Coronavirus disease 2019 pandemic and alterations of body composition.

Abstract

COVID-19 can occur in a range of presentation from asymptomatic to severe forms. Among the major risk factors for worse severity, malnutrition for excess or undernutrition and body composition play a role in the response to the infection. Fat accumulation and lean mass loss can affect whole-body functioning: on the short term, susceptibility and immunological response to the virus, inflammatory reaction, metabolic and respiratory distress, and on the long term disease outcomes such as LOS, time required for a complete recovery, risk of ICUAW and long-term disabilities, or eventually risk of death.

This manuscript aims to review evidence collected during COVID-19 pandemic, and to provide information on the impact of body composition on severity and outcomes of the disease both on short and long term, analysing methods used for body composition assessment. Malnutrition screening tools will be discussed to screen, diagnose, and treat those group of patients at higher risk of COVID-19 severe presentation, worse outcomes, and long-term disabilities or even death.

Subjects with malnutrition, sarcopenia, obesity and/or sarcopenic obesity, and elderly with impaired body composition or risk of malnutrition require tailored MNT to improve outcomes of the critical illness and to prevent the risk of developing chronic impairments.

“Coronavirus disease 2019” (COVID-19) outbreak was declared pandemic on March 11^th, for the global diffusion of the novel “severe acute respiratory syndrome coronavirus 2” (SARS-Cov-2) causing the disease. COVID-19 can occur in a wide range of presentation from asymptomatic forms to mild or severe forms. Severe illness presentation requires hospitalization in acute or intensive care units (ICU) with respiratory support and invasive mechanical ventilation (IMV). Major risk factors of a more severe presentation and risk of death are age, male sex, and the presence of one or more chronic comorbidities, such as cardiac, kidney, pulmonary diseases, hypertension, diabetes, and obesity [1-2].

The body composition of the organism exposed to the virus plays an important role in the response to the infection, both on the short term, considering susceptibility and immunological response to the virus, inflammatory reaction, body condition related to metabolic and respiratory distress, but also on the long term needed for a complete recovery after weeks of illness. Malnutrition for excess or undernutrition can cause fat accumulation and lean mass loss affecting the quality of body composition and whole-body functioning.

This manuscript aims to review evidence collected during COVID-19 pandemic emergency, which is still ongoing worldwide, and to provide information on the impact of body composition on severity and outcomes of the disease both on short and long term, analysing methods used for its assessment.

Another important assessment for patients undergoing acute respiratory distress syndrome (ARDS) is to analyse the risk or presence of malnutrition at the time of hospitalization, home discharge, and during the recovery from an illness requiring weeks in bed or home confinement.

During pandemic emergency, assessing body composition is particularly difficult in such overwhelmed clinical scenario. Nevertheless, some studies managed to collect data through computer tomography (CT) scan performed for the clinical assessment of pneumonia at chest level, sometimes extending imaging to the abdominal region. While on a regular basis, bioimpedentiometry (BIA) is considered a feasible and repeatable method for assessment and monitoring of its changes.

Malnutrition prevalence and screening

Screening tools to assess the presence or risk of malnutrition are multiple and can be chosen depending on the ideal clinical or validated setting (TABLE 1, [3**-9]). The high prevalence of malnutrition in patients hospitalized for critical illness requires a prompt admission assessment to manage clinical outcomes and recovery, while some patients at risk can become malnourished along the hospitalization. Moreover, elderly subjects are a group at higher risk of malnutrition and at the same time worse COVID-19 outcomes compared to the rest of the population.

TABLE 1: Malnutrition screening tools:

description of item and scores to assess presence or risk of malnutrition used in different hospital and community settings.

