Early Empiric Antibiotic Use in Patients Hospitalized With COVID-19: A Retrospective Cohort Study.

OBJECTIVE: To investigate temporal trends and outcomes associated with early antibiotic prescribing in patients hospitalized with COVID-19. DESIGN: Retrospective propensity-matched cohort study using the National COVID Cohort Collaborative (N3C) database. SETTING: Sixty-six health systems throughout the United States that were contributing to the N3C database. Centers that had fewer than 500 admissions in their dataset were excluded. PATIENTS: Patients hospitalized with COVID-19 were included. Patients were defined to have early antibiotic use if they received at least 3 calendar days of intravenous antibiotics within the first 5 days of admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 322,867 qualifying first hospitalizations, 43,089 patients received early empiric antibiotics. Antibiotic use declined across all centers in the data collection period, from March 2020 (23%) to June 2022 (9.6%). Average rates of early empiric antibiotic use (EEAU) also varied significantly between centers (deviance explained 7.33% vs 20.0%, p < 0.001). Antibiotic use decreased slightly by day 2 of hospitalization and was significantly reduced by day 5. Mechanical ventilation before day 2 (odds ratio [OR] 3.57; 95% CI, 3.42-3.72), extracorporeal membrane oxygenation before day 2 (OR 2.14; 95% CI, 1.75-2.61), and early vasopressor use (OR 1.85; 95% CI, 1.78-1.93) but not region of residence was associated with EEAU. After propensity matching, EEAU was associated with an increased risk for in-hospital mortality (OR 1.27; 95% CI, 1.23-1.33), prolonged mechanical ventilation (OR 1.65; 95% CI, 1.50-1.82), late broad-spectrum antibiotic exposure (OR 3.24; 95% CI, 2.99-3.52), and late Clostridium difficile infection (OR 1.60; 95% CI, 1.37-1.87). CONCLUSIONS: Although treatment of COVID-19 patients with empiric antibiotics has declined during the pandemic, the frequency of use remains high. There is significant inter-center variation in antibiotic prescribing practices and evidence of potential harm. Our findings are hypothesis-generating and future work should prospectively compare outcomes and adverse events.

Further evidence of a type 2 inflammatory signature in chronic obstructive pulmonary disease or emphysema.

BACKGROUND: There is increasing recognition of a type 2 (T2) inflammatory pattern in a subset of patients with chronic obstructive pulmonary disease (COPD) or emphysema, characterized by blood and airway eosinophilia. The mechanism underlying this is not well established. The recognition that CD125 (interleukin [IL]-5 receptor alpha) is expressed on some lung neutrophils and eosinophils in patients with asthma led us to speculate that CD125 may also be expressed on lung neutrophils in patients with COPD or emphysema. OBJECTIVE: To interrogate the expression of CD125 on lung neutrophils (and, when present, eosinophils) in patients with COPD/emphysema and identify a meaningful biomarker to predict neutrophil CD125 expression, including other markers of T2 inflammation. METHODS: We obtained blood and bronchoalveolar lavage (BAL) samples from patients with physician-diagnosed COPD/emphysema undergoing a clinically indicated bronchoscopy. RESULTS: We found that a highly variable percentage of BAL neutrophils indeed expressed surface CD125 (0%-78.7%), with obvious clustering of CD125high and CD125low patterns. No correlation was found with clinical characteristics, blood or BAL eosinophil or neutrophil counts, BAL cytokines, or BAL eosinophil CD125 expression. CONCLUSION: We conclude that, similar to asthma, lung neutrophils from patients with COPD display interleukin-5 receptor alpha (CD125) on their surface. This along with the frequent presence of IL-4 and IL-5 in airway fluid further suggests a possible role of the T2 pathway in contributing to COPD severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03984799.

Pathophysiologic Signature of Impending ICU Hypoglycemia in Bedside Monitoring and Electronic Health Record Data: Model Development and External Validation.

