DNA polymorphisms in inflammatory and endocrine signals linked to frailty are also associated with obesity: data from the FRASNET cohort.

Background: Obesity and frailty are prevalent geriatric conditions that share some pathophysiological mechanisms and are associated with adverse clinical outcomes. The relationship between frailty, obesity, and polymorphism remains inadequately explored. Single nucleotide polymorphisms (SNPs) offer insights into genetic predispositions that may influence the development of both frailty and obesity. Methods: We aimed at investigating whether SNPs associated with frailty also play a role in obesity. Data were collected from the FRASNET cross-sectional study, which included community-dwelling older individuals residing in Milan and nearby areas. Participants were recruited through random sampling. They underwent multidimensional geriatric assessments, which included the collection of blood samples for SNP analysis. Frailty was assessed using the frailty index, and body composition was evaluated using bioelectrical impedance analysis and anthropometric measures. Results: SNPs related to frailty and linked to the renin-angiotensin system (CYP11B2 rs1799998, AGT rs5051, and AGTR1 rs2131127), apoptosis pathways (CASP8 rs6747918), growth hormone signaling (GHR rs6180), inflammation (TLR4 rs5030717, CD33 rs3865444, and FN1 rs7567647), adducin (ADD3 rs3731566), and the 9p21-23 region (rs518054) were found to be associated with various measures of obesity in community-dwelling older adults. Conclusions: Frailty-related SNPs contribute to obesity in community-dwelling older adults. We identified a novel association between adducin SNPs and visceral fat, which has not been previously reported. Detecting genetic predispositions to obesity and frailty early could aid in identifying individuals at risk, facilitating the adoption of preventive interventions. This represents an initial step toward promoting early intervention strategies.

Acute Sarcopenia: Mechanisms and Management.

BACKGROUND: Acute sarcopenia refers to the swift decline in muscle function and mass following acute events such as illness, surgery, trauma, or burns that presents significant challenges in hospitalized older adults. METHODS: narrative review to describe the mechanisms and management of acute sarcopenia. RESULTS: The prevalence of acute sarcopenia ranges from 28% to 69%, likely underdiagnosed due to the absence of muscle mass and function assessments in most clinical settings. Systemic inflammation, immune-endocrine dysregulation, and anabolic resistance are identified as key pathophysiological factors. Interventions include early mobilization, resistance exercise, neuromuscular electrical stimulation, and nutritional strategies such as protein supplementation, leucine, ß-hydroxy-ß-methyl-butyrate, omega-3 fatty acids, and creatine monohydrate. Pharmaceuticals show variable efficacy. CONCLUSIONS: Future research should prioritize serial monitoring of muscle parameters, identification of predictive biomarkers, and the involvement of multidisciplinary teams from hospital admission to address sarcopenia. Early and targeted interventions are crucial to improve outcomes and prevent long-term disability associated with acute sarcopenia.

Sarcopenic obesity and pre-sarcopenia contribute to frailty in community-dwelling Italian older people: data from the FRASNET study.

BACKGROUND: The ageing process is characterized by a change of body composition with an increase of fat mass and a reduction of muscle mass. Above a certain threshold these alterations configure a condition named sarcopenic obesity (SO). SO is associated with physical frailty in Asian and Brazilian populations. SO impacts on physical frailty in other ethnic groups but its influence on general frailty which is multidimensional and includes cognitive, social and physical factors, remain insufficiently explored in the Italian population. METHODS: Frailty was measured in community dwelling Italian older adults enrolled in the FRASNET study with the frailty index (FI). The FI quantifies frailty as the ratio of the number of present health deficits to the total number of health deficits considered. Regression analyses were performed to assess the association between body composition categories and frailty. Classification and regression tree models were run to evaluate the frailty predictors. RESULTS: One Thousand One Hundred Fourteen participants of the FRASNET study were included in the present analysis. The sample was composed for the 60.5% by females and its median age was 72 years. The median FI score was 0.11 (IQR 0.07-0.20); 234 individuals (21%) were frail (FI ≥ 0.25). SO (B 0.074, 95% C.I. 0.05-0.1, p < 0.001) and pre-sarcopenia (without obesity B 0.03, 95% C.I, 0.007-0.044, p < 0.001, with obesity B 0.11, 95% C.I. 0.05-0.16, p < 0.001) were associated with frailty. Fat mass percentage predicted frailty in people aged 65-70 years whereas, muscle strength predicted general frailty in people aged 70-81 years. CONCLUSION: Pre-sarcopenia and SO represent potentially treatable predictors of frailty.

