Association of subpleural ground-glass opacities with respiratory failure and RNAemia in COVID-19.

OBJECTIVES: To examine the radiological patterns specifically associated with hypoxemic respiratory failure in patients with coronavirus disease (COVID-19). METHODS: We enrolled patients with COVID-19 confirmed by qPCR in this prospective observational cohort study. We explored the association of clinical, radiological, and microbiological data with the development of hypoxemic respiratory failure after COVID-19 onset. Semi-quantitative CT scores and dominant CT patterns were retrospectively determined for each patient. The microbiological evaluation included checking the SARS-CoV-2 viral load by qPCR using nasal swab and serum specimens. RESULTS: Of the 214 eligible patients, 75 developed hypoxemic respiratory failure and 139 did not. The CT score was significantly higher in patients who developed hypoxemic respiratory failure than in those did not (median [interquartile range]: 9 [6-14] vs 0 [0-3]; p < 0.001). The dominant CT patterns were subpleural ground-glass opacities (GGOs) extending beyond the segmental area (n = 44); defined as "extended GGOs." Multivariable analysis showed that hypoxemic respiratory failure was significantly associated with extended GGOs (odds ratio [OR] 29.6; 95% confidence interval [CI], 9.3-120; p < 0.001), and a CT score > 4 (OR 12.7; 95% CI, 5.3-33; p < 0.001). The incidence of RNAemia was significantly higher in patients with extended GGOs (58.3%) than in those without any pulmonary lesion (14.7%; p < 0.001). CONCLUSIONS: Extended GGOs along the subpleural area were strongly associated with hypoxemia and viremia in patients with COVID-19. KEY POINTS: • Extended ground-glass opacities (GGOs) along the subpleural area and a CT score > 4, in the early phase of COVID-19, were independently associated with the development of hypoxemic respiratory failure. • The absence of pulmonary lesions on CT in the early phase of COVID-19 was associated with a lower risk of developing hypoxemic respiratory failure. • Compared to patients with other CT findings, the extended GGOs and a higher CT score were also associated with a higher incidence of RNAemia.

Breath-holding physiology, radiological severity and adverse outcomes in COVID-19 patients: A prospective validation study.

BACKGROUND AND OBJECTIVE: COVID-19 remains a major cause of respiratory failure, and means to identify future deterioration is needed. We recently developed a prediction score based on breath-holding manoeuvres (desaturation and maximal duration) to predict incident adverse COVID-19 outcomes. Here we prospectively validated our breath-holding prediction score in COVID-19 patients, and assessed associations with radiological scores of pulmonary involvement. METHODS: Hospitalized COVID-19 patients (N = 110, three recruitment centres) performed breath-holds at admission to provide a prediction score (Messineo et al.) based on mean desaturation (20-s breath-holds) and maximal breath-hold duration, plus baseline saturation, body mass index and cardiovascular disease. Odds ratios for incident adverse outcomes (composite of bi-level ventilatory support, ICU admission and death) were described for patients with versus without elevated scores (>0). Regression examined associations with chest x-ray (Brixia score) and computed tomography (CT; 3D-software quantification). Additional comparisons were made with the previously-validated '4C-score'. RESULTS: Elevated prediction score was associated with adverse COVID-19 outcomes (N = 12/110), OR[95%CI] = 4.54[1.17-17.83], p = 0.030 (positive predictive value = 9/48, negative predictive value = 59/62). Results were diminished with removal of mean desaturation from the prediction score (OR = 3.30[0.93-11.72]). The prediction score rose linearly with Brixia score (ß[95%CI] = 0.13[0.02-0.23], p = 0.026, N = 103) and CT-based quantification (ß = 1.02[0.39-1.65], p = 0.002, N = 45). Mean desaturation was also associated with both radiological assessment. Elevated 4C-scores (≥high-risk category) had a weaker association with adverse outcomes (OR = 2.44[0.62-9.56]). CONCLUSION: An elevated breath-holding prediction score is associated with almost five-fold increased adverse COVID-19 outcome risk, and with pulmonary deficits observed in chest imaging. Breath-holding may identify COVID-19 patients at risk of future respiratory failure.

