Different aspects related to obesity and the COVID-19 pandemic

Until 2020, obesity was the main pandemic of the 21st century^{(24-Reference Lee26)}. Nevertheless, obesity has never received urgent attention, as occurs with the rapid spreading of infectious diseases. Now, the world faces the confluence of two overlapping public health problems: COVID-19 and obesity – with its associated co-morbidities^{(Reference Ryan and Ravussin22)}.

According to the WHO^{(Reference World Health27)}, global obesity has almost tripled since 1975. More alarming data are that, in 2018, 40 million children under 5 years of age were overweight or obese. The USA, the country at the top of the COVID-19 pandemic ranking, is also one of the leaders in the prevalence of obesity⁽²⁸⁾.

Despite the alarming numbers of overweight and obesity cases, the WHO^{(Reference World Health27)} considers obesity to be preventable. Classic interventions, with the highest degree of therapeutic recommendation, consist of practising regular physical activity, important in the anti-inflammatory response and reduction of changes in cytokines associated with the strengthening of cellular immune function in obesity^{(Reference Souza, Matos and Dos Santos29)}. Limiting the intake of energy from fats, reducing salt and sugars, and increasing the consumption of vegetables, fruits and whole grains is also essential^{(Reference World Health27)}. However, these measures are not easy to adhere to, considering that patients with obesity and its associated morbidities keep increasing in prevalence^{(Reference Afshin, Reitsma and Murray30,Reference Berry31)} .

With the ongoing COVID-19 pandemic, these recommendations have been reinforced by relevant agencies of the UN, which consider that a balanced, diversified and nutritious diet is a crucial way of promoting health and nutritional well-being⁽¹¹⁾. This nutritional care plays a critical role in the immune system^{(Reference Childs, Calder and Miles3,Reference Zhang and Liu4)} .

Altered microbiota diversity occurs in most individuals with obesity, and a mutual interplay exists between gut microbiota and the immune system^{(Reference Pindjakova, Sartini and Lo Re32)}. According to Morais et al. ^{(Reference Morais, Passos and Maciel33)}, the administration of probiotics could be a promising adjuvant alternative in the treatment of SARS-CoV-2 infection in addition to adequate intake of nutrients and bioactive compounds from unprocessed food.

Inadequate intake of vitamins and minerals, food processing and industrialisation are related to obesity and the co-regulating of the intestinal microbial ecosystems. Increased energy intake, influenced by lifestyle changes resulting from urbanisation and globalisation, has promoted an obesogenic environment^{(Reference Pindjakova, Sartini and Lo Re32,Reference Monteiro and Cannon34-Reference Falcao, Lyra and Morais38)} . Although consuming ultra-processed foods is associated with obesity and its co-morbidities^{(Reference Chazelas, Srour and Desmetz39)}, only recently studies related this consumption to damage in the immune system^{(Reference Jordan, Adab and Cheng13,Reference Andersen, Murphy and Fernandez14)} . Cohort studies are also being conducted to clarify the real impact of ultra-processed foods on health^{(Reference Silva, Giatti and de Figueiredo40,Reference Medeiros, Azevedo and Mesquita41)} .

Thus, the viability of widespread interventions related to this dietary pattern and their sustainability needs to be evaluated, considering the possibility of generating economic and social impact^{(Reference Afshin, Reitsma and Murray30,Reference Dietz42)} . These new interventions should add to the continued adoption of recommendations and strategies aligned with the guidelines given by competent entities in generating data and managing aspects related to nutritional surveillance, food protection, quality of food and food security. These concerns have been raised given COVID-19⁽¹¹⁾, as food biodiversity is an opportunity to increase food and nutrition security today^{(Reference Jacob, Medeiros and Albuquerque43)}.

Multisectoral and evidence-based policy actions to deal with the global nutrition crisis have risen. Consequently, obesity has been targeted in several aspects, even though some measures are still unpopular and do not present immediate results. Actions in health systems, economic incentives, concerns about the school and work environment, quality and labelling standards, and innovation, entrepreneurship and sustainability are being implemented^{(Reference Bezerra, Oliveira and Pinheiro44-Reference da Cunha, Rolim and Damasceno47)}.

Overweight and obesity cause other non-communicable diseases that affect the reserves of many nutrients^{(Reference Aquino, da Cunha and Pereira48-Reference Cunha, Pereira and de Aquino52)}. Overweight and obesity lead to adverse metabolic effects on blood pressure, lipid profile, insulin resistance, low-grade inflammation, and, consequently worse prognosis for viral infections, and this seems to be the same for SARS-CoV-2^{(Reference Calder, Carr and Gombart2,Reference Dietz and Santos-Burgoa12,Reference Jordan, Adab and Cheng13,Reference Bornstein, Dalan and Hopkins15)} .

However, most deaths from non-communicable diseases could be prevented with known behavioural and pharmaceutical interventions. Several initiatives for preventing and controlling non-communicable diseases have been adopted over the last decades, supported by the WHO. These initiatives are currently being tested in the treatment of COVID-19, especially in cases where obesity is also present^{(Reference Bornstein, Dalan and Hopkins15,Reference Mamber, Krakowka and Osborn19,Reference Sanders, Monogue and Jodlowski20)} .