Micronized/ultramicronized palmitoylethanolamide improves depression and fatigue in coronavirus disease 2019 (COVID-19) survivors.

Coronavirus disease 2019 (COVID-19) may lead to neuropsychiatric sequelae. Palmitoylethanolamide (PEA) is an anti-inflammatory and neuroprotective amide used in depressive syndromes. Here we investigate whether micronized/ultramicronized (m/um) PEA improves neuropsychiatric sequelae in COVID-19 survivors. Patients evaluated at our post-COVID-19 outpatient clinic between February and August 2021 and presenting neuropsychiatric manifestations ( n  = 98) were offered treatment with m/umPEA 600 mg twice daily for 3 months. Those accepting m/umPEA therapy ( n  = 57) were compared with those who did not ( n  = 41), in terms of depression, fatigue, chronic pain and subjective well-being, through validated scales administered pre- and posttreatment. The two groups did not differ in terms of demographics, comorbidities, psychiatric history, antidepressant therapy, acute COVID-19 severity and baseline neuropsychiatric status. Patients receiving m/umPEA showed a greater improvement in depression and fatigue (both P  < 0.05). Conversely, no association was found with changes in chronic pain or subjective well-being. At multivariable logistic regression, m/umPEA predicted neuropsychiatric improvement independently of age, sex and baseline neuropsychiatric status. Worse pretreatment fatigue and subjective well-being identified those who most likely benefited from treatment. In conclusion, despite its retrospective nature, our study suggests that m/umPEA may improve depression and fatigue in COVID-19 survivors, justifying future research in this setting.

Exploring the Association between Delirium and Malnutrition in COVID-19 Survivors: A Geriatric Perspective.

Older individuals face an elevated risk of developing geriatric syndromes when confronted with acute stressors like COVID-19. We assessed the connection between in-hospital delirium, malnutrition, and frailty in a cohort of COVID-19 survivors. Patients aged ≥65, hospitalized in a tertiary hospital in Milan for SARS-CoV-2 pneumonia, were enrolled and screened for in-hospital delirium with the 4 'A's Test (4AT) performed twice daily (morning and evening) during hospital stay. Malnutrition was assessed with the malnutrition universal screening tool (MUST) at hospital admission and with the mini-nutritional assessment short-form (MNA-SF) one month after hospital discharge. Frailty was computed with the frailty index one month after hospital discharge. Fifty patients (median age 78.5, 56% male) were enrolled. At hospital admission, 10% were malnourished. The 13 patients (26%) who developed delirium were frailer (7 vs. 4), experienced a higher in-hospital mortality (5 vs. 3), and were more malnourished one month after discharge (3 of the 4 patients with delirium vs. 6 of the 28 patients without delirium who presented at follow up). The 4AT scores correlated with the MNA-SF scores (r = -0.55, p = 0.006) and frailty (r = 0.35, p = 0.001). Frailty also correlated with MUST (r = 0.3, p = 0.04), MNA-SF (r = -0.42, p = 0.02), and hospitalization length (r = 0.44, p = 0.001). Delirium, malnutrition, and frailty are correlated in COVID-19 survivors. Screening for these geriatric syndromes should be incorporated in routine clinical practice.

Physical and psychological sequelae at three months after acute illness in COVID-19 survivors.

