopenia needs to be confirmed by using other techniques that measure muscle mass, such as Dual-Energy X-ray Absorptiometry (DXA), Bioelectrical Impedance Analysis (BIA), Computed Tomography scan (CT), and Magnetic Resonance Imaging (MRI) ^[1].

Maintaining sufficient muscle mass and strength is important for healthy living. Acute sarcopenia is known to occur during COVID-19, especially in older patients, with direct implications for post-COVID-19 function and recovery ^[2]. Parenteral steroids used in patients with severe COVID-19 also contribute by increasing muscle protein breakdown ^[2]. Therefore, nutritional therapy to restore muscle mass is an important aspect in the management of post-COVID-19 syndrome. A recent systematic review and meta-analysis, evaluating nutritional interventions to improve muscle mass, muscle strength, and physical performance in older subjects, concluded that protein supplementation on top of resistance training can be used to increase muscle mass and muscle strength ^[3]. According to this review, the minimum daily protein requirement for healthy elderly subjects is 0.83 g of good-quality protein per kilogram body weight per day.

In addition, β-hydroxy-β-methylbutyrate or creatine supplementation was also effective, whilst the best evidence was available for the use of leucine, an essential amino acid ^[3]. This intervention—as supplements or in the form of a balanced diet—could apply also for muscle mass restoration in patients with post-COVID-19 syndrome, thereby favoring a faster physical recovery.

The gut microbiota plays a unique metabolic function in the host. Indeed, reduced microbial diversity and gut dysbiosis have been recently implicated in host chronic diseases (i.e., inflammatory bowel disease, type 2 diabetes, cardiovascular disease, and colorectal cancer) ^[4]. Furthermore, the gut can communicate with the brain using neural, inflammatory, and hormonal signaling pathways, thus influencing psychological well-being ^[4].

Patients with COVID-19 have shown alterations in the composition of the gut microbiota, especially in the context of antibiotic use, and this can have both short- and long-term consequences for physical and psychological well-being, including recovery and the occurrence/severity of post-COVID-19 syndrome ^[5]. Studies have shown that protein, fats, digestible and non-digestible carbohydrates, probiotics, and polyphenols all induce shifts in the composition of the gut microbiota ^[6][7]. 

Recent studies showed that a significant proportion of COVID-19 patients suffer from prolonged post-COVID-19 fatigue syndrome, with symptoms resembling chronic fatigue syndrome (CFS) ^[8]. The pathophysiology is complex and involves autonomic dysfunction, endocrine disturbances, and reactive mood disorders (i.e., depression or anxiety), combined with genetic, environmental, and socio-economic predispositions ^[8]. At present, there is insufficient high-level evidence to directly support the use of nutritional supplements and modified diets to relieve symptoms in patients with post-COVID fatigue syndrome. However, there is evidence to support that the deficiency of some nutrients (i.e., vitamin C, vitamin B group, sodium, magnesium, zinc, folic acid, l-carnitine, l-tryptophan, essential fatty acids, and coenzyme Q10) seems to be important in the severity and progression of CFS symptoms by increasing oxidative stress ^[9]. Recently, several trials focusing on CFS patients have reported the benefit of antioxidants and lipids to reduce CFS symptoms. Indeed, the supplementation of glycophospholipid–antioxidant–vitamin demonstrated an improvement in the overall fatigue scores of moderate subjects measured using the Piper Fatigue Scale (PFS) ^[9]. Therefore, adequate nutritional supplements including essential fatty acids and antioxidants, or the same given in the form of a balanced healthy diet, could help in the control/alleviation of post-COVID-19 fatigue syndrome.