OBJECTIVES: We tested the hypothesis that routine monitoring data could describe a detailed and distinct pathophysiologic phenotype of impending hypoglycemia in adult ICU patients. DESIGN: Retrospective analysis leading to model development and validation. SETTING: All ICU admissions wherein patients received insulin therapy during a 4-year period at the University of Virginia Medical Center. Each ICU was equipped with continuous physiologic monitoring systems whose signals were archived in an electronic data warehouse along with the entire medical record. PATIENTS: Eleven thousand eight hundred forty-seven ICU patient admissions. INTERVENTIONS: The primary outcome was hypoglycemia, defined as any episode of blood glucose less than 70 mg/dL where 50% dextrose injection was administered within 1 hour. We used 61 physiologic markers (including vital signs, laboratory values, demographics, and continuous cardiorespiratory monitoring variables) to inform the model. MEASUREMENTS AND MAIN RESULTS: Our dataset consisted of 11,847 ICU patient admissions, 721 (6.1%) of which had one or more hypoglycemic episodes. Multivariable logistic regression analysis revealed a pathophysiologic signature of 41 independent variables that best characterized ICU hypoglycemia. The final model had a cross-validated area under the receiver operating characteristic curve of 0.83 (95% CI, 0.78-0.87) for prediction of impending ICU hypoglycemia. We externally validated the model in the Medical Information Mart for Intensive Care III critical care dataset, where it also demonstrated good performance with an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77-0.81). CONCLUSIONS: We used data from a large number of critically ill inpatients to develop and externally validate a predictive model of impending ICU hypoglycemia. Future steps include incorporating this model into a clinical decision support system and testing its effects in a multicenter randomized controlled clinical trial.

Blood Transcriptomics Predicts Progression of Pulmonary Fibrosis and Associated Natural Killer Cells.

Rationale: Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objectives: To identify a predictor using short-term longitudinal changes in gene expression that forecasts future FVC decline and to characterize involved pathways and cell types. Methods: Seventy-four patients from COMET (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in IPF) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-sequencing data from healthy control subjects were used as references to characterize cell type compositions from bulk peripheral blood mononuclear RNA-sequencing data that were associated with FVC decline. Measurements and Main Results: The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared with a cross-sectional model. The FVC predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were downregulated and upregulated, respectively. Cellular deconvolution using single-cell RNA-sequencing data identified natural killer cells as significantly correlated with progression. Conclusions: Serial transcriptomic change predicts future FVC decline. An analysis of cell types involved in the progressor signature supports the novel involvement of natural killer cells in IPF progression.

Adoption of a dedicated multidisciplinary team is associated with improved survival in acute pulmonary embolism.

BACKGROUND: Acute pulmonary embolism remains a significant cause of mortality and morbidity worldwide. Benefit of recently developed multidisciplinary PE response teams (PERT) with higher utilization of advanced therapies has not been established. METHODS: To evaluate patient-centered outcomes and cost-effectiveness of a multidisciplinary PERT we performed a retrospective analysis of 554 patients with acute PE at the university of Virginia between July 2014 and June 2015 (pre-PERT era) and between April 2017 through October 2018 (PERT era). Six-month survival, hospital length-of-stay (LOS), type of PE therapy, and in-hospital bleeding were assessed upon collected data. RESULTS: 317 consecutive patients were treated for acute PE during an 18-month period following institution of a multidisciplinary PE program; for 120 patients PERT was activated (PA), the remaining 197 patients with acute PE were considered as a separate, contemporary group (NPA). The historical, comparator cohort (PP) was composed of 237 patients. These 3 groups were similar in terms of baseline demographics, comorbidities and risk, as assessed by the Pulmonary Embolism Severity Index (PESI). Patients in the historical cohort demonstrated worsened survival when compared with patients treated during the PERT era. During the PERT era no statistically significant difference in survival was observed in the PA group when compared to the NPA group despite significantly higher severity of illness among PA patients. Hospital LOS was not different in the PA group when compared to either the NPA or PP group. Hospital costs did not differ among the 3 cohorts. 30-day re-admission rates were significantly lower during the PERT era. Rates of advanced therapies were significantly higher during the PERT era (9.1% vs. 2%) and were concentrated in the PA group (21.7% vs. 1.5%) without any significant rise in in-hospital bleeding complications. CONCLUSIONS: At our institution, all-cause mortality in patients with acute PE has significantly and durably decreased with the adoption of a PERT program without incurring additional hospital costs or protracting hospital LOS. Our data suggest that the adoption of a multidisciplinary approach at some institutions may provide benefit to select patients with acute PE.