BACKGROUND: Coronavirus disease 2019 (COVID-19) may leave behind an altered health status early after recovery. We evaluated the clinical status of COVID-19 survivors at three months after hospital discharge. METHODS: In this prospective observational cohort study, hospitalized patients aged ≥18 years, evaluated at one (M1) and three (M3) months post-discharge were enrolled. 251 patients (71.3% males, median [IQR] age 61.8 [53.5-70.7] years) were included. Median (IQR) time from discharge to M3 was 89 (79.5-101) days. Primary outcome was residual respiratory dysfunction (RRD), defined by tachypnea, moderate to very severe dyspnea, or peripheral oxygen saturation ≤95% on room air at M3. RESULTS: RRD was found in 30.4% of patients, with no significant difference compared with M1. Chronic obstructive pulmonary disease and length of stay were independent predictors of RRD at multivariable logistic regression (OR [95% CI]: 4.13 [1.17-16.88], P=0.033; OR [95% CI]: 1.02 [1.00-1.04], P=0.047, respectively). Obesity and C-reactive protein levels upon admission were additional predictors at regression tree analysis. Impaired quality of life (QoL) was reported by 53.2% of patients. Anxiety and insomnia were each present in 25.5% of patients, and PTSD in 22.4%. No difference was found between M1 and M3 in QoL, anxiety or PTSD. Insomnia decreased at M3. Current major psychiatric disorder as well as anxiety, insomnia and PSTD at M1 independently predicted PTSD at M3. CONCLUSIONS: Clinical damage may persist at three months after discharge in COVID-19 survivors. Post-recovery follow-up is an essential component of patient management.

High Risk of Secondary Infections Following Thrombotic Complications in Patients With COVID-19.

Background: This study's primary aim was to evaluate the impact of thrombotic complications on the development of secondary infections. The secondary aim was to compare the etiology of secondary infections in patients with and without thrombotic complications. Methods: This was a cohort study (NCT04318366) of coronavirus disease 2019 (COVID-19) patients hospitalized at IRCCS San Raffaele Hospital between February 25 and June 30, 2020. Incidence rates (IRs) were calculated by univariable Poisson regression as the number of cases per 1000 person-days of follow-up (PDFU) with 95% confidence intervals. The cumulative incidence functions of secondary infections according to thrombotic complications were compared with Gray's method accounting for competing risk of death. A multivariable Fine-Gray model was applied to assess factors associated with risk of secondary infections. Results: Overall, 109/904 patients had 176 secondary infections (IR, 10.0; 95% CI, 8.8-11.5; per 1000-PDFU). The IRs of secondary infections among patients with or without thrombotic complications were 15.0 (95% CI, 10.7-21.0) and 9.3 (95% CI, 7.9-11.0) per 1000-PDFU, respectively (P = .017). At multivariable analysis, thrombotic complications were associated with the development of secondary infections (subdistribution hazard ratio, 1.788; 95% CI, 1.018-3.140; P = .043). The etiology of secondary infections was similar in patients with and without thrombotic complications. Conclusions: In patients with COVID-19, thrombotic complications were associated with a high risk of secondary infections.

Prevalence of Long COVID-19 Symptoms After Hospital Discharge in Frail and Robust Patients.

Background: A motley postacute symptomatology may develop after COVID-19, irrespective of the acute disease severity, age, and comorbidities. Frail individuals have reduced physiological reserves and manifested a worse COVID-19 course, during the acute setting. However, it is still unknown, whether frailty may subtend some long COVID-19 manifestations. We explored the prevalence of long COVID-19 disturbs in COVID-19 survivals. Methods: This was an observational study. Patients aged 65 years or older were followed-up 1, 3, and 6 months after hospitalization for COVID-19 pneumonia. Results: A total of 382 patients were enrolled. Frail patients were more malnourished (median Mini Nutritional Assessment Short Form score 8 vs. 9, p = 0.001), at higher risk of sarcopenia [median Strength, Assistance with walking, Rising from a chair, Climbing stairs, and Falls (SARC-F) score 3 vs. 1.5, p = 0.003], and manifested a worse physical performance [median Short Physical Performance Battery (SPPB) score 10 vs. 11, p = 0.0007] than robust individuals, after hospital discharge following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. Frailty was significantly associated with: (i) confusion, as a presenting symptom of COVID-19 [odds ratio (OR) 77.84, 95% CI 4.23-1432.49, p = 0.003]; (ii) malnutrition (MNA-SF: adjusted B -5.63, 95% CI -8.39 to -2.87, p < 0.001), risk of sarcopenia (SARC-F: adjusted B 9.11, 95% CI 3.10-15.13, p = 0.003), impaired muscle performance (SPPB: B -3.47, 95% CI -6.33 to -0.61, p = 0.02), complaints in mobility (adjusted OR 1674200.27, 95% CI 4.52-619924741831.25, p = 0.03), in self-care (adjusted OR 553305.56, 95% CI 376.37-813413358.35, p < 0.001), and in performing usual activities of daily living (OR 71.57, 95% CI 2.87-1782.53, p = 0.009) at 1-month follow-up; (iii) dyspnea [modified Medical Research Council (mMRC): B 4.83, 95% CI 1.32-8.33, p = 0.007] and risk of sarcopenia (SARC-F: B 7.12, 95% CI 2.17-12.07, p = 0.005) at 3-month follow-up; and (iv) difficulties in self-care (OR 2746.89, 95% CI 6.44-1172310.83, p = 0.01) at the 6-month follow-up. In a subgroup of patients (78 individuals), the prevalence of frailty increased at the 1-month follow-up compared to baseline (p = 0.009). Conclusion: The precocious identification of frail COVID-19 survivors, who manifest more motor and respiratory complaints during the follow-up, could improve the long-term management of these COVID-19 sequelae.