Follow-up lung ultrasound to monitor lung failure in COVID-19 ICU patients.

OBJECTIVES: Point-of-care lung ultrasound (LU) is an established tool in the first assessment of patients with coronavirus disease (COVID-19). To assess the progression or regression of respiratory failure in critically ill patients with COVID-19 on Intensive Care Unit (ICU) by using LU. MATERIALS AND METHODS: We analyzed all patients admitted to Internal Intensive Care Unit, Ludwig-Maximilians-University (LMU) of Munich, from March 2020 to December 2020 suffering lung failure caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). LU was performed according to a standardized protocol at baseline and at follow up every other day for the first 15 days using a lung ultrasound score (LUSS). Ventilation data were collected simultaneously. RESULTS: Our study included 42 patients. At admission to ICU, 19 of them (45%) were mechanically ventilated. Of the non-invasive ventilated ones (n = 23, 55%), eleven patients required invasive ventilation over the course. While LUS did not differ at admission to ICU between the invasive ventilated ones (at baseline or during ICU stay) compared to the non-invasive ventilated ones (12±4 vs 11±2 points, p = 0.2497), LUS was significantly lower at d7 for those, who had no need for invasive ventilation over the course (13±5 vs 7±4 points, p = 0.0046). Median time of invasive ventilation counted 18 days; the 90-day mortality was 24% (n = 10) in our cohort. In case of increasing LUS between day 1 (d1) and day 7 (d7), 92% (n = 12/13) required invasive ventilation, while it was 57% (n = 10/17) in case of decreasing LUS. At d7 we found significant correlation between LU and FiO2 (Pearson 0.591; p = 0.033), p/F ratio (Pearson -0.723; p = 0.005), PEEP (Pearson 0.495; p = 0.043), pplat (Pearson 0.617; p = 0.008) and compliance (Pearson -0.572; p = 0.016). CONCLUSION: LUS can be a useful tool in monitoring of progression and regression of respiratory failure and in indicating intubation in patients with COVID-19 in the ICU.

A proposed lung ultrasound and phenotypic algorithm for the care of COVID-19 patients with acute respiratory failure.

Pulmonary complications are the most common clinical manifestations of coronavirus disease (COVID-19). From recent clinical observation, two phenotypes have emerged: a low elastance or L-type and a high elastance or H-type. Clinical presentation, pathophysiology, pulmonary mechanics, radiological and ultrasound findings of these two phenotypes are different. Consequently, the therapeutic approach also varies between the two. We propose a management algorithm that combines the respiratory rate and oxygenation index with bedside lung ultrasound examination and monitoring that could help determine earlier the requirement for intubation and other surveillance of COVID-19 patients with respiratory failure.

RéSUMé: Les complications pulmonaires du coronavirus (COVID-19) constituent ses manifestations cliniques les plus fréquentes. De récentes observations cliniques ont fait émerger deux phénotypes : le phénotype à élastance faible ou type L (low), et le phénotype à élastance élevée, ou type H (high). La présentation clinique, la physiopathologie, les mécanismes pulmonaires, ainsi que les observations radiologiques et échographiques de ces deux différents phénotypes sont différents. L'approche thérapeutique variera par conséquent selon le phénotype des patients atteints de COVID-19 souffrant d'insuffisance respiratoire.

Chronic diseases, chest computed tomography, and laboratory tests as predictors of severe respiratory failure and death in elderly Brazilian patients hospitalized with COVID-19: a prospective cohort study.