Besides obesity emerging as a significant important risk factor for the severity of COVID-19, the lockdown imposed by COVID-19 may also increase the prevalence of obesity^{(Reference Hellewell, Abbott and Gimma53)}. For example, most weight-loss programmes and nutritional interventions, such as bariatric surgery, are currently restricted. Additionally, self-isolation measures adopted in some countries will directly affect food consumption at this time of anxiety, and restrict mobility and physical activity. Thus, the effects of increased overweight and obesity may persist for an extended period^{(Reference Kissler, Tedijanto and Goldstein54)}, even considering the alternating isolation. This increase may be especially true in vulnerable populations that already presented food and nutritional insecurity as social-health issues and may worsen the evolution of the COVID-19 pandemic even more^{(11,Reference Calazans, Pequeno and Camara55-Reference Ribeiro, Garcia and Dametto60)} .

Finally, this global urgency to combat COVID-19 may generate more confidence in processed and industrialised foods compared with fresh food, conditioned by hygienic-sanitary safety, longer shelf life and easier stocking⁽⁶¹⁾. According to Butler & Barrientos^{(Reference Butler and Barrientos62)} and Muscogiuri et al. ^{(Reference Muscogiuri, Barrea and Savastano63)}, it is essential to improve broader access to healthy foods rich in vitamins, minerals, bioactive compounds and antioxidants to reduce susceptibility and long-term complications of COVID-19. Diet composition and obesity have a widespread role in immunity^{(Reference Pindjakova, Sartini and Lo Re32)}, affecting the severity of respiratory diseases and other infections.

Obesity and impaired immune response

Impaired immune response in individuals with obesity is not a novel feature, and this has been evidenced by high vaccine failure^{(Reference Sheridan, Paich and Handy64)} and more complications from infections^{(Reference Bandaru, Rajkumar and Nappanveettil65)}. Worsened response to infections in the presence of obesity was observed in Asian (1957–1960) and Hong Kong (1968) influenzas, leading to higher mortality and prolonged illness duration. The H1N1 pandemic in 2009 was also more severe in patients with obesity, causing more hospitalisations and deaths^{(Reference Luzi and Radaelli66)}. The same seems to be true for the COVID-19 pandemic^{(Reference Simonnet, Chetboun and Poissy23,Reference Luzi and Radaelli66)} , and there are some immunological explanations for these facts.

One of these explanations underlies the fact that obesity causes stress and dysfunction in many tissues, including the adipose tissue, liver, skeletal muscle, pancreas, gut and respiratory tract. Most of these alterations present an intricate association with inflammation, determined by the immune cells activated in the adipose tissue^{(Reference Andersen, Murphy and Fernandez14)}.

Low-grade chronic inflammation, characterised by a higher concentration, in basal levels, of the pro-inflammatory cytokines TNF-α, IL-1β, monocyte chemoattractant protein-1 (MCP-1) and IL-6, is an obesity hallmark. These cytokines are mainly produced by visceral and subcutaneous adipose tissue-activated macrophages and enlarged adipocytes^{(Reference Cox, West and Cripps67)}. Classically, this production was considered separately for obesity and pathogens, but now it is accepted that both cause chronic cellular stress, activating shared signalling pathways. The primary difference between these two activations is that the response to pathogens is acute and highly inflammatory. In obesity, the low-grade tissue inflammation provides a physiological immune adaptation. Disruption of this adaptation causes the transition from metabolically healthy obesity to the metabolic syndrome^{(Reference Thomas and Apovian68)}.

Although the order of the determining factors for obesity-induced inflammation in humans is not precisely described, animal models have shown that overfeeding causes oxidative stress and an increase in NEFA in the adipose tissue^{(Reference Thomas and Apovian68)}. These factors induce the activation of classical macrophages (M1), which are highly inflammatory cells, producing IL-1β, TNF-α and IL-6. TNF-α reduces insulin sensitivity, and the inflammatory cytokines induce more lipolysis with the release of more NEFA, creating an upstream pathway for the inflammation^{(Reference Wynn, Chawla and Pollard69)}.

The enlarging white adipose tissues, in turn, release the CCL2, CCL5 and CCL8 chemokines, which recruit more inflammatory monocytes to the adipose tissue. Concisely, in the absence of obesity, adipose tissue macrophages represent 10–15 % of stromal cells and present markers associated with the maintenance of insulin sensitivity by the production of IL-10. In this context, alternative macrophages (M2) are more activated, producing IL-10 after stimulation by IL-4 and IL-13. Adiponectin is also higher in lean animals and humans and inhibits the activation of M1. In contrast, during obesity in mice and humans, inflammatory monocytes are recruited to adipose tissue, increasing macrophage content to 45–60 %^{(Reference Andersen, Murphy and Fernandez14,Reference Wynn, Chawla and Pollard69)} .

The inflammation and stress in the adipose tissue induce adipocyte apoptosis and the release of chemotactic mediators. Apoptosis and the chemotactic mediators promote inflammatory leucocyte infiltration. The inflammatory leucocytes produce resistin and IL-1β and induce M1 and adipocytes to produce more TNF-α, IL-6 and monocyte chemoattractant protein-1 (MCP-1), causing a vicious cycle of inflammation^{(Reference Cox, West and Cripps67-Reference Wynn, Chawla and Pollard69)}.

These inflammatory alterations in the adipose tissue underlie the chronic systemic inflammation and the metabolic changes in obesity. These changes are mediated, besides insulin resistance, by unfavourable hormone milieu. Low adiponectin (an anti-inflammatory adipokine) and high leptin (pro-inflammatory adipokine) production is observed in obesity, ultimately stimulating NF-κB-mediated pro-inflammatory gene transcription and reducing PPAR-α and PPAR-γ transcriptional activity. This hormone profile also leads to dysregulation of the immune response and may concur with the obesity-linked complications during infections^{(Reference Ouchi, Parker and Lugus70)}.