Screening Test	Approach	Setting	Description of Items	Score
MUST(4,8)	3 questions	Hospital, home care, community	0-1-2points for each question: - BMI - Unintentional weight loss - Reduced food intake or acute illness	Risk of malnutrition (≥ 2/6): 0 low 1 medium 2 high
MNA(4-5,8)	18 domains	Hospital, home care, community	Same as MNA-sf plus: lives independently, medication, pressure ulcers, number of meals, intake protein, fruit, vegetable, fluids intake, mode of feeding, self-view of nutritional status, self-assessment of health status, mid-arm circumference, calf circumference in cm.	≥ 24 no risk 17–23.5 risk < 17 malnutrition
MNA-sf (4,8)	6 domains	Hospitalized/institutionalized elderly	- BMI - Unintentional weight loss - Reduced food intake - Mobility - Physical stress/acute illness - Cognitive status	12–14 normal 8–11 risk 0–7 malnutrition
NRS-2002 (4,8)	2 levels (same items): - I risk screening -II grading	Hospital	-BMI -Unintentional weight loss -Reduced food intake -Disease severity - Age ≥70 years	Risk ≥ 3 (level 1) Grading severity (level 2): 1 mild 2 moderate 3 severe
(m)NUTRIC (4,6)	Health status	ICU	- Age - Illness - Inflammation	≥5 high risk <5 low risk
NRI (4,8)	= (1.519 × serum albumin (g/L) + 41.7 × (present weight/usual weight)	Hospital/home care	- Albumin - Weight	Risk of malnutrition < 83.5 high risk 83.5–97.5 moderate 97.5–100 mild risk > 100 no risk
GNRI (4)	= (14.89 × albumin (g/dL)) + (41.7 × (body weight/ideal body weight))	Hospitalized elderly	- Albumin - Weight	Risk of malnutrition < 82 high 82–91 moderate 92–98 low > 98 no risk
R-MAPP (7)		Primary care (remote)	Composed of 2 validated test: MUST + SARC-F(9)	Treat if MUST ≥ 2 and SARC-F ≥4
GLIM (3)	2-step: - I risk screening - II assessment severity of malnutrition	Clinical settings	3 phenotypic criteria (unintentional weight loss, low BMI, reduced muscle mass) + 2 etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden)	Malnutrition diagnosis at least 1 phenotypic + 1 etiologic criterion AND Malnutrition Grading: moderate-severe

Abbreviations: MUST Malnutrition Universal Screening Tool; MNA Mini Nutritional Assessment; MNA-sf Mini Nutritional Assessment-short form; NRS-2002 Nutritional Risk Screening tool 2002; (m)NUTRIC score (modified) Nutrition Risk in the Critically ill score; NRI Nutritional Risk Index; GNRI Geriatric Nutritional Risk Index; R-MAPP Remote – Malnutrition APP (also named Remote Malnutrition in Primary Practice), SARC-F (5-item questionnaire: Strength, Assistance with walking, Rise from a chair, Climb stairs and Falls); GLIM Global Leadership Initiative on Malnutrition, ICU intensive care unit, BMI body mass index

A Chinese cohort revealed presence of malnutrition, assessed by mini nutritional assessment (MNA), in elderly patients (age >65 years) hospitalized with COVID-19 higher than expected (52.7%) with 27.5% of them at risk of malnutrition, especially those having diabetes, low calf circumference, and low albumin [5]. This could be explained by the acute state of the disease, as it will be further discussed.

The relevance of malnutrition risk or presence as prognostic factor in COVID-19 patients is confirmed by higher mortality, especially for those admitted to ICU. Indeed, those patients classified malnourished at the mNUTRIC score had double the chance to die during a mean hospitalization of 28 days for higher incidences of ARDS, acute myocardial injury, secondary infection, shock and higher chance to need vasopressors [6*].

Assessing by particular questionnaire or screening tools the risk or presence of malnutrition, can only in part predict impairment in the body composition state in subjects during the acute phase of the disease, but it also has a prognostic value for the recovery phase. Therefore, tools to assess the nutritional state in subjects even not requiring hospitalization, have been proposed in primary care to be performed also remotely [7]. Higher risk of malnutrition is related to significantly longer length of stay (LOS), higher hospital expenses, worse disease severity [8].

Methods to assess body composition

Although highly necessary for a clinical and prognostic assessment of subjects, especially if affected by acute illness, screening tools do not provide information on body composition. Malnutrition can, indeed, overlap with altered body composition in addition to sarcopenia and/or cachexia [9], but so far no validated screening tool is able to properly assess and distinguish between these different conditions. Body composition changes with aging affects health state to the extent that alterations, such as sarcopenia, show high mortality in geriatric patients with acute illness [10].

Multiple methods can be uses to analyse the body different compartments and each method has its sensibility, but this review will not analyse this specific details, as the method of choice reported in each study has been chosen mainly by clinical convenience and experience at each different centre. The studies reported, therefore, are mainly retrospective or cross-sectional with data collected during the emergency of the pandemic.

BMI

The simplest methods to provide information on the body would be body mass index (BMI) calculation, although sometimes performing collection of height and weight in bedridden patients results difficult. A positive relation between BMI and worse severity and outcomes in COVID-19 will be further discussed (see later “Obesity and Sarcopenic Obesity”). However, BMI do not provide a detailed characterization of fat and lean body mass compartments or any information on their distribution.

BIA

Bioelectrical impedance-analysis (BIA) represents a practical tool to provide information on skeletal muscle mass (SMM), easily performed in subjects hospitalized or outpatients at relatively low-cost. BIA measures the opposition to an alternating current at different frequency, usually between 50 kHz and 250 kHz, passing through body compartments (resistance) and the delay in conduction by membranes (reactance). Different prediction equations have been developed to quantify body mass compartments, especially water and cellular mass. These equations, including variables like gender, age, weight, and height, require validation to be used in specific populations [11]. The phase angle, showing the relation between reactance and resistance, is considered an important marker of cellular integrity, also described as an independent predictor of long-term mortality in ICU admitted patients [12].

