Circulating proteins to predict COVID-19 severity.

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care.

Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae.

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals.

INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

COVID-19: A Multimodality Review of Radiologic Techniques, Clinical Utility, and Imaging Features.

In this article we will review the imaging features of coronavirus disease 2019 (COVID-19) across multiple modalities, including radiography, CT, MRI, PET/CT, and US. Given that COVID-19 primarily affects the lung parenchyma by causing pneumonia, our directive is to focus on thoracic findings associated with COVID-19. We aim to enhance radiologists' understanding of this disease to help guide diagnosis and management. Supplemental material is available for this article. © RSNA, 2020.

Portable Chest Radiography as an Exclusionary Test for Adverse Clinical Outcomes During the COVID-19 Pandemic.

BACKGROUND: Chest radiography (CXR) often is performed in the acute setting to help understand the extent of respiratory disease in patients with COVID-19, but a clearly defined role for negative chest radiograph results in assessing patients has not been described. RESEARCH QUESTION: Is portable CXR an effective exclusionary test for future adverse clinical outcomes in patients suspected of having COVID-19? STUDY DESIGN AND METHODS: Charts of consecutive patients suspected of having COVID-19 at five EDs in New York City between March 19, 2020, and April 23, 2020, were reviewed. Patients were categorized based on absence of findings on initial CXR. The primary outcomes were hospital admission, mechanical ventilation, ARDS, and mortality. RESULTS: Three thousand two hundred forty-five adult patients, 474 (14.6%) with negative initial CXR results, were reviewed. Among all patients, negative initial CXR results were associated with a low probability of future adverse clinical outcomes, with negative likelihood ratios of 0.27 (95% CI, 0.23-0.31) for hospital admission, 0.24 (95% CI, 0.16-0.37) for mechanical ventilation, 0.19 (95% CI, 0.09-0.40) for ARDS, and 0.38 (95% CI, 0.29-0.51) for mortality. Among the subset of 955 patients younger than 65 years and with a duration of symptoms of at least 5 days, no patients with negative CXR results died, and the negative likelihood ratios were 0.17 (95% CI, 0.12-0.25) for hospital admission, 0.09 (95% CI, 0.02-0.36) for mechanical ventilation, and 0.09 (95% CI, 0.01-0.64) for ARDS. INTERPRETATION: Initial CXR in adult patients suspected of having COVID-19 is a strong exclusionary test for hospital admission, mechanical ventilation, ARDS, and mortality. The value of CXR as an exclusionary test for adverse clinical outcomes is highest among young adults, patients with few comorbidities, and those with a prolonged duration of symptoms.

Coronary artery calcification in COVID-19 patients: an imaging biomarker for adverse clinical outcomes.

BACKGROUND: Recent studies have demonstrated a complex interplay between comorbid cardiovascular disease, COVID-19 pathophysiology, and poor clinical outcomes. Coronary artery calcification (CAC) may therefore aid in risk stratification of COVID-19 patients. METHODS: Non-contrast chest CT studies on 180 COVID-19 patients ≥ age 21 admitted from March 1, 2020 to April 27, 2020 were retrospectively reviewed by two radiologists to determine CAC scores. Following feature selection, multivariable logistic regression was utilized to evaluate the relationship between CAC scores and patient outcomes. RESULTS: The presence of any identified CAC was associated with intubation (AOR: 3.6, CI: 1.4-9.6) and mortality (AOR: 3.2, CI: 1.4-7.9). Severe CAC was independently associated with intubation (AOR: 4.0, CI: 1.3-13) and mortality (AOR: 5.1, CI: 1.9-15). A greater CAC score (UOR: 1.2, CI: 1.02-1.3) and number of vessels with calcium (UOR: 1.3, CI: 1.02-1.6) was associated with mortality. Visualized coronary stent or coronary artery bypass graft surgery (CABG) had no statistically significant association with intubation (AOR: 1.9, CI: 0.4-7.7) or death (AOR: 3.4, CI: 1.0-12). CONCLUSION: COVID-19 patients with any CAC were more likely to require intubation and die than those without CAC. Increasing CAC and number of affected arteries was associated with mortality. Severe CAC was associated with higher intubation risk. Prior CABG or stenting had no association with elevated intubation or death.