Obesity also negatively alters the lymphoid tissue structure and function. This impairment occurs by ectopic lipid accumulation in the bone marrow, thymus and secondary lymphoid organs, changing the immune tissue architecture^{(Reference Yang, Youm and Vandanmagsar71,Reference Kanneganti and Dixit72)} . This architecture is essential to the development of functional leucocytes through the critical interactions within the immune cells^{(Reference Andersen, Murphy and Fernandez14)}. These tissue structure changes alter leucocyte populations’ distributions, lymphocyte activity, and immune defences and are linked to a compromised response of innate lymphoid cells^{(Reference Rolot and O’Sullivan73)}.

Interestingly, accumulation of fat tissue in the lymphoid tissues naturally occurs in senescence and impairs immunity in the elderly^{(Reference Camell, Günther and Lee74-Reference Dixit76)}. In animal models, energy restriction has been found to block this fat accumulation and is associated with increased immunity and longer lifespan. Thus, obesity can cause premature ‘ageing’ of the immune system^{(Reference Yang, Youm and Vandanmagsar71,Reference Kanneganti and Dixit72)} . This fact may be one of the causes putting individuals with obesity at risk for severe influenza and COVID-19 evolutions, with increased mortality. Further studies should address how immunomodulation induced by diets and other agents could revert the effects of fat accumulation on lymphoid tissues from individuals with obesity and older individuals in the context of SARS-CoV-2 infection.

Obesity alters gut microbiota^{(Reference Cox, West and Cripps67)} and several studies have associated oxidative stress with dysbiosis^{(Reference Silva-Maia, Batista and Correa77,Reference Weiss and Hennet78)} , which is the disruption of healthy microbiota^{(Reference Lazar, Ditu and Pircalabioru79)}. Evidence suggests that intestinal microflora may be responsible for the development of the low-grade inflammation in obesity. This could possibly occur by microflora dysfunctions in the intestinal barrier, increasing its permeability and inducing endotoxaemia, characterised by an increase in gut-derived plasma lipopolysaccharide^{(Reference Cani, Osto and Geurts80,Reference Cani, Possemiers and Van de Wiele81)} .

Studies in animal models have shown that communication between the gut, adipose tissue and brain is essential for maintaining energy balance. This communication is impaired during obesity and type 2 diabetes^{(Reference Geurts, Neyrinck and Delzenne82)}. In this context, metabolic endotoxaemia has been identified as one of the main factors leading to the development of metabolic inflammation and insulin resistance because the increase in plasma lipopolysaccharide induces M1^{(Reference Boutagy, McMillan and Frisard83)}. The adipokines secreted by the adipose tissue might also affect the airway function. Leptin is involved in neonatal lung development, surfactant production^{(Reference Torday, Powell and Farmer84,Reference De Blasio, Boije and Kempster85)} and regulation of ventilatory drive^{(Reference Torday, Powell and Farmer84,Reference Bassi, Furuya and Menani86)} . Studies have consistently shown the association of high leptin concentrations and asthma^{(Reference Sideleva, Suratt and Black87,Reference Sood, Ford and Camargo88)} .

Considering respiratory infections, most of the knowledge linking obesity and immunity comes from experimental models of influenza^{(Reference Mancuso89)}. In diet-induced obesity (DIO) mice with influenza A infection, impaired host defence was associated with a decrease in type I interferon (IFN-α and IFN-β), a delay in IL-6 and TNF-α expression, that increased to higher concentrations than those in lean animals, and impaired the cytotoxicity of natural killer cells^{(Reference Smith, Sheridan and Harp90)}. Further studies also revealed that, after influenza infection, DIO reduced dendritic cells’ ability to present antigens to T cells, impairing monocyte and CD8⁺ T cell recruitment and reducing IL-2 and IL-12 production^{(Reference Smith, Sheridan and Tseng91)}. DIO mice also demonstrated an inability to produce and maintain functional antigen-specific memory CD8⁺ T cells for influenza viruses^{(Reference Karlsson, Sheridan and Beck92,Reference Karlsson, Sheridan and Beck93)} . Additionally, effector CD8⁺ T cells presented a lower ability to kill influenza-infected cells, and compromised healing of pulmonary epithelial cells, resulting in microvascular permeability and protein leak^{(Reference Mancuso89)}.

Thus, obesity causes stress and disruption of several tissues, with inflammation mainly in the adipose and lymphoid tissues, gut and respiratory tract. The stress and inflammation determine the altered activation of leucocyte subpopulations. These changes impair the immune response, increasing the risk for the evolution of infections to severe disease, and might be the leading causes for increased mortality in patients with obesity and COVID-19 (Fig. 1).