The importance of this measurements is off-balanced by the large variation in over or dehydration, as frequently happens in critically ill subjects. Nevertheless, BIA measurements were found acceptable for critically ill geriatric patients [13], but more reliable and reproducible in euvolemic subjects.

Performing BIA measurements, a group in Netherlands found no independent association of body composition values (fat mass, visceral fat area, and fat-free mass) with disease severity comparing ICU against ward admitted COVID-19 subjects. However, a composite score composed of mortality, morbidity, and ICU admission, revealed that a low phase angle was associated with COVID-19 severity [14*]. Fluid overload, defined as extracellular-water-ratio (ECW/TBW), was also associated with higher risk of mortality, particularly in ICU patients.

ULTRASOUND

Performing ultrasonography (US) is another costless and repeatable method to assess adipose subcutaneous tissue and muscle quality and quantity of SMM, but it is highly operator dependent, therefore easily biased. Muscle mass modifications, assessed mostly on lower limb and sometimes upper limb, have been described in patients after long-stay ICU, by US imaging showing non-homogenous features of muscle tissue with reduced mass [15]. However, pandemic did not allow such measurement and no US study in COVID-19 has been reported.

DEXA and MRI

Dual-energy X-ray absorptiometry (DEXA) and Magnetic resonance imaging (MRI) are two techniques with low-dose or no radiation exposure, easy to perform, able to accurately measure fat and fat-free mass, but expensive for clinical or routine study. Although these methods are considered the most accurate and precise, together with computed tomography scan, to evaluate body composition and skeletal muscle quantity and quality, no study was able to collect DEXA and MRI imaging in COVID-19 subjects during the early phase of the pandemic.

CT

Conversely, some COVID-19 studies report data analysis of computed tomography (CT) scans at the chest level, which represents a diagnostic tool for pneumonia, weather positive or not to SARS-CoV-2. Different measures to estimate body composition by CT have been used, mainly to quantify subcutaneous fat mass and visceral adiposity. For instance, the ratio of waist circumference per paravertebral muscle circumference (FMR) as potential surrogate of body composition and obesity, provides prognostic value for the patient outcome and the need of an ICU treatment in a 22-day follow-up [16*]. Accordingly, total abdominal and visceral adipose tissue (VAT) is associated with worse COVID-19 severity as assessed by a lung severity score (LSS) and need for hospitalization, ICU or IMV [17**-18*]. VAT can be reliably estimated by chest CT, at the level of the first lumbar vertebra (Th12-L1; L1-L2), instead of lower levels (L4-L5), to provide quantification of visceral fat area (VFA) and upper abdominal circumference. Moreover, CT single axial slice at L3 vertebral body assessing VAT, subcutaneous adipose tissue (SAT), total adipose tissue (TAT), and VAT/TAT, along with age, gender, sex and BMI can be used in a clinical model to predict the need for hospitalization, better than using BMI alone [18*]. Increment by ten square centimeters of VAT increases 1.37-fold and a 1.32-fold the likelihood of ICU treatment and mechanical ventilation, while each additional centimeter of circumference increases these chances 1.13-fold and 1.25-fold [19]. Another CT study reveals that, independently of BMI, age and sex adjusted, every mm of VAT increases 1.16 times (95% CI 1.07–1.26; P ,0.0001), the risk of ICU admission for COVID-19, that was associated with a 30% higher VAT and a 30% lower SAT, independent of age and sex [20**].

CT-scan is paramount in assessing fat distribution by visceral adiposity as described through VAT/SAT ratio, and also intramuscular fat (IMF), both described as independent risk factors of critical illness (odds ratio: 2.47; 95% CI: 1.05-5.98, P=0.040 and 11.90 95% CI: 4.50-36.14; P < 0.001) with increased risk of mechanical ventilation and death [21**]. Furthermore, when analysing the younger cohort of subjects (< 60 years), high visceral adiposity and high IMF deposition show even higher risk for critical COVID-19 illness (OR: 7.58, 95% CI: 1.7-42.21, P = 0.011), (OR: 18.67, 95% CI: 3.64-147.42, P = 0.001) [21**].

Obesity and Sarcopenic Obesity

In adults with obesity, increased risk of severe COVID-19 is reported not only in subjects younger than 60 years old [21**], but also younger than 40 years old [22*] with CT findings of excessive fat expansion at visceral and epicardial regions. In addition, increased liver fat [22*-23] with metabolic associated fatty liver disease (MAFLD) increases more than six times the chance of disease severity.