In addition to the impact on physical health, post-COVID-19 syndrome also affects psychological well-being, including the development of anxiety, depression, post-traumatic stress disorder (PTSD), and cognitive impairment ^[10]. The association between nutrition and psychological well-being has gained increasing attention during recent years. Epidemiological studies have shown a reduced risk of depression associated with high fruit and vegetable intake ^[11]. Indeed, the supplementation of glycophospholipid–antioxidant–vitamin demonstrated an improvement in the overall fatigue scores of moderate subjects measured using the Piper Fatigue Scale (PFS) ^[11]. Furthermore, experimental exposure of healthy volunteers to diets with a high glycemic index has been shown to increase the occurrence of depressive symptoms ^[12]. In addition, studies have also shown that the Mediterranean diet can reduce markers of inflammation, while high intake of saturated and trans-fats and refined carbohydrates could result in cognitive decline and hippocampal dysfunction, leading to impaired psychological well-being ^[11][13]. Furthermore, it is worth mentioning that lipids constitute approximately 50–70% of the brain’s dry weight, and changes in the lipid environment of the brain result in functional alterations of the activities of receptors and other membrane proteins, with an impact on neurotransmission ^[14]. Notably, it has been demonstrated that diets rich in omega-3 fatty acids upregulated genes involved in maintaining synaptic function and plasticity in animals, and enhanced cognitive functioning in humans ^[14]. Additionally, omega-3 fatty acid deficiency is associated with an increased risk of developing various psychiatric disorders, and they are important for the maintenance of psychological well-being ^[14]. Therefore, it is evident that an overall healthy diet rich in fruits and vegetables, and bioactive compound constituents such as omega-3 fatty acids, with low intake of trans-fats and refined carbohydrates, can enhance psychological well-being, and, therefore, could play a role in recovery from post-COVID-19 syndrome.

2. Dietary Recommendations for Patients with Post-COVID-19 Syndrome

2.1. Energy Intake

The energy requirements for patients with post-COVID-19 syndrome depend on their actual nutritional status. Most individuals experienced unintentional weight reduction during COVID-19 infection, due to increased inflammation, appetite loss linked to taste/smell alterations, and swallowing disorders. In addition, patients might present early satiety and fullness after eating and drinking ^[15][16][17]. Therefore, it is important to correct the imbalance between energy expenditure and energy intake. Over the estimation of individual energy requirements (according to age, gender, and weight), patients can be advised regarding practical strategies to increase their food intake, such as consuming smaller and more frequent meals (six meals/day, snacking every 3 hours), drinking away from meals to avoid early satiety, and limiting foods or beverages labeled “light”, “low fat”, or “low calorie”. Ready-to-drink, low-volume oral nutritional supplements might be considered to increase energy intake ^[18]. Nevertheless, some patients were overweight/obese before COVID-19 infection, whereas some individuals gained weight during confinement for variations in eating habits, stress, mental burden, and physical activity ^[19][20][21]. 

2.2. Macronutrients

The protein requirement should be higher in patients with post-COVID-19 syndrome to improve sarcopenia and avoid further wasting of muscle mass ^[22]. Patients should be recommended to include high-quality proteins, both from plant and animal sources, and to consume 15-30 g protein/meal, depending on body weight, to ensure their intake of all the essential amino acids, which might exert an anti-inflammatory effect ^[23][24]. Moreover, some studies suggested that consuming protein during the day might prevent autophagy ^[25]. Therefore, it could be useful to include a protein source at each meal and snack. In addition, certain amino acids, i.e., arginine and glutamine, might be supplemented by virtue of their known role in the modulation of the immune response ^[24].

As for fat intake, a daily intake of 1.5–3 g/day of omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) should be advised to improve inflammation. Interestingly, it has been shown that omega-3 fatty acids might inhibit the viral replication of enveloped viruses—such as COVID-19—possibly reducing the risk of new infections ^[26]. Moreover, the consumption of extra-virgin olive oil should be increased to provide adequate intake of monounsaturated fatty acids, tocopherols, and polyphenols, which have demonstrated anti-inflammatory and antioxidant properties ^[27].

Finally, total carbohydrate intake is not a major concern in patients with post-COVID-19 syndrome. However, the consumption of carbohydrate sources with a low glycemic index is highly recommended. Indeed, the intake of food with a high glycemic index has been associated with increased inflammation and oxidative stress ^[28][29]. Furthermore, the intake of viscous and fermentable fibers (i.e., β-glucan and arabinoxylans from wholegrain, pectins from fruit, vegetables, and legumes) should be increased by virtue of its prebiotic effect towards butyrate-producing bacteria, which has been associated with reduced inflammation in the host ^[30][31].

2.3. Micronutrients

The role of nutrition, particularly trace elements and vitamins in modulating immunity, has received much interest during the pandemic. Indeed, a pilot study assessed micronutrient status in hospitalized patients for COVID-19 showing micronutrient deficiency, particularly in vitamin D (76%) and selenium (42%) ^[32].