Fig. 1. Obesity and immune alterations in different tissues leading to impaired immune response and increased risk for the evolution of respiratory infectious to severe disease. Obesity determines the stress and disruption of many tissues’ integrity leading to inflammation. In the adipose tissue, the enlarging adipocytes present oxidative stress and increase the release of NEFA in the adipose tissue, activating classical macrophages (M1), which produce IL-1β, TNF-α and IL-6. An unfavourable hormone milieu also promotes inflammation: low adiponectin and high leptin productions are observed in obesity. In the lymphoid tissue, lipid accumulation occurs in the bone marrow, thymus and secondary lymphoid organs, altering the immune tissue architecture similarly to findings observed in ageing. In the gut, oxidative stress causes dysbiosis, increasing gut permeability and inducing endotoxaemia, characterised by an increase in gut-derived plasma lipopolysaccharide, which induces inflammation. In the lungs, experimental diet-induced obesity studies of influenza infections showed the reduced ability of dendritic cells (DC) to present antigens (Ag) to T cells, impairing monocyte and CD8⁺ T cell recruitment and reducing IL-2 and IL-12 production. Effector CD8⁺ T cells demonstrated a lower ability to kill influenza-infected cells, and the healing of pulmonary epithelial cells is compromised, resulting in microvascular permeability and protein leak. Overall, the inflammation induced by obesity causes altered activation of leucocyte subpopulations, impairing the immune response and increasing the risk of the evolution of respiratory infection to severe disease. ↑, Increase; ↓, decrease.

Obesity, co-morbidities and COVID-19: a triple burden

In addition to disruption of the immune system, obesity can result in metabolic dysfunction leading to dyslipidaemia, insulin resistance, type 2 diabetes, hypertension and CVD, all of which increase patients’ vulnerability to SARS-CoV-2 infection^{(Reference Kassir94)}. Thus, obesity plays a crucial role in the pathogenesis of COVID-19.

Dietz & Santos-Burgoa^{(Reference Dietz and Santos-Burgoa12)} suggested that the increased prevalence of obesity in older Italian adults compared with in Chinese could explain the higher COVID-19 mortality in Italy. Studies in both animals and human subjects have shown that obesity is directly related to more severe respiratory infections^{(Reference Mancuso89)}. The H1N1 influenza pandemic (2009) reinforced this evidence since multiple cohort studies showed that obesity and morbid obesity are independent risk factors that increase hospitalisation, admission and time in an intensive care unit (ICU)^{(Reference Hanslik, Boelle and Flahault95,Reference Morgan, Bramley and Fowlkes96)} . In Spain, a study observed that obesity was the most common co-morbidity (48 %) in patients admitted to ICU with SARS-CoV-2 infection^{(Reference Barrasa, Rello and Tejada97)}.

Although all the possible pathways of interaction between COVID-19 and obesity are still not wholly understood, the discussion concerning the impact of the high prevalence of obesity and coronavirus infection has arisen. Possibly, the interaction between these two important public health concerns occurs through multiple overlapping pathways, some of which will be discussed in this section. Data on this topic are still limiting, and for now, only a few studies have addressed the triple burden of obesity, its co-morbidities and COVID-19 or even other coronavirus diseases. Those data are summarised in Table 1.

Table 1. Studies concerning co-morbidities of obesity and coronavirus infections

SARS, severe acute respiratory syndrome; MERS-CoV, Middle East respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SOC3, suppressor of cytokine signalling 3; ACE2, angiotensin-converting enzyme 2; SREBP1, sterol regulatory element-binding protein 1; MAFLD, metabolic associated fatty liver disease; COVID-19, coronavirus disease 2019.

Patients with obesity can present compromised pulmonary ventilation dynamics because overweight increases pressure in the diaphragm, making breathing more difficult during infection, promoting a relative increase in the anatomical dead space. Thus, decreased expiratory reserve volume, functional capacity and respiratory system compliance occur^{(Reference Dietz and Santos-Burgoa12,Reference Luzi and Radaelli66,Reference Al Heialy, Hachim and Senok98)} . In general, abdominal obesity can impair the ventilation in the lungs’ base, resulting in reduced oxygen saturation of the blood^{(Reference Dixon and Peters99)} and obstructive sleep apnoea associated with an increased risk of CVD and metabolic disease^{(Reference Gottlieb and Punjabi100)}. This problem can contribute to daytime alveolar hypoventilation (obesity hypoventilation syndrome) and apparent respiratory failure^{(Reference Schwartz, Patil and Laffan101)}.

Obesity can also contribute to the development of more virulent diseases, and permissive mutations might be triggered by delayed interferon responses that favour viral replication^{(Reference Honce and Karlsson102)}. Meliopoulos et al. ^{(Reference Meliopoulos, Livingston and Van de Velde103)}, using an obese mouse model, showed that the lungs of obese mice increased the expression of epithelial integrin 6, which was associated with the severity of lung disease in an influenza virus infection.

Patients with hyperglycaemia and type 2 diabetes have a state of metabolic inflammation, promoting the release of inflammatory cytokines^{(Reference Mehta, McAuley and Brown104)}. In cases of COVID-19, this condition might be one of the triggering factors to the so-called cytokine storm (a high cytokine release), consequently leading to death due to multiple organ failure. Kulcsar et al. ^{(Reference Kulcsar, Coleman and Beck105)} (Table 1), using mice with type 2 diabetes induced by administering a high-fat diet, observed that upon infection with MERS-CoV (Middle East respiratory syndrome coronavirus), diabetic mice had a prolonged phase of severe disease and delayed recovery, regardless of virus titres. These results were attributed to a dysregulated immune response, characterised by lower TNF-α, IL-6, IL-12b and Arg1 expression levels and higher IL-17a expression levels.