Nonurgent commercial air travel after nonhemorrhagic cerebrovascular accident.

Nonurgent commercial air travel in patients who have experienced a nonhemorrhagic cerebrovascular accident (CVA) may occur, particularly in the elderly traveling population. A recent CVA, particularly occurring during a person's travel, presents a significant challenge to the patient, companions, family, and health care team. Specific medical recommendation, based on accumulated scientific data and interpreted by medical experts, is needed so that travel health care professionals can appropriately guide the patient. Unfortunately, such recommendations are almost entirely lacking despite the relative frequency of CVA and air travel. This article reviews the existing recommendations with conclusions based on both these limited data and rationale conjecture.

Air travel of patients with abdominal aortic aneurysm: urgent air medical evacuation and nonurgent commercial air repatriation.

Abdominal aortic aneurysm (AAA) presents across a spectrum of severity. Although some resources suggest a theoretic risk for rupture related to air travel, this claim remains unproven. In fact, there are little data from which to make evidence-based recommendations. Air medical evacuation of a patient with either an AAA at risk of imminent rupture or status post recent rupture can be performed, assuming that local surgical care is not available and that transfer is taking the patient to a higher level of medical intervention. Furthermore, medical opinion suggests that patients with asymptomatic and/or surgically corrected AAA can safely travel by commercial aircraft for nonurgent reasons, assuming that other issues including postoperative needs are appropriately addressed. In this discussion, answers to the following issues are sought: flight safety for urgent evacuation and nonurgent repatriation scenarios, waiting time to fly nonurgently after AAA diagnosis, and the need for medical accompaniment.

Cardiorespiratory Dynamics During Prone Positioning for Severe Ards: A Retrospective Cohort Study.

Objectives: To elucidate the changes in cardiorespiratory dynamics during neuromuscular blockade and prone positioning and determine the associations between changes in cardiorespiratory dynamics following prone positioning and mortality. Design: Single center retrospective cohort study of patients admitted to the medical ICU between June 1, 2020 and September 1, 2022 who received prone positioning while mechanically ventilated. Results: Our final cohort consisted of 136 patients. Prone position was associated with an improvement in A-a gradient of 113 mmHg (95% CrI 78 - 149) between the pre-proning values and 10 hours post proning. Norepinephrine dose did not significantly change before and after prone positioning (Estimated difference: 0.04 mcg/min 95% CrI -1.00 - 1.07). For the outcome of 7-d mortality, there was a high probability that the baseline factors of increasing age, male sex, and higher baseline A-a gradient were associated with increased risk of death. Increased total vasopressor requirement and increased in PCO2 were associated with worse prognosis while a decrease in instantaneous heart rate and a decrease in heart rate variability were associated with improved prognosis. Conclusion: The immediate changes in prone positioning primarily impact respiratory physiology, with limited influence on circulatory parameters. Predictors of short-term mortality after prone positioning include both respiratory and cardiovascular parameters suggesting that extrapulmonary effects, such as improvement in right ventricular heart function, might also contribute to the benefit of prone positioning.

Age Prediction From 12-lead Electrocardiograms Using Deep Learning: A Comparison of Four Models on a Contemporary, Freely Available Dataset.

The 12-lead electrocardiogram (ECG) is routine in clinical use and deep learning approaches have been shown to have the identify features not immediately apparent to human interpreters including age and sex. ECG predicted age has been identified as a predictor of long-term mortality. Here we compare four models for age and sex prediction on a contemporary, freely available dataset.