A Pilot Study of the Efficacy and Economical Sustainability of Acute Coronavirus Disease 2019 Patient Management in an Outpatient Setting.

Objective: To report a preliminary experience of outpatient management of patients with Coronavirus disease 2019 (COVID-19) through an innovative approach of healthcare delivery. Patients and Methods: Patients evaluated at the Mild-to-Moderate COVID-19 Outpatient clinics (MMCOs) of San Raffaele University Hospital and Luigi Sacco University Hospital in Milan, Italy, from 1 October 2020 to 31 October 2021 were included. Patients were referred by general practitioners (GPs), Emergency Department (ED) physicians or hospital specialists (HS) in case of moderate COVID-19. A classification and regression tree (CART) model predicting ED referral by MMCO physicians was developed to aid GPs identify those deserving immediate ED admission. Cost-effectiveness analysis was also performed. Results: A total of 660 patients were included. The majority (70%) was referred by GPs, 21% by the ED and 9% by HS. Patients referred by GPs had more severe disease as assessed by peripheral oxygen saturation (SpO2), ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), C-reactive protein (CRP) levels and interstitial involvement at lung ultrasound. Among them, 18% were addressed to the ED following MMCO assessment. CART analysis identified three independent predictors, namely home-measured SpO2, age and body mass index (BMI), that robustly divide patients into risk groups of COVID-19 severity. Home-measured SpO2 < 95% and BMI ≥ 33 Kg/m2 defined the high-risk group. The model yielded an accuracy (95% CI) of 83 (77-88)%. Outpatient management of COVID-19 patients allowed the national healthcare system to spare 1,490,422.05 € when compared with inpatient care. Conclusion: Mild-to-moderate COVID-19 outpatient clinics were effective and sustainable in managing COVID-19 patients and allowed to alleviate pressure on EDs and hospital wards, favoring effort redirection toward non-COVID-19 patients.

Myosteatosis Significantly Predicts Persistent Dyspnea and Mobility Problems in COVID-19 Survivors.

Background: Persistent symptoms including dyspnea and functional impairment are common in COVID-19 survivors. Poor muscle quality (myosteatosis) associates with poor short-term outcomes in COVID-19 patients. The aim of this observational study was to assess the relationship between myosteatosis diagnosed during acute COVID-19 and patient-reported outcomes at 6 months after discharge. Methods: Myosteatosis was diagnosed based on CT-derived skeletal muscle radiation attenuation (SM-RA) measured during hospitalization in 97 COVID-19 survivors who had available anthropometric and clinical data upon admission and at the 6-month follow-up after discharge. Dyspnea in daily activities was assessed using the modified Medical Research Council (mMRC) scale for dyspnea. Health-related quality of life was measured using the European quality of life questionnaire three-level version (EQ-5D-3L). Results: Characteristics of patients with (lowest sex- and age-specific tertile of SM-RA) or without myosteatosis during acute COVID-19 were similar. At 6 months, patients with myosteatosis had greater rates of obesity (48.4 vs. 27.7%, p = 0.046), abdominal obesity (80.0 vs. 47.6%, p = 0.003), dyspnea (32.3 vs. 12.5%, p = 0.021) and mobility problems (32.3 vs. 12.5%, p = 0.004). Myosteatosis diagnosed during acute COVID-19 was the only significant predictor of persistent dyspnea (OR 3.19 [95% C.I. 1.04; 9.87], p = 0.043) and mobility problems (OR 3.70 [95% C.I. 1.25; 10.95], p = 0.018) at 6 months at logistic regression adjusted for sex, age, and BMI. Conclusion: Myosteatosis diagnosed during acute COVID-19 significantly predicts persistent dyspnea and mobility problems at 6 months after hospital discharge independent of age, sex, and body mass. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04318366].