Ectopic fat deposition can drive organ malfunction, in pro- inflammatory environment with increased adipokines and inflammatory cytokines like TNF-alpha, leptin, and IL-6, leading to impaired immune response to SARS-CoV-2 infection and severe complications.

Excessive fat mass often hides a loss of lean body mass in subject with obesity, that after a long ICU hospitalization are at higher risk to develop sarcopenia. A report of body composition imaging after 20 days of bed-rest in ICU reveals a loss of both fat (9%) and lean mass, but increased liver fat attenuation, due to prolonged increased energy expenditure, insulin resistance, and chronic inflammatory state [23]. Sarcopenic obesity, a state of coexistence of excessive fat mass and low mass and function of muscle mass, is associated with worse clinical outcome [24**].

Undoubtedly, worse illness severity and clinical outcomes, defined as need for hospitalization (OR 1.76), ICU admission (OR 1.67), need for IMV (OR 2.19), longer LOS, or death (OR 1.37), are reported for subjects with obesity up to 39% higher risk compared to non-obese population [25-26*]. However, fat distribution and muscle mass quality are better predictor of disease than BMI and total fat.

Sarcopenia, weight loss and ICUAW

Sarcopenia, a deterioration of muscle mass and function occurring in subjects with obesity or older adults, contributes to the compromised respiratory function in acutely ill COVID-19 patients. Impaired muscular quality affecting unfavourable outcomes can be present in subjects already malnourished at the time of the admission or can also develop during hospital stay [27**-28]. Notably, muscle wasting occurs rapidly, characterized by fibre denervation at the neuromuscular junction and upregulation of protein breakdown, not counteracted by muscle protein synthesis, already suppressed within two-three days of inactivity [29**]. Indeed, after 10 days the loss of muscle mass is about 6% and after 30 days about 10%.

Therefore, prompt evaluation of nutritional status and body composition is a crucial step in patients with COVID-19 both in clinical and community setting. Indeed, weight loss higher than 5% and risk of malnutrition can occur even after discharge, during recovery phase, or even in patient managed at home [27**], often in relation to disease duration.

Acute state of inflammation and bed rest contribute to the loss of lean body mass, for increased energy and protein requirements, with subjects in ARDS losing up to 18% of the body weight [27**]. Whether inactivity is simultaneous to positive energy balance, fat mass deposition can occur, together with impaired glucose homeostasis, especially for reduced muscle insulin-sensitivity, consequently promoting the pro-inflammatory state of the disease, and increasing the risk of cytokine storm [29**]. Remarkably, inactivity negatively impacts on muscular, cardiovascular, metabolic, endocrine and nervous systems, both at short and long term, by overlapping of chronic low-grade with acute-state inflammation, and aggravating lean mass catabolism.

During or after prolonged stay in ICU, a muscular weakness due to neuropathy, myopathy and muscle atrophy caused by critical illness and pharmacological intervention, has been described as intensive care unit-acquired weakness (ICUAW) [15]. The loss of muscle mass reaches up to 80% of elderly ICU patients, and in the long term up to 30% report transient disabilities, for instance dysphagia, sometimes permanent disabilities. ICUAW constitutes an important predictor of long-term mortality and morbidity [15, 30**], affecting nutritional status and body composition on both short and long term.

Conclusion and Medical Nutrition Therapy (MNT)

In conclusion, MNT should be tailored and promptly applied to prevent or treat malnutrition in adults with suspected or confirmed COVID-19 infection in both clinical and community setting. Regular assessments for body composition and malnutrition screening tools should be performed to evaluate prognostic features especially in high risk groups, as described for older adults, subjects with obesity and/or sarcopenia, malnourished or with chronic comorbidities. Frail subjects require bed rest along the hospitalization or even after discharge and home confinement often forces to inactivity, sedentarism, social distancing, with negative impact on psychological and nutritional state.

In post-COVID-19 patients, a specific nutritional and motor rehabilitation should be provided to prevent and/or treat malnutrition, improving body composition to help a quick recovery, reduce complications or mortality, and improve both short- and long-term prognosis [30**].

KEY POINTS.

• Malnutrition and body composition assessment are pivotal during a critical illness as prognostic factor for worse disease outcomes and high risk of long-term chronic disabilities.

• During COVID-19 outbreak, severe form of disease presentation and higher risk of mortality were found in specific population groups such as elderly, sarcopenic, or subjects with obesity and malnutrition.

• Methods to analyse body composition could be performed even during the COVID-19 emergency to assess fat accumulation (in obesity, MAFLD,…) and lean mass loss (in sarcopenia, cachexia, elderly subjects,…), both affecting short and long-term outcomes.

• Tailored MNT is required in each high-risk group to prevent or treat the specific impairment during critical illness (e.g. COVID-19) to improve the short and long-term outcomes of the disease preventing chronic disabilities (e.g. ICUAW).