BACKGROUND: The primary risk factors for severe respiratory failure and death in the elderly hospitalized with COVID-19 remain unclear. OBJECTIVE: To determine the association of chronic diseases, chest computed tomography (CT), and laboratory tests with severe respiratory failure and mortality in older adults hospitalized with COVID-19. METHOD: This was a prospective cohort with 201 hospitalized older adults with COVID-19. Chronic diseases, chest CT, laboratory tests, and other data were collected within the first 48 h of hospitalization. Outcomes were progression to severe respiratory failure with the need of mechanical ventilation (SRF/MV) and death. RESULTS: The mean age was 72.7 ± 9.2 years, and 63.2% were men. SRF/MV occurred in 16.9% (p < 0.001), and death occurred in 8%. In the adjusted regression analyses, lung involvement over 50% [odds ratio (OR): 3.09 (1.03-9.28; 0.043)], C-reactive protein (CRP) > 80 ng/mL [OR: 2.97 (0.99-8.93; 0.052)], Vitamin D < 40 ng/mL [OR: 6.41 (1.21-33.88; 0.029)], and hemoglobin < 12 g/mL [OR: 3.32 (1.20-9.20; 0.020)] were independent predictors for SFR/MV, while chronic atrial fibrillation [OR: 26.72 (3.87-184.11; 0.001)], cancer history [OR:8.32 (1.28-53.91; 0.026)] and IL-6 > 40 pg/mL [OR:10.01 (1.66-60.13; 0.012)] were independent predictors of death. CONCLUSION: In hospitalized older adults with COVID-19, tomographic pulmonary involvement > 50%, anemia, vitamin D below 40 ng/mL, and CRP above 80 mg/L were independent risk factors for progression to SRF/MV. The presence of chronic atrial fibrillation, previous cancer, IL-6 > 40 pg/mL, and anemia were independent predictors of death.

Severity of respiratory failure and computed chest tomography in acute COVID-19 correlates with pulmonary function and respiratory symptoms after infection with SARS-CoV-2: An observational longitudinal study over 12 months.

INTRODUCTION: Prospective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse. We aim to determine reductions in pulmonary function and respiratory related quality of life up to 12 months after acute COVID-19. METHODS: Patients with acute COVID-19 were enrolled into an ongoing single-centre, prospective observational study and prospectively examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate respiratory limitations. Patients were stratified according to severity of acute COVID-19. RESULTS: Median age of all patients was 57 years, 37.8% were female. Higher age, male sex and higher BMI were associated with acute-COVID-19 severity (p < 0.0001, 0.001 and 0.004 respectively). Also, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity. In patients with restriction and impaired diffusion capacity, FVC improved over 12 months from 61.32 to 71.82, TLC from 68.92 to 76.95, DLCO from 60.18 to 68.98 and KCO from 81.28 to 87.80 (percent predicted values; p = 0.002, 0.045, 0.0002 and 0.0005). The CT-score of lung involvement in the acute phase was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with initially mild disease. CONCLUSION: Severity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection.

Development of an Image-Based HCS-Compatible Method for Endothelial Barrier Function Assessment.

The recent renascence of phenotypic drug discovery (PDD) is catalyzed by its ability to identify first-in-class drugs and deliver results when the exact molecular mechanism is partially obscure. Acute respiratory distress syndrome (ARDS) is a severe, life-threatening condition with a high mortality rate that has increased in frequency due to the COVID-19 pandemic. Despite decades of laboratory and clinical study, no efficient pharmacological therapy for ARDS has been found. An increase in endothelial permeability is the primary event in ARDS onset, causing the development of pulmonary edema that leads to respiratory failure. Currently, the detailed molecular mechanisms regulating endothelial permeability are poorly understood. Therefore, the use of the PDD approach in the search for efficient ARDS treatment can be more productive than classic target-based drug discovery (TDD), but its use requires a new cell-based assay compatible with high-throughput (HTS) and high-content (HCS) screening. Here we report the development of a new plate-based image cytometry method to measure endothelial barrier function. The incorporation of image cytometry in combination with digital image analysis substantially decreases assay variability and increases the signal window. This new method simultaneously allows for rapid measurement of cell monolayer permeability and cytological analysis. The time-course of permeability increase in human pulmonary artery endothelial cells (HPAECs) in response to the thrombin and tumor necrosis factor α treatment correlates with previously published data obtained by transendothelial resistance (TER) measurements. Furthermore, the proposed image cytometry method can be easily adapted for HTS/HCS applications.

Lung ultrasound predicts non-invasive ventilation outcome in COVID-19 acute respiratory failure: a pilot study.