Evaluation of Muscle Mass and Stiffness with Limb Ultrasound in COVID-19 Survivors.

BACKGROUND: acute illnesses, like COVID-19, can act as a catabolic stimulus on muscles. So far, no study has evaluated muscle mass and quality through limb ultrasound in post-COVID-19 patients. METHODS: cross sectional observational study, including patients seen one month after hospital discharge for SARS-CoV-2 pneumonia. The patients underwent a multidimensional evaluation. Moreover, we performed dominant medial gastrocnemius ultrasound (US) to characterize their muscle mass and quality. RESULTS: two hundred fifty-nine individuals (median age 67, 59.8% males) were included in the study. COVID-19 survivors with reduced muscle strength had a lower muscle US thickness (1.6 versus 1.73 cm, p =0.02) and a higher muscle stiffness (87 versus 76.3, p = 0.004) compared to patients with normal muscle strength. Also, patients with reduced Short Physical Performance Battery (SPPB) scores had a lower muscle US thickness (1.3 versus 1.71 cm, p = 0.01) and a higher muscle stiffness (104.9 versus 81.07, p = 0.04) compared to individuals with normal SPPB scores. The finding of increased muscle stiffness was also confirmed in patients with a pathological value (≥ 4) at the sarcopenia screening tool SARC-F (103.0 versus 79.55, p < 0.001). Muscle stiffness emerged as a significant predictor of probable sarcopenia (adjusted OR 1.02, 95% C.I. 1.002 - 1.04, p = 0.03). The optimal ultrasound cut-offs for probable sarcopenia were 1.51 cm for muscle thickness (p= 0.017) and 73.95 for muscle stiffness (p = 0.004). DISCUSSION: we described muscle ultrasound characteristics in post COVID-19 patients. Muscle ultrasound could be an innovative tool to assess muscle mass and quality in this population. Our preliminary findings need to be confirmed by future studies comparing muscle ultrasound with already validated techniques for measuring muscle mass and quality.

A Nomogram-Based Model to Predict Respiratory Dysfunction at 6 Months in Non-Critical COVID-19 Survivors.

Objective: To assess the prevalence of respiratory sequelae of Coronavirus disease 2019 (COVID-19) survivors at 6 months after hospital discharge and develop a model to identify at-risk patients. Patients and Methods: In this prospective cohort study, hospitalized, non-critical COVID-19 patients evaluated at 6-month follow-up between 26 August, 2020 and 16 December, 2020 were included. Primary outcome was respiratory dysfunction at 6 months, defined as at least one among tachypnea at rest, percent predicted 6-min walking distance at 6-min walking test (6MWT) ≤ 70%, pre-post 6MWT difference in Borg score ≥ 1 or a difference between pre- and post-6MWT oxygen saturation ≥ 5%. A nomogram-based multivariable logistic regression model was built to predict primary outcome. Validation relied on 2000-resample bootstrap. The model was compared to one based uniquely on degree of hypoxemia at admission. Results: Overall, 316 patients were included, of whom 118 (37.3%) showed respiratory dysfunction at 6 months. The nomogram relied on sex, obesity, chronic obstructive pulmonary disease, degree of hypoxemia at admission, and non-invasive ventilation. It was 73.0% (95% confidence interval 67.3-78.4%) accurate in predicting primary outcome and exhibited minimal departure from ideal prediction. Compared to the model including only hypoxemia at admission, the nomogram showed higher accuracy (73.0 vs 59.1%, P < 0.001) and greater net-benefit in decision curve analyses. When the model included also respiratory data at 1 month, it yielded better accuracy (78.2 vs. 73.2%) and more favorable net-benefit than the original model. Conclusion: The newly developed nomograms accurately identify patients at risk of persistent respiratory dysfunction and may help inform clinical priorities.

Residual lung damage following ARDS in COVID-19 ICU survivors.