The Dearth of Representation in FDA Approved Drug Trials.

The generalizability of data derived from randomized controlled trials is of paramount importance given their utility in the Food & Drug Administration (FDA) drug approval process. An essential part of this process is the inclusion of reliably reported gender, race and ethnicity data in trials that lead to FDA drug approval. Despite previous mandates by the FDA and Clinicaltrials.gov, gender and race-specific data remains under reported. We reviewed 100 most recently approved FDA medications, and abstracted the clinical trial data from Clinicaltrials.gov that supported their approval. We then compared these FDA approved trials to non-FDA approved trials from the same year and of similar size. We found that 40% of the FDA trials were missing race/ethnicity information, while 24% of these trials did not include gender information. We demonstrate that there remains a significant amount of missing gender and racial/ethnic data in trials that lead to FDA-approved medications.

Analysis of iron status after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis.

BACKGROUND: Iron deficiency is highly prevalent in people with cystic fibrosis (PwCF). While elexacaftor/tezacaftor/ivacaftor (ETI) has shown remarkable improvements in respiratory symptoms in PwCF, the effect of ETI on iron status remains unknown. This study aims to identify the effect of ETI on iron status in PwCF. METHODS: A single-center retrospective cohort study of 127 adult PwCF was conducted to assess the impact of ETI on iron, ferritin, transferrin levels, and percent saturation of transferrin (PSAT). Data were collected from the electronic medical record from January 2017 to September 2022, encompassing 2 years before and after ETI initiation. The primary outcome was serum iron parameters: iron, ferritin, transferrin, and PSAT levels following ETI treatment. Secondary outcomes analyzed iron supplementation. Univariate and multivariate mixed-effects models were used for the analysis of ETI. RESULTS: After adjusting for covariates, following ETI initiation, the mean iron level increased by 20.24 µg/dL (p < .001), ferritin levels were 31.4% (p < .001) higher, PSAT showed a 5.09 percentage point increase (p < .001), and transferrin levels increased by 2.71 mg/dL (p = .439). Patients with and without iron supplementation experienced a significant increase in iron after ETI (p < .001). CONCLUSIONS: ETI is associated with a significant increase in iron, ferritin, and PSAT levels. Patients with and without iron supplementation demonstrated a significant increase in iron. This study shows the benefits of ETI on iron status in PwCF. However, further translational studies are required to understand the impact of ETI on iron absorption and metabolism in PwCF.

Real world study on elexacaftor-tezacaftor-ivacaftor impact on cholesterol levels in adults with cystic fibrosis.

INTRODUCTION: The introduction of the highly effective modulator therapy elexacaftor-tezacaftor-ivacaftor (ETI) has revolutionized the care of persons with cystic fibrosis (PwCF) with major improvements seen in lung function and body mass index. The effects of ETI therapy in real-world cohorts on other parameters such as cholesterol levels are largely unknown. METHODS: A single-center, retrospective chart review study was conducted to assess the change in lipid panels before and after ETI initiation. The study investigated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels using both a univariate and multivariate mixed-effects model to evaluate the change after initiation of ETI in a cohort of PwCF. RESULTS: There were 128 adult PwCF included in the analysis. Statistically significant changes were seen in both univariate and multivariate analyses for TC, LDL-C, and HDL-C. On multivariate analysis, TC increased by an average of 15.0 mg/dL after ETI initiation (p < 0.0001), LDL-C increased by an average of 9.3 mg/dL (p < 0.001), and HDL-C increased by an average of 3.8 mg/dL (p < 0.001) after ETI initiation. CONCLUSION: In this real-world cohort of PwCF, cholesterol parameters increased after initiation with ETI therapy. Further consideration may need to be given for PwCF in regards to screening for cardiometabolic risk factors as PwCF age as well as the potential need for cholesterol-lowering therapies.

In-Hospital Cardiac Arrest.

This article reviews the epidemiology and management of in-hospital cardiac arrest.

Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis.