Recently, Hoffmann et al. ^{(Reference Hoffmann, Kleine-Weber and Schroeder21)} elucidated that SARS-CoV-2 enters human cells through spike glycoprotein found on the virus’s surface. This spike is capable of binding to ACE2, which is expressed in the mouth^{(Reference Xu, Zhong and Deng106)}, lung^{(Reference Hoffmann, Kleine-Weber and Schroeder21)}, intestine^{(Reference Wang, Zhao and Liu107)} and kidney^{(Reference Fan, Li and Ding108)}. Studies have already shown that the renin–angiotensin system modulates the metabolism and endocrine function of adipocytes^{(Reference Engeli, Negrel and Sharma109)}, so this will have significant consequences in patients with obesity infected with SARS-CoV-2.

Bornstein et al. ^{(Reference Bornstein, Dalan and Hopkins15)} discuss that individuals with insulin resistance or diabetes and hypertension may have this clinical condition aggravated due to an imbalance in the pathways that regulate the activities of ACE1 and ACE2. An increase in the activation of angiotensin receptors (AT1R and AT2R) is promoted, causing higher pro-inflammatory responses, and stimulating aldosterone secretion. As a result, there is an increment in local vascular permeability, which worsens the respiratory syndrome. Besides, type 2 diabetes induces the expression of ACE in tissues other than the lung, such as the liver and heart, so this may contribute to the death of patients due to multiple organ failure in cases of SARS-CoV-2. They observed a high risk to the development of severe hypoxia and death related to the hyperglycaemia and ketosis effects in severe acute respiratory syndrome (SARS) (Table 1).

The clinical condition of patients diagnosed with SARS-CoV-2 worsens more intensely in a pre-existing CVD, related to increased ACE2 secretion^{(Reference Zheng, Ma and Zhang110)}. As reviewed by Tan & Aboulhosn^{(Reference Tan and Aboulhosn111)}, several studies have shown that patients with CVD (hypertension and coronary artery disease) require considerable attention in the ICU due to the higher possibility of developing a severe clinical condition of COVID-19.

Obesity and diabetes are directly related to unregulated lipid synthesis and clearance. Al Heialy et al. ^{(Reference Al Heialy, Hachim and Senok98)}, through the re-analysis of public available transcriptomic data, showed that unregulated lipogenesis leads to high expression of ACE2 in individuals with obesity. This mechanism is consequently related to worse lung injury in SARS-CoV-2 infections (Table 1).

Moreover, abdominal fat is associated with metabolic risk factors that contribute to increased coronary risk. Among these factors are abnormalities in the coagulation system^{(Reference Von Eyben, Mouritsen and Holm112)}. According to the review by Blokhin & Lentz^{(Reference Blokhin and Lentz113)}, fibrinolysis is the process of degradation of the fibrin clot by plasmin, whose rate is down-regulated by a serine protease inhibitor secreted by the vascular endothelium, liver and adipose tissue called plasminogen activator inhibitor-1 (PAI-1). The expression of the inhibitor undergoes positive regulation in visceral adipose tissue in obesity. According to the review by Blokhin & Lentz^{(Reference Blokhin and Lentz113)}, high plasma levels of PAI-1 are observed in patients with obesity or the metabolic syndrome. Studies show that TNF-α positively regulates the expression of PAI-1, which suggests that high levels of this activator are related to the chronic inflammatory state of obesity. Preclinical studies demonstrate the association between obesity, high levels of PAI-1, and thrombosis, which reinforces that PAI-1 plays a crucial role in promoting the prothrombotic effects of obesity.

There is an increased risk of disseminated intravascular coagulation and venous thromboembolism as complications in COVID-19^{(Reference Kollias, Kyriakoulis and Dimakakos114)}, and this may be even worse in patients with obesity. Shock and disseminated intravascular coagulation are associated causes of organ dysfunction in sepsis, and abnormal coagulation has been found in non-survivors of COVID-19. Yin et al. ^{(Reference Yin, Huang and Li115)} observed that the platelet count in patients with COVID-19 was significantly higher than in the non-COVID group. They attributed this increase to the reactive increase in thrombopoietin after the lung infection, characterising more severe inflammatory reaction and hypercoagulability in COVID-19.

Patients with acute coronary syndrome deserve greater care by specialist clinicians because cardiac functional reserve may be compromised due to myocardial ischaemia or necrosis. When infected with SARS-CoV-2, these patients may have a myocardial infarction (type 1), increased myocardial demand, ischaemia and necrosis, leading to myocardial infarction type 2. They may also have an increase in the metabolic demand that leads to heart failure and death^{(Reference Zheng, Ma and Zhang110)}.

According to Kovesdy et al. ^{(Reference Kovesdy, Furth and Zoccali116)}, metabolic changes in obesity might also affect the kidneys through the induction of hypertension and type 2 diabetes. Numerous renal system changes can occur, including ectopic lipid accumulation, increased fat deposition in the renal site, development of glomerular hypertension, increased glomerular permeability due to damage to the glomerular filtration barrier related to hyperfiltration, development of glomerulomegaly, and focal or segmental glomerulosclerosis. Insulin resistance and obesity are also related to the increased risk of developing nephrolithiasis. Body weight is associated with lower urinary pH and increased urinary oxalate, excretion of acids, Na⁺ and phosphate. Thus, patients with obesity-associated kidney complications may be more severely affected by SARS-CoV-2 infections. Xu et al. ^{(Reference Xu, Zhang and Gong117)} were able to locate the expression and distribution of the ACE2 and TMPRSS genes in the renal cells of patients diagnosed with COVID-19, through single-cell transcriptome sequencing (scRNA) analysis. They found that the podocytes and cells of the proximal straight tubules were infected by SARS-CoV-2, which resulted in chronic kidney failure induced by the virus.