BACKGROUND: Coronavirus disease 2019 acute respiratory distress syndrome (COVID-19 ARDS) is a disease that often requires invasive ventilation. Little is known about COVID-19 ARDS sequelae. We assessed the mid-term lung status of COVID-19 survivors and investigated factors associated with pulmonary sequelae. METHODS: All adult COVID-19 patients admitted to the intensive care unit from 25th February to 27th April 2020 were included. Lung function was evaluated through chest CT scan and pulmonary function tests (PFT). Logistic regression was used to identify predictors of persisting lung alterations. RESULTS: Forty-nine patients (75%) completed lung assessment. Chest CT scan was performed after a median (interquartile range) time of 97 (89-105) days, whilst PFT after 142 (133-160) days. The median age was 58 (52-65) years and most patients were male (90%). The median duration of mechanical ventilation was 11 (6-16) days. Median tidal volume/ideal body weight (TV/IBW) was 6.8 (5.71-7.67) ml/Kg. 59% and 63% of patients showed radiological and functional lung sequelae, respectively. The diffusion capacity of carbon monoxide (DLCO ) was reduced by 59%, with a median per cent of predicted DLCO of 72.1 (57.9-93.9) %. Mean TV/IBW during invasive ventilation emerged as an independent predictor of persistent CT scan abnormalities, whilst the duration of mechanical ventilation was an independent predictor of both CT and PFT abnormalities. The extension of lung involvement at hospital admission (evaluated through Radiographic Assessment of Lung Edema, RALE score) independently predicted the risk of persistent alterations in PFTs. CONCLUSIONS: Both the extent of lung parenchymal involvement and mechanical ventilation protocols predict morphological and functional lung abnormalities months after COVID-19.

Case Report: Nintedaninb May Accelerate Lung Recovery in Critical Coronavirus Disease 2019.

Severe Coronavirus disease 2019 (COVID-19) is characterized by acute respiratory distress syndrome (ARDS) which may lead to long-lasting pulmonary sequelae in the survivors. COVID-19 shares common molecular signatures with interstitial lung diseases (ILDs), including pro-angiogenic and tissue-remodeling mechanisms mediated by vascular endothelial growth factor receptor (VEGF-R), fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R). Nintedanib mainly targets these factors and is approved for ILDs. Therefore, we administered nintedanib through compassionate use to three patients with COVID-19 pneumonia requiring extra-corporeal membrane-oxygenation (ECMO). Here, we describe our experience in an attempt to explore the role of nintedanib in lung recovery in COVID-19. Three obese patients aged between 42 and 52 years were started on nintedanib due to difficulty in obtaining lung function restoration and weaning from ECMO support following the removal of orotracheal intubation (OTI). Soon after the start of the treatment, systemic inflammation and respiratory function rapidly improved and ECMO support was withdrawn. Serial chest CT scans confirmed the progressive lung amelioration, also reflected by functional tests during follow-up. Nintedanib was well-tolerated by all the three patients at the dosage used for ILDs and continued for 2-3 months based on drug availability. Although caution in interpreting events is required; it is tempting to speculate that nintedanib may have contributed to modulate lung inflammation and remodeling and to sustain lung repair. Altogether, nintedanib appears as a promising agent in patients with severe COVID-19 and delayed respiratory function recovery, for whom molecularly targeted therapies are still lacking. Clinical trials are necessary to confirm our observations.

Six-month respiratory outcomes and exercise capacity of COVID-19 acute respiratory failure patients treated with continuous positive airway pressure.

BACKGROUND: COVID-19 long-term sequelae are ill-defined since only a few studies have explored the long-term consequences of this disease so far. AIMS: To evaluate the 6-month respiratory outcome and exercise capacity of COVID-19 acute respiratory failure (ARF) patients treated with continuous positive airway pressure (CPAP) during the first wave of the ongoing COVID-19 pandemic. METHODS: A retrospective observational study included COVID-19 patients with ARF. Interventions included CPAP during hospitalisation and 6-month follow up. Frailty assessment was carried out through frailty index (FI), pO2 /FiO2 during hospitalisation and at follow up, respiratory parameters, 6-min walking test (6MWT) and the modified British Medical Research Council (mMRC) and Borg scale at follow up. RESULTS: More than half of the patients had no dyspnoea according to the mMRC scale. Lower in-hospital pO2 /FiO2 correlated with higher Borg scale levels after 6MWT (ρ 0.27; P 0.04) at the follow-up visit. FI was positively correlated with length of hospitalisation (ρ 0.3; P 0.03) and negatively with the 6MWT distance walked (ρ -0.36; P 0.004). CONCLUSIONS: Robust and frail patients with COVID-19 ARF treated with CPAP outside the intensive care unit setting had good respiratory parameters and exercise capacity at 6-month follow up, although more severe patients had slightly poorer respiratory performance compared with patients with higher PaO2 /FiO2 and lower FI.