RATIONALE: Contribution of central lung tissues to pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unknown. OBJECTIVE: To ascertain the relationship between cell types of IPF-central and IPF-peripheral lung explants using RNA sequencing (RNA-seq) transcriptome. METHODS: Biopsies of paired IPF-central and IPF-peripheral along with non-IPF lungs were selected by reviewing H&E data. Criteria for differentially expressed genes (DEG) were set at false discovery rate <5% and fold change >2. Computational cell composition deconvolution was performed. Signature scores were computed for each cell type. FINDINGS: Comparison of central IPF versus non-IPF identified 1723 DEG (1522 upregulated and 201 downregulated). Sixty-two per cent (938/1522) of the mutually upregulated genes in central IPF genes were also upregulated in peripheral IPF versus non-IPF. Moreover, 85 IPF central-associated genes (CAG) were upregulated in central IPF versus both peripheral IPF and central non-IPF. IPF single-cell RNA-seq analysis revealed the highest CAG signature score in myofibroblasts and significantly correlated with a previously published activated fibroblasts signature (r=0.88, p=1.6×10-4). CAG signature scores were significantly higher in IPF than in non-IPF myofibroblasts (p=0.013). Network analysis of central-IPF genes identified a module significantly correlated with the deconvoluted proportion of myofibroblasts in central IPF and anti-correlated with inflammation foci trait in peripheral IPF. The module genes were over-represented in idiopathic pulmonary fibrosis signalling pathways. INTERPRETATION: Gene expression in central IPF lung regions demonstrates active myofibroblast features that contributes to disease progression. Further elucidation of pathological transcriptomic state of cells in the central regions of the IPF lung that are relatively spared from morphological rearrangements may provide insights into molecular changes in the IPF progression.

The Intensive Care Unit Bundle Board: A Novel Real-Time Data Visualization Tool to Improve Maintenance Care for Invasive Catheters.

BACKGROUND: Critically ill patients are at greater risk of healthcare-associated infections (HAIs). The use of maintenance bundles helps to reduce this risk but also generates a rapid accumulation of complex data that is difficult to aggregate and subsequently act upon. OBJECTIVES: We hypothesized that a digital display summarizing nursing documentation of invasive catheters (including central venous access devices, arterial catheters, and urinary catheters) would improve invasive device maintenance care and documentation. Our secondary objectives were to see if this summary would reduce the duration of problematic conditions, that is, characteristics associated with increased risk of infection. METHODS: We developed and implemented a data visualization tool called the "Bundle Board" to display nursing observations on invasive devices. The intervention was studied in a 28-bed medical intensive care unit (MICU). The Bundle Board was piloted for 6 weeks in June 2022 and followed by a comparison phase, where one MICU had Bundle Board access and another MICU at the same center did not. We retrospectively applied tile color coding logic to prior nursing documentation from 2021 until the pilot phase to facilitate comparison pre- and post-Bundle Board release. RESULTS: After adjusting for time, other quality improvement efforts, and nursing shift, multiple linear regression demonstrated a statistically significant improvement in the completion of catheter care and documentation during the pilot phase (p < 0.0001) and comparison phase (p = 0.002). The median duration of documented problematic conditions was significantly reduced during the pilot phase (p < 0.0001) and in the MICU with the Bundle Board (comparison phase, p = 0.027). CONCLUSION: We successfully developed a data visualization tool that changed ICU provider behavior, resulting in increased completion and documentation of maintenance care and reduced duration of problematic conditions for invasive catheters in MICU patients.

The use of a 4-step algorithm in the electrocardiographic diagnosis of ST-segment elevation myocardial infarction by novice interpreters.