Zheng et al. ^{(Reference Zheng, Gao and Wang118)} highlight that patients with metabolic associated non-alcoholic fatty liver disease generally have obesity. As a result, they have metabolic risk factors that may generate a higher risk of respiratory illnesses. Consequently, this can contribute to increased severity of SAR-CoV-2 infection (Table 1).

Thus, obesity and its low-grade chronic inflammation induce the onset of the most diverse co-morbidities. Obesity and its co-morbidities, in turn, increase the risk for severe COVID-19. The SARS-CoV-2 infection itself might provoke a broad spectrum of inflammatory responses, aggravating the inflammation of obesity and its co-morbidities and inducing the cytokine storm, characterising the triple burden between obesity, co-morbidities, and COVID-19 that increases mortality (Fig. 2).

Fig. 2. Obesity, co-morbidities and COVID-19 (coronavirus disease 2019): the triple burden. Obesity and its co-morbidities induce low-grade chronic inflammation and an increase in angiotensin-converting enzyme 2 (ACE2) receptors present in the lungs, intestine and kidneys. COVID-19, in turn, also induces inflammation and alterations overlapping those induced by obesity and its co-morbidities. These alterations occur as the disease severity increases and are in: glycaemia – increasing blood glucose; the renin–angiotensin system – causing higher pro-inflammatory responses; lung function – increasing vascular permeability and lung injury; the coagulation system – increasing prothrombotic effects; kidney function – inducing chronic kidney failure. Possible pathways to explain these worsened alterations in patients with obesity and with co-morbidities are: in the lungs – a higher ACE2 expression, unregulated lipogenesis and inflammation; in the coagulation system – a higher concentration of plasminogen activator inhibitor-1; and in the kidney – a higher expression of ACE2 and transmembrane protease serine (TMPRSS) genes. These overlapping alterations and inflammation associated with the cytokine storm induced by COVID-19 increase the risk of complications in patients with obesity, such as respiratory failure, septic shock, multiple organ failure, and, ultimately, increased mortality.

Impact of COVID-19 on the nutritional management of obesity

The first symptoms of COVID-19, such as cough, myalgia, fever and shortness of breath, are similar to other common viral infections^{(Reference Puig-Domingo, Marazuela and Giustina119)} and, in general, individuals can be recovering at home. However, patients with obesity should be aware that they may have more complicated clinical courses, as previously discussed.

When presenting with fever, even if not thirsty, COVID-19 patients should continue drinking fluids to support the body’s ability to fight the virus and the immune function. The American Society for Parenteral and Enteral Nutrition (ASPEN)⁽¹²⁰⁾ recommends drinking water or clear liquid fluids every hour, at least 3 litres/d, and to monitor for signs of dehydration during COVID-19. There have been reports of olfactory and gustatory dysfunctions, like anosmia and ageusia, in patients with mild-to-moderate SARS-CoV-2 infection^{(Reference Russell, Moss and Rigg121-Reference Lechien, Chiesa-Estomba and De Siati123)}. These symptoms can underlie the loss of appetite, also related as a symptom of COVID-19.

Loss of appetite is a symptom of COVID-19^{(Reference Lechien, Chiesa-Estomba and De Siati123)} and has already been linked to inflammation^{(Reference Sieske, Janssen and Babel124)}. Regardless of age or an individual’s BMI, people with a loss of appetite decrease energy and micronutrient consumption^{(Reference Dent, Hoogendijk and Wright125,Reference Caccialanza, Laviano and Lobascio126)} . Nutrients have been extensively related to improvement of the immune status and, consequently, the response to COVID-19. Fresh and minimally processed foods, sources of vitamins C, A, D and E, B vitamins, n-3 PUFA, Se, Fe and Zn should be encouraged^{(Reference Zhang and Liu4,Reference Ellulu127)} . The dietary references intake values of these vitamins and minerals were proposed for healthy individuals by the Institute of Medicine and should be met by the consumption of these foods^(128-131).

Evidence suggests that obesity may decrease fat-soluble vitamins and vitamin C concentrations in the plasma^{(Reference Godala, Materek-Kusmierkiewicz and Moczulski50,Reference Wortsman, Matsuoka and Chen132,Reference Amin, Siddiqui and Uddin133)} . For vitamin A or β-carotene (vitamin A precursor), this reduction occurs due to a lower intake of these nutrients and/or higher deposition in the adipose tissue, decreasing its bioavailability^{(Reference Beydoun, Chen and Jha134,Reference Coronel and Pinos135)} .

Vitamin A deficiency has been associated with lower vitamin C concentrations. In a group of 191 patients with the metabolic syndrome, vitamin C deficiency increased 3·5-fold the risk of vitamin A deficiency^{(Reference Godala, Materek-Kusmierkiewicz and Moczulski50)}. Vitamin A (or its precursors) can be provided by a large amount of fresh or minimally processed foods, such as milk and dairy products, vegetables, fruits (for example, cantaloupe melon), eggs, and oils^{(Reference da Cunha, Rolim and Damasceno47,Reference Medeiros, Gomes and Amaral136)} . Males have daily requirements slightly higher than females⁽¹²⁹⁾. Citric fruits and dark green vegetables are the main sources of ascorbate in the human diet. One portion of orange, kiwi, guava, cantaloupe melon, broccoli or Brussels sprouts has a minimum of 50 % of the RDA of vitamin C^{(131,Reference Fenech, Amaya and Valpuesta137)} .