Clinical and Chest Radiography Features Determine Patient Outcomes in Young and Middle-aged Adults with COVID-19.

Background Chest radiography has not been validated for its prognostic utility in evaluating patients with coronavirus disease 2019 (COVID-19). Purpose To analyze the prognostic value of a chest radiograph severity scoring system for younger (nonelderly) patients with COVID-19 at initial presentation to the emergency department (ED); outcomes of interest included hospitalization, intubation, prolonged stay, sepsis, and death. Materials and Methods In this retrospective study, patients between the ages of 21 and 50 years who presented to the ED of an urban multicenter health system from March 10 to March 26, 2020, with COVID-19 confirmation on real-time reverse transcriptase polymerase chain reaction were identified. Each patient's ED chest radiograph was divided into six zones and examined for opacities by two cardiothoracic radiologists, and scores were collated into a total concordant lung zone severity score. Clinical and laboratory variables were collected. Multivariable logistic regression was used to evaluate the relationship between clinical parameters, chest radiograph scores, and patient outcomes. Results The study included 338 patients: 210 men (62%), with median age of 39 years (interquartile range, 31-45 years). After adjustment for demographics and comorbidities, independent predictors of hospital admission (n = 145, 43%) were chest radiograph severity score of 2 or more (odds ratio, 6.2; 95% confidence interval [CI]: 3.5, 11; P < .001) and obesity (odds ratio, 2.4 [95% CI: 1.1, 5.4] or morbid obesity). Among patients who were admitted, a chest radiograph score of 3 or more was an independent predictor of intubation (n = 28) (odds ratio, 4.7; 95% CI: 1.8, 13; P = .002) as was hospital site. No significant difference was found in primary outcomes across race and ethnicity or those with a history of tobacco use, asthma, or diabetes mellitus type II. Conclusion For patients aged 21-50 years with coronavirus disease 2019 presenting to the emergency department, a chest radiograph severity score was predictive of risk for hospital admission and intubation. © RSNA, 2020 Online supplemental material is available for this article.

Spontaneous subcutaneous emphysema and pneumomediastinum in non-intubated patients with COVID-19.

PURPOSE: We describe the presenting characteristics and hospital course of 11 novel coronavirus (COVID-19) patients who developed spontaneous subcutaneous emphysema (SE) with or without pneumomediastinum (SPM) in the absence of prior mechanical ventilation. MATERIALS AND METHODS: A total of 11 non-intubated COVID-19 patients (8 male and 3 female, median age 61 years) developed SE and SPM between March 15 and April 30, 2020 at a multi-center urban health system in New York City. Demographics (age, gender, smoking status, comorbid conditions, and body-mass index), clinical variables (temperature, oxygen saturation, and symptoms), and laboratory values (white blood cell count, C-reactive protein, D-dimer, and peak interleukin-6) were collected. Chest radiography (CXR) and computed tomography (CT) were analyzed for SE, SPM, and pneumothorax by a board-certified cardiothoracic-fellowship trained radiologist. RESULTS: Eleven non-intubated patients developed SE, 36% (4/11) of whom had SE on their initial CXR. Concomitant SPM was apparent in 91% (10/11) of patients, and 45% (5/11) also developed pneumothorax. Patients developed SE on average 13.3 days (SD: 6.3) following symptom onset. No patients reported a history of smoking. The most common comorbidities included hypertension (6/11), diabetes mellitus (5/11), asthma (3/11), dyslipidemia (3/11), and renal disease (2/11). Four (36%) patients expired during hospitalization. CONCLUSION: SE and SPM were observed in a cohort of 11 non-intubated COVID-19 patients without any known cause or history of invasive ventilation. Further investigation is required to elucidate the underlying mechanism in this patient population.