BACKGROUND: The aim of this study is to determine relationships between lung aeration assessed by lung ultrasound (LUS) with non-invasive ventilation (NIMV) outcome, intensive care unit (ICU) admission and mechanical ventilation (MV) needs in COVID-19 respiratory failure. METHODS: A cohort of adult patients with COVID-19 respiratory failure underwent LUS during initial assessment. A simplified LUS protocol consisting in scanning six areas, three for each side, was adopted. A score from 0 to 3 was assigned to each area. Comprehensive LUS score (LUSsc) was calculated as the sum of the score in all areas. LUSsc, the amount of involved sonographic lung areas (LUSq), the number of lung quadrants radiographically infiltrated and the degree of oxygenation impairment at admission (SpO2/FiO2 ratio) were compared to NIMV Outcome, MV needs and ICU admission. RESULTS: Among 85 patients prospectively included in the analysis, 49 of 61 needed MV. LUSsc and LUSq were higher in patients who required MV (median 12 [IQR 8-14] and median 6 [IQR 4-6], respectively) than in those who did not (6 [IQR 2-9] and 3 [IQR 1-5], respectively), both P<0.001. NIMV trial failed in 26 patients out 36. LUSsc and LUSq were significantly higher in patients who failed NIMV than in those who did not. From ROC analysis, LUSsc ≥12 and LUSq ≥5 gave the best cut-off values for NIMV failure prediction (AUC=0.95, 95%CI 0.83-0.99 and AUC=0.81, 95% CI 0.65-0.91, respectively). CONCLUSIONS: Our data suggest LUS as a possible tool for identifying patients who are likely to require MV and ICU admission or to fail a NIMV trial.

Low diaphragm muscle mass predicts adverse outcome in patients hospitalized for COVID-19 pneumonia: an exploratory pilot study.

BACKGROUND: The aim of this study was to evaluate whether measurement of diaphragm thickness (DT) by ultrasonography may be a clinically useful noninvasive method for identifying patients at risk of adverse outcomes defined as need of invasive mechanical ventilation or death. METHODS: We prospectively enrolled 77 patients with laboratory-confirmed COVID-19 infection admitted to our intermediate care unit in Pisa between March 5 and March 30, 2020, with follow-up until hospital discharge or death. Logistic regression was used identify variables potentially associated with adverse outcomes and those P<0.10 were entered into a multivariate logistic regression model. Cumulative probability for lack of adverse outcomes in patients with or without low baseline diaphragm muscle mass was calculated with the Kaplan-Meier product-limit estimator. RESULTS: The main findings of this study are that: 1) patients who developed adverse outcomes had thinner diaphragm than those who did not (2.0 vs. 2.2 mm, P=0.001); and 2) DT and lymphocyte count were independent significant predictors of adverse outcomes, with end-expiratory DT being the strongest (ß=-708; OR=0.492; P=0.018). CONCLUSIONS: Diaphragmatic ultrasound may be a valid tool to evaluate the risk of respiratory failure. Evaluating the need of mechanical ventilation treatment should be based not only on PaO2/FiO2, but on a more comprehensive assessment including DT because if the lungs become less compliant a thinner diaphragm, albeit free of intrinsic abnormality, may become exhausted, thus contributing to severe respiratory failure.

An analysis of the radiological factors associated with respiratory failure in COVID-19 pneumonia and the CT features among different age categories.

PURPOSE: To investigate CT patterns of COVID-19 pneumonia associated with respiratory failure (RF) focused on the distribution of lesions. MATERIALS AND METHODS: Eighty-five patients with COVID-19 pneumonia were reviewed. CT findings were classified as follows: Type A; patchy ground glass attenuation (GGA) with/without air-space consolidation, Type B; non-segmental GGA with/without air-space consolidation in both the central and peripheral lung portions especially with subpleural spare, and Type C; non-segmental GGA with/without air-space consolidation predominantly distributed in the peripheral lung portion without subpleural spare. We analyzed CT patterns and clinical factors associated with RF, including age categories. RESULTS: The number of patients with Type A, B and C was 31 (37%), 24 (28%) and 30 (35%), respectively. Type C and hypertension were independently associated with RF. On comparing between Types B and C, the frequency of traction bronchiectasis was higher in Type C than in Type B (P < 0.001). The ratio of Type C in patients ≥ 65 years old (66%) was higher than in patients < 40 years old (P < 0.001) and 40-49 years old (P = 0.001). CONCLUSION: The Type C, increasing with age, was associated with RF. Traction bronchiectasis in the lesion was more frequent in Type C than in Type B. Secondary abstract A lesion adjacent to the pleura and hypertension is associated with respiratory failure in patients with COVID-19. The frequency of a lesion adjacent to the pleura increased with age. The distribution of lesions is a useful parameter to predict respiratory failure.