A major source of vitamin D for most humans comes from exposure of the skin to sunlight. Thus, exposure of arms and legs to 0·5 minimal erythemal doses is equivalent to ingesting approximately 3000 IU (75 μg) of vitamin D₃. Some foods naturally contain vitamin D₂ or vitamin D₃ (cold water fishes, like sardines, tuna, salmon; egg yolk; shitake mushrooms) and fortified food (milk, butter, cheese, yogurts, breakfast cereal). Pharmaceutical and supplemental sources have different contents of vitamin D₂ or D₃^{(Reference Holick, Binkley and Bischoff-Ferrari138)}.

The Endocrine Society Clinical Practice recognises that obesity is associated with vitamin D deficiency and suggests that the daily requirements are higher than the Institute of Medicine values⁽¹²⁸⁾, ranging from 1500 to 2000 IU/d (38 to 50 μg/d) and upper-level intakes until 10 000 IU/d (250 μg/d)^{(Reference Holick, Binkley and Bischoff-Ferrari138)}. Vitamin D supplementation to raise serum 25-hydroxyvitamin D (25(OH)D) concentrations at least 40–50 ng/ml (100–125 nmol/l) would be an important step in preventing COVID-19 infection and spread^{(Reference Grant, Lahore and McDonnell139)}.

The relationship between Zn, obesity and diabetes is well described, showing how this trace element influences lipid and insulin profiles, adiposity, inflammatory processes and insulin resistance^{(Reference Prasad140-Reference Lais, de Lima Vale and Xavier143)}. Recent studies have shown that overweight people and individuals with obesity had lower Zn serum levels than normal-weight individuals^{(Reference Rios-Lugo and Madrigal-Arellano142,Reference Gu, Xiang and Zhang144)} . These lower Zn levels in biological fluids have been associated with a higher risk of developing insulin resistance, inflammation, hypertension and hypertriacylglycerolaemia^{(Reference Olechnowicz, Tinkov and Skalny145)}. Another study revealed that an energy-restricted diet with 30 mg/d of Zn reduced inflammatory markers, insulin resistance, anthropometric measurements and appetite in individuals with obesity^{(Reference Khorsandi, Nikpayam and Yousefi146)}.

Zn is in many foods, including meat, fish, oysters, nuts and legumes. Although the absorption varies by substrate, this trace element plays a role as an immunonutrient together with vitamins A, C, E and D, and Se and Fe^{(Reference Maxfield and Crane147,Reference Reddavide, Rotolo and Caruso148)} . Besides, high Zn²⁺ concentrations can mitigate viral RNA replication. A study showed that the replication of RNA-dependent RNA polymerase (RdRp) from coronavirus (SARS-CoV nsp12) was inhibited by increased Zn²⁺ concentrations^{(Reference Te Velthuis, Van den Worm and Sims149)}.

Dysbiosis has been observed in patients infected with COVID-19. Some experiences in managing this alteration have reported the administration of prebiotics and probiotics^{(Reference Xu, Cai and Shen150)}. There is a mutual interaction between obesity, gut microbiota and the adaptive immune system^{(Reference Pindjakova, Sartini and Lo Re32,Reference Cox, West and Cripps67)} . These interactions possibly increase the inflammatory status in patients with viral infections, as discussed by Gogokhia et al. ^{(Reference Gogokhia, Taur and Juluru151)} in patients with HIV.

Other symptoms of COVID-19 that contribute to the maintenance of overweight and obesity are severe fatigue or myalgia. These can lead to decreased physical activity^{(Reference Carter, Baranauskas and Fly152,Reference Gasmi, Noor and Tippairote153)} . Physical inactivity leads not only to weight gain but also to a loss in immune competence^{(Reference Barazzoni, Bischoff and Breda154,Reference Lippi, Henry and Bovo155)} . Staying home made it more challenging to maintain motivation to a physical activity schedule. For those patients with obesity following nutritional counselling and using medication for co-morbidities and other conditions related to obesity, purchasing healthy food and medicines might be difficult, especially during a lockdown.

The period of social distancing imposed in most countries can be particularly challenging for individuals in treatment for obesity^{(Reference Carter, Baranauskas and Fly152,Reference Lippi, Henry and Bovo155)} . For these cases, it is essential to maintain a stock of medicines and groceries^{(Reference Lippi, Henry and Bovo155)}, and have a fresh food delivery service, so that these items can be replaced more frequently. The amount of contact and support from clinical visits influences motivation to maintain lifestyle changes for weight loss. Teleconference, telehealth and mobile devices may be an effective alternative to provide this patient support and counselling process^{(Reference Barazzoni, Bischoff and Breda154,Reference Severin, Sabbahi and Mahmoud156)} . In this social isolation context, sensations that trigger food consumption are also difficult to contain, such as anxiety and depression^{(Reference Lippi, Henry and Bovo155)}. The boredom caused by the broken routine leads to food craving in an attempt to achieve mood improvement. Therefore, keeping fresh foods and planning meals could help tackle homestay’s adverse health effects^{(Reference Muscogiuri, Barrea and Savastano63)}.

In response to the COVID-19 pandemic outbreak, the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) postponed all elective surgical and endoscopic bariatric surgery to keep hospital resources available to COVID-19 coping^{(Reference Yang, Wang and Shikora157)}. As mentioned, this can negatively affect individuals since following a low-energy diet and medical weight management can be difficult, causing immeasurable impacts on health^{(Reference Tewksbury, Williams and Dumon158-Reference Stahel160)}. Stahel^{(Reference Stahel160)} classified bariatric surgery as elective discretionary that could be postponed for 3 months. Additionally, this author proposed a decision-making algorithm for utilisation during the current COVID-19 pandemic.