Robust prediction of mortality of COVID-19 patients based on quantitative, operator-independent, lung CT densitometry.

PURPOSE: To train and validate a predictive model of mortality for hospitalized COVID-19 patients based on lung densitometry. METHODS: Two-hundred-fifty-one patients with respiratory symptoms underwent CT few days after hospitalization. "Aerated" (AV), "consolidated" (CV) and "intermediate" (IV) lung sub-volumes were quantified by an operator-independent method based on individual HU maximum gradient recognition. AV, CV, IV, CV/AV, IV/AV, and HU of the first peak position were extracted. Relevant clinical parameters were prospectively collected. The population was composed by training (n = 166) and validation (n = 85) consecutive cohorts, and backward multi-variate logistic regression was applied on the training group to build a CT_model. Similarly, models including only clinical parameters (CLIN_model) and both CT/clinical parameters (COMB_model) were developed. Model's performances were assessed by goodness-of-fit (H&L-test), calibration and discrimination. Model's performances were tested in the validation group. RESULTS: Forty-three patients died (25/18 in training/validation). CT_model included AVmax (i.e. maximum AV between lungs), CV and CV/AE, while CLIN_model included random glycemia, C-reactive protein and biological drugs (protective). Goodness-of-fit and discrimination were similar (H&L:0.70 vs 0.80; AUC:0.80 vs 0.80). COMB_model including AVmax, CV, CV/AE, random glycemia, biological drugs and active cancer, outperformed both models (H&L:0.91; AUC:0.89, 95%CI:0.82-0.93). All models showed good calibration (R2:0.77-0.97). Despite several patient's characteristics were different between training and validation cohorts, performances in the validation cohort confirmed good calibration (R2:0-70-0.81) and discrimination for CT_model/COMB_model (AUC:0.72/0.76), while CLIN_model performed worse (AUC:0.64). CONCLUSIONS: Few automatically extracted densitometry parameters with clear functional meaning predicted mortality of COVID-19 patients. Combined with clinical features, the resulting predictive model showed higher discrimination/calibration.

Weight trajectories and abdominal adiposity in COVID-19 survivors with overweight/obesity.

BACKGROUND: COVID-19 is associated with unintentional weight loss. Little is known on whether and how patients regain the lost weight. We assessed changes in weight and abdominal adiposity over a three-month follow-up after discharge in COVID-19 survivors. METHODS: In this sub-study of a large prospective observational investigation, we collected data from individuals who had been hospitalized for COVID-19 and re-evaluated at one (V1) and three (V2) months after discharge. Patient characteristics upon admission and anthropometrics, waist circumference and hunger levels assessed during follow-up were analyzed across BMI categories. RESULTS: One-hundred-eighty-five COVID-19 survivors (71% male, median age 62.1 [54.3; 72.1] years, 80% with overweight/obesity) were included. Median BMI did not change from admission to V1 in normal weight subjects (-0.5 [-1.2; 0.6] kg/m2, p = 0.08), but significantly decreased in subjects with overweight (-0.8 [-1.8; 0.3] kg/m2, p < 0.001) or obesity (-1.38 [-3.4; -0.3] kg/m2, p < 0.001; p < 0.05 vs. normal weight or obesity). Median BMI did not change from V1 to V2 in normal weight individuals (+0.26 [-0.34; 1.15] kg/m2, p = 0.12), but significantly increased in subjects with overweight (+0.4 [0.0; 1.0] kg/m2, p < 0.001) or obesity (+0.89 [0.0; 1.6] kg/m2, p < 0.001; p = 0.01 vs. normal weight). Waist circumference significantly increased from V1 to V2 in the whole group (p < 0.001), driven by the groups with overweight or obesity. At multivariable regression analyses, male sex, hunger at V1 and initial weight loss predicted weight gain at V2. CONCLUSIONS: Patients with overweight or obesity hospitalized for COVID-19 exhibit rapid, wide weight fluctuations that may worsen body composition (abdominal adiposity). CLINICALTRIALS. GOV REGISTRATION: NCT04318366.