The electrocardiographic (ECG) diagnosis of ST-segment elevation myocardial infarction (STEMI) represents a challenge to all health care providers, particularly so for the novice ECG interpreter. We have developed--and present in this article--a 4-step algorithm that will detect STEMI in most instances in the prehospital and other nonemergency department (ED) settings. The algorithm should be used in adult patients with chest pain or equivalent presentation who are suspected of STEMI. It inquires as to the presence of ST-segment elevation as well as the presence of STEMI confounding/mimicking patterns; the algorithm also makes use of reciprocal ST-segment depression as an adjunct in the ECG diagnosis of STEMI. If STEMI is detected by this algorithm, then management decisions can be made based upon this ECG diagnosis. If STEMI is not detected using this algorithm, then we can only note that STEMI is not "ruled in"; importantly, STEMI is not "ruled out." In fact, more expert interpretation of the ECG will be possible once the patient (and/or the ECG) arrive in the ED where ECG review can be made with the more complex interpretation used by expert physician interpreters.

Change in End-Tidal Co2 After Mini-Fluid Challenge to Determine Fluid Responsiveness.

Distributive shock is a major cause of morbidity and mortality in the ICU. IV fluid resuscitation is a vital intervention to improve cardiac output and end-organ perfusion during the initial resuscitation and for those who remain fluid responsive. Noninvasive measures of fluid responsiveness are lacking. The aim of this study is to assess whether changes in end-tidal co2 after mini-fluid challenge, or 250 mL bolus, can predict fluid responsiveness in mechanically ventilated patients with distributive shock. DESIGN: Single-center prospective study. SETTING: Patients were enrolled from 2019 to 2021 from the medical ICU within a single academic hospital. PATIENTS: Thirty-eight patients with paired measurements of fluid responsiveness as determined by bioreactance who were admitted to the ICU with a diagnosis of distributive shock and on mechanical ventilation. INTERVENTIONS: Stroke volume index (SVI), cardiac index, heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and ETco2 were measured before and after completion of a mini-fluid challenge. Test characteristics of change in ETco2 (ΔETco2) greater than or equal to 2 after mini-fluid challenge to determine fluid responsiveness were calculated with percentage change in SVI greater than or equal to 10% used as the reference standard. MEASUREMENTS AND MAIN RESULTS: The sensitivity and specificity of a ΔETco2 greater than or equal to 2 mm Hg as a predictor of a change in SVI greater than or equal to 10% following a mini-fluid challenge were 20.0% and 91.3%, respectively. The area under the receiver operating characteristic curve was 0.62. CONCLUSIONS: A ΔETco2 greater than or equal to 2 mm Hg after mini-fluid challenge has limited test performance for determining fluid responsiveness in intubated patients with distributive shock.

Convalescent Plasma for Preventing Critical Illness in COVID-19: a Phase 2 Trial and Immune Profile.

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring frequent adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting. We tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28-day mortality or alter levels of specific antibody responses before and after CIP infusion. In a single-arm phase II study, patients >18 years-old with respiratory symptoms with confirmed COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 h of admission. Levels of SARS-CoV-2 detected by PCR in the respiratory tract and circulating anti-SARS-CoV-2 antibody titers were sequentially measured before and after CIP transfusion. Twenty-nine patients were transfused high titer CIP and 48 contemporaneous comparable controls were identified. All classes of antibodies to the three SARS-CoV-2 target proteins were significantly increased at days 7 and 14 post-transfusion compared with baseline (P < 0.01). Anti-nucleocapsid IgA levels were reduced at day 28, suggesting that the initial rise may have been due to the contribution of CIP. The groups were well-balanced, without statistically significant differences in demographics or co-morbidities or use of remdesivir or dexamethasone. In participants transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298). IMPORTANCE Transfusion of high-titer CIP to non-critically ill patients early after admission with COVID-19 respiratory disease was associated with significantly increased anti-SARS-CoV-2 specific antibodies (compared to baseline) and a non-significant reduction in ICU transfer and death (compared to controls). This prospective phase II trial provides a suggestion that the antiviral effects of CIP from early in the COVID-19 pandemic may delay progression to critical illness and death in specific patient populations. This study informs the optimal timing and potential population of use for CIP in COVID-19, particularly in settings without access to other interventions, or in planning for future coronavirus pandemics.