The role of vitamin D in reducing infections is carried out through several mechanisms. These include the induction of cathelicidins and defensins, diminishing virus survival and replication, and keeping undamaged the epithelial layers ^[33]. Those specifically related to COVID-19 infection include the reduction of pro-inflammatory cytokine concentrations and augmenting ACE2 levels ^[34]. It should be noted that the effects of vitamin D supplementation on indices of inflammation and oxidative stress have also been studied in other diseases, such as diabetic patients ^[35][36] and hypertensive patients ^[37], as well as its effect on calcium metabolism and broad non-calcemic gene expression ^[38]. Another disease that has been related to low concentrations of 25-hydroxyvitamin D (25(OH)D) is breast cancer, seeing that higher concentrations of this vitamin are associated with a lower risk of breast cancer ^[39].

Notably, vitamin D deficiency has been reported to be common in patients with cardiovascular disease (CVD) ^[40][41]. The Mendelian randomization analyses performed in four population-based cohort studies found an inverse association between the results of coronary heart disease, stroke, and all-cause mortality with a low serum concentration of this vitamin ^[42]. Acharya et al. observed that in patients with vitamin D deficiency and no history of myocardial infarction, treatment with a certain level of 25(OH)D was associated with a significantly lower risk of mortality from all causes ^[43].

Therefore, the ESPEN guidelines ^[18] and others ^[44] recommend that patients should consume 100% of the recommended daily intake (RDA). Higher intakes would be required ^[45], and a multivitamin and mineral supplement should be advised at least once daily for patients with micronutrient deficiency. The international nutritional recommendation suggests the importance of vitamin D intake (400 IU), particularly in patients with lower exposure to sunlight (i.e., long-term confinement or hospitalization) ^[32][46].

2.4. Nutraceuticals

As for immunostimulators, milk proteins and peptides (bovine lactoferrin, lactoperoxidase, serum albumin, β-lactoglobulin, and α-lactalbumin) have been used as effective immune boosters ^[47], although the mechanisms underlying this beneficial effect are not completely clear. Furthermore, probiotics (i.e., Lactobacillus and Bifidobacteria) might improve the immune response, favoring the competition with pathogens for colonization in the gut and maintaining intestinal barrier integrity, thus reducing permeability to a pathogen and its microbial metabolites ^[48].

Finally, some nutritional compounds have been proposed as immunomodulators for the treatment of COVID-19 or to attenuate its symptoms. Glychophosphopeptical (AM3), a glucan glycophosphopeptid, can modulate both innate and adaptive immunity ^[49]. Polypodium leucotomos extract is known for its pleiotropic effect on different pathways related to the immune response ^[50]. Glutamine is a conditionally essential amino acid that plays a critical role in the modulation of the “cytokine storm” during COVID-19 infection ^[51].

2.5. Mediterranean Diet

Mounting evidence demonstrates that dietary intake (including nutrients and non-nutritive bioactive compounds) could modulate inflammation and the immune system. Therefore, the combination of different foods with these properties in a whole dietary pattern can be used as a useful nutritional approach for patients with post-COVID-19 syndrome.

The Mediterranean diet is characterized by many bioactive compounds with anti- inflammatory and antioxidant activities (monounsaturated and omega-3 fatty acids, and vitamins, minerals, and phytochemicals, respectively) ^[52]. Indeed, several studies confirmed the anti-inflammatory and immunomodulatory effects of a Mediterranean diet on several diseases associated with chronic low-grade inflammation ^[53]. Interestingly, observational studies highlighted an association between adherence to the Mediterranean diet and better outcomes in patients with COVID-19 (mortality, recovery rate) as well as risk of COVID-19 infection in different populations ^{[26][54][55][56][57]} Therefore, it is recommended to consume more plant-based foods (fruit, vegetables, wholegrain, and legumes), high-quality animal proteins (fish, lean meat, poultry, eggs, and low-fat cheese), and extra-virgin olive oil as the principal source of fat ^[58].

Lastly, adequate hydration (30 mL/kg actual body weight) is important for the complete recovery of patients with post-COVID-19 syndrome ^[59]. Therefore, these patients should increase their daily fluid intake (2.5–3 L/day) by consuming water, milk, fruit juice, broth, sports drinks, coffee, and tea.