Predictors of Pneumothorax/Pneumomediastinum in Mechanically Ventilated COVID-19 Patients.

OBJECTIVE: To determine the incidence, predictors, and outcome of pneumothorax (PNX)/pneumomediastinum (PMD) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). DESIGN: Observational study. SETTING: Tertiary-care university hospital. PARTICIPANTS: One hundred sixteen consecutive critically ill, invasively ventilated patients with COVID-19 ARDS. INTERVENTIONS: The authors collected demographic, mechanical ventilation, imaging, laboratory, and outcome data. Primary outcome was the incidence of PNX/PMD. Multiple logistic regression analyses were performed to identify predictors of PNX/PMD. MEASUREMENTS AND MAIN RESULTS: PNX/PMD occurred in a total of 28 patients (24.1%), with 22 patients developing PNX (19.0%) and 13 developing PMD (11.2%). Mean time to development of PNX/PMD was 14 ± 11 days from intubation. The authors found no significant difference in mechanical ventilation parameters between patients who developed PNX/PMD and those who did not. Mechanical ventilation parameters were within recommended limits for protective ventilation in both groups. Ninety-five percent of patients with PNX/PMD had the Macklin effect (linear collections of air contiguous to the bronchovascular sheaths) on a baseline computed tomography scan, and tended to have a higher lung involvement at intensive care unit (ICU) admission (Radiographic Assessment of Lung Edema score 32.2 ± 13.4 v 18.7 ± 9.8 in patients without PNX/PMD, p = 0.08). Time from symptom onset to intubation and time from total bilirubin on day two after ICU admission were the only independent predictors of PNX/PMD. Mortality was 60.7% in patients who developed PNX/PMD versus 38.6% in those who did not (p = 0.04). CONCLUSION: PNX/PMD occurs frequently in COVID-19 patients with ARDS requiring mechanical ventilation, and is associated with increased mortality. Development of PNX/PMD seems to occur despite use of protective mechanical ventilation and has a radiologic predictor sign.

Antibody response to multiple antigens of SARS-CoV-2 in patients with diabetes: an observational cohort study.

AIMS/HYPOTHESIS: The aim of the study was to characterise the humoral response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with diabetes. Demonstrating the ability to mount an appropriate antibody response in the presence of hyperglycaemia is relevant for the comprehension of mechanisms related to the observed worse clinical outcome of coronavirus disease 2019 (COVID-19) pneumonia in patients with diabetes and for the development of any future vaccination campaign to prevent SARS-CoV-2 infection. METHODS: Using a highly specific and sensitive measurement of antibodies by fluid-phase luciferase immunoprecipitation assays, we characterised the IgG, IgM and IgA response against multiple antigens of SARS-CoV-2 in a cohort of 509 patients with documented diagnosis of COVID-19, prospectively followed at our institution. We analysed clinical outcomes and antibody titres according to the presence of hyperglycaemia, i.e., either diagnosed or undiagnosed diabetes, at the time of, or during, hospitalisation. RESULTS: Among patients with confirmed COVID-19, 139 (27.3%) had diabetes: 90 (17.7%) had diabetes diagnosed prior to the hospital admission (comorbid diabetes) while 49 (9.6%) had diabetes diagnosed at the time of admission (newly diagnosed). Diabetes was associated with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leucocytosis and neutrophilia. Diabetes was independently associated with risk of death (HR 2.32 [95% CI 1.44, 3.75], p = 0.001), even after adjustment for age, sex and other relevant comorbidities. Moreover, a strong association between higher glucose levels and risk of death was documented irrespective of diabetes diagnosis (HR 1.14 × 1.1 mmol/l [95% CI 1.08, 1.21], p < 0.001). The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable, as for timing and antibody titres, to that of non-diabetic patients, with marginal differences, and was not influenced by glucose levels. Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike receptor-binding domain (RBD) was predictive of survival rate, both in the presence or absence of diabetes. CONCLUSIONS/INTERPRETATION: The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycaemia was not the result of an impaired humoral response against SARS-CoV-2. RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARs-COV-2 in people with diabetes. Graphical abstract.