Lung ultrasonography for long-term follow-up of COVID-19 survivors compared to chest CT scan.

BACKGROUND: While lung ultrasonography (LUS) has utility for the evaluation of the acute phase of COVID-19 related lung disease, its role in long-term follow-up of this condition has not been well described. The objective of this study is to compare LUS and chest computed tomography (CT) results in COVID-19 survivors with the intent of defining the utility of LUS for long-term follow-up of COVID-19 respiratory disease. METHODS: Prospective observational study that enrolled consecutive survivors of COVID-19 with acute hypoxemic respiratory failure (HARF) admitted to the Respiratory Intensive Care Unit. Three months following hospital discharge, patients underwent LUS, chest CT, body plethysmography and laboratory testing, the comparison of which forms the basis of this report. RESULTS: 38 patients were enrolled, with a total of 190 lobes analysed: men 27/38 (71.1%), mean age 60.6 y (SD 10.4). LUS findings and pulmonary function tests outcomes were compared between patients with and without ILD, showing a statistically significant difference in terms of LUS score (p: 0.0002), FEV1 (p: 0.0039) and FVC (p: 0.012). ROC curve both in lobe by lobe and in patient's overall analysis revealed an outstanding ILD discrimination ability of LUS (AUC: 0.94 and 0.95 respectively) with a substantial Cohen's coefficient (K: 0.74 and 0.69). CONCLUSIONS: LUS has an outstanding discrimination ability compared to CT in identifying an ILD of at least mild grade in the post COVID-19 follow-up. LUS should be considered as the first-line tool in follow-up programs, while chest CT could be performed based on LUS findings.

Successful use of CPAP in a pregnant patient with COVID-19 pneumonia.

A 35-year-old nurse, who was 27 weeks pregnant at the time, was admitted to hospital with a short history of cough, fever and worsening shortness of breath. Oral and nasopharyngeal swabs were positive for SARS-CoV-2 on real-time viral PCR. During her admission, her breathing further deteriorated and she developed type 1 respiratory failure. A decision was made to trial treatment with continuous positive airway pressure (CPAP) as a means of avoiding intubation. The patient tolerated this well and made rapid improvements on this therapy. She was quickly weaned off and fully recovered before being discharged home. This case highlights the potential for CPAP to be used as a means of avoiding mechanical ventilation and iatrogenic preterm birth in COVID-19 pneumonia in pregnancy. Furthermore, it highlights the need for robust evidence to support this treatment.

Delayed COVID respiratory failure: what every front line healthcare worker needs to know.

The pandemic of COVID-19 has presented several diagnostic challenges in both recognition of acute disease and also the temporal presentation of disease convalescence with return to normal activity. We present a case of delayed clinical progression of COVID-19 associated respiratory failure on day 25 after initial symptom onset and, notably, after initial full resolution of symptoms and negative RT-PCR nasopharyngeal testing. The patient's delayed presentation of exertional dyspnea and the utilization of specific characteristics of chest radiography in confirmation with laboratory cytokine measurement allowed for clinical re-categorization of the patient's status to active COVID-19 clinical disease and changed acute management. COVID-19 positive patients should be advised to continue to monitor for respiratory deterioration for a greatly extended period of time, even if RT-PCR testing is negative and initial clinical symptoms have resolved. Frontline healthcare workers, including first responders and primary care providers, also need to be aware to monitor for and recognize this delayed presentation.