The clinical spectrum of the SARS-CoV-2 infection ranges from mild disease with non-specific signs to symptoms of acute respiratory illness^{(Reference Puig-Domingo, Marazuela and Giustina119)}. In situations of worsening symptoms, individuals must seek medical attention. Currently, several channels are available such as phone calls, chats, videoconferences, where it is possible to consult and ask questions to specialists^{(Reference Severin, Sabbahi and Mahmoud156)}.

However, sometimes the individual must go to a health service for examinations and even for specific hospitalisation care when diagnosed with COVID-19^{(Reference Puig-Domingo, Marazuela and Giustina119)}. Hospitalised patients with obesity should be kept on oral feeding whenever possible. Early nutritional supplementation of non-ICU hospitalised patients aims to supply energy and protein that may have its needs increased in situations of infection and inflammation by a coronavirus^{(Reference Caccialanza, Laviano and Lobascio126)}. If oral feeding is not tolerated and/or respiratory conditions require non-invasive ventilation or continuous positive airway pressure, supplemental/total parenteral nutrition may be a choice to avoid complications related to concurrent use of face masks and enteral nutrition^{(Reference Caccialanza, Laviano and Lobascio126)}.

Obesity increases the risk of hospitalisation^{(Reference Barazzoni, Bischoff and Breda154)}. As previously discussed, in situations of more considerable aggravation, an overreaction of the immune system leading to the lungs’ autoimmune aggression could be involved in the most severe acute distress respiratory syndrome^{(Reference Puig-Domingo, Marazuela and Giustina119)}. Therefore, it may be necessary to continue treatment in ICU, especially for adequate ventilatory support considering the high pulmonary demand characterising COVID-19.

According to the recent European Society for Parenteral and Enteral Nutrition (ESPEN) guidelines, enteral nutrition may be superior to parenteral nutrition because of a lower risk of infection and is security for patients who receive mechanical ventilation^{(Reference Barazzoni, Bischoff and Breda154)}. Prone position ventilation is the therapy of choice in acute respiratory distress syndrome patients with obesity^{(Reference Schetz, De Jong and Deane161)}, and enteral nutrition in this position is not a limitation, being viable and safe.

However, situations such as uncontrolled shock, hypercapnia, acidosis and life-threatening hypoxaemia require a delay in enteral nutrition^{(Reference Laviano, Koverech and Zanetti162)}. In cases of impaired enteral nutrition, parenteral nutrition should be suggested. It is vital to consider the target level for blood glucose between 6 and 8 mmol/l, monitoring blood TAG and electrolytes, including phosphate, K⁺ and Mg^{2+(Reference Barazzoni, Bischoff and Breda154)}.

The best way to determine the energy needs of individuals is indirect calorimetry. If this is not available, Caccialanza et al. ^{(Reference Caccialanza, Laviano and Lobascio126)} suggest that the total amount of energy should be estimated by multiplying the resting energy expenditure calculated by the Harris–Benedict equation by a 1·5 stress-factor (in patients with obesity (BMI > 30 kg/m ^{Reference Calder, Carr and Gombart2} ), ideal body weight used in the equation), and 1·3 to 1·5 g of proteins/kg of ideal body weight^{(Reference Caccialanza, Laviano and Lobascio126,Reference Barazzoni, Bischoff and Breda154)} .

Another option for energy estimation is to use 11–14 kcal/kg per d (46–59 kJ/kg per d) with actual body weight for critically ill patients with BMI 30–50 kg/m ^{Reference Calder, Carr and Gombart2} , and 22–25 kcal/kg per d (92–105 kJ/kg per d) with ideal body weight for critically ill patients with BMI > 50 kg/m ^{Reference Calder, Carr and Gombart2} , as proposed by Mogensen et al. ^{(Reference Mogensen, Andrew and Corona163)}, when analysing patients with obesity and with super-obesity on mechanical breathing. Schetz et al. ^{(Reference Schetz, De Jong and Deane161)}, for energy from non-protein sources, consider an energy ratio from fat and carbohydrates between 30:70 % (subjects with no respiratory deficiency) to 50:50 % (ventilated patients)^{(Reference Barazzoni, Bischoff and Breda154)}.

Thus, the nutritional management of SARS-CoV-2 infection in patients with obesity, although not fully established yet, must consider the infection’s severity. Several nutrients deserve special attention in immunomodulation, such as vitamins A, D and C, and minerals, such as Zn. Prebiotics and probiotics may also be necessary for COVID-19 management, especially in patients with obesity. With the advances of research in the area, health professionals and researchers should establish protocols to ensure proper care.

Final considerations

The SARS-Cov-2 infection has become pandemic, overlapping with obesity and its co-morbidities. Obesity and its co-morbidities create an unfavourable inflammatory environment that enhances the risk of severe COVID-19. Therefore, obesity must be recognised as an independent risk factor for COVID-19 severity to better define public health policy and protect susceptible individuals, including specific social distancing measures. These measures can also contribute to preventing collapse of the health care system. Further research should define proper therapeutics for COVID-19, and nutritional therapy is an essential measure for treating COVID-19 in patients with obesity. Research should establish protocols, considering the severity of the disease.