Machine learning links unresolving secondary pneumonia to mortality in patients with severe pneumonia, including COVID-19.

BACKGROUNDDespite guidelines promoting the prevention and aggressive treatment of ventilator-associated pneumonia (VAP), the importance of VAP as a driver of outcomes in mechanically ventilated patients, including patients with severe COVID-19, remains unclear. We aimed to determine the contribution of unsuccessful treatment of VAP to mortality for patients with severe pneumonia.METHODSWe performed a single-center, prospective cohort study of 585 mechanically ventilated patients with severe pneumonia and respiratory failure, 190 of whom had COVID-19, who underwent at least 1 bronchoalveolar lavage. A panel of intensive care unit (ICU) physicians adjudicated the pneumonia episodes and endpoints on the basis of clinical and microbiological data. Given the relatively long ICU length of stay (LOS) among patients with COVID-19, we developed a machine-learning approach called CarpeDiem, which grouped similar ICU patient-days into clinical states based on electronic health record data.RESULTSCarpeDiem revealed that the long ICU LOS among patients with COVID-19 was attributable to long stays in clinical states characterized primarily by respiratory failure. While VAP was not associated with mortality overall, the mortality rate was higher for patients with 1 episode of unsuccessfully treated VAP compared with those with successfully treated VAP (76.4% versus 17.6%, P < 0.001). For all patients, including those with COVID-19, CarpeDiem demonstrated that unresolving VAP was associated with a transitions to clinical states associated with higher mortality.CONCLUSIONSUnsuccessful treatment of VAP is associated with higher mortality. The relatively long LOS for patients with COVID-19 was primarily due to prolonged respiratory failure, placing them at higher risk of VAP.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID), NIH grant U19AI135964; National Heart, Lung, and Blood Institute (NHLBI), NIH grants R01HL147575, R01HL149883, R01HL153122, R01HL153312, R01HL154686, R01HL158139, P01HL071643, and P01HL154998; National Heart, Lung, and Blood Institute (NHLBI), NIH training grants T32HL076139 and F32HL162377; National Institute on Aging (NIA), NIH grants K99AG068544, R21AG075423, and P01AG049665; National Library of Medicine (NLM), NIH grant R01LM013337; National Center for Advancing Translational Sciences (NCATS), NIH grant U01TR003528; Veterans Affairs grant I01CX001777; Chicago Biomedical Consortium grant; Northwestern University Dixon Translational Science Award; Simpson Querrey Lung Institute for Translational Science (SQLIFTS); Canning Thoracic Institute of Northwestern Medicine.

Impact of VV ECMO Use as Bridge to Lung Transplant in Patients with COVID-19 Associated Acute Respiratory Distress Syndrome

Lung transplantation is a potentially lifesaving treatment for critically ill patients with COVID-19-associated acute respiratory distress syndrome (ARDS). Many patients require extracorporeal membrane oxygenation (ECMO) as life-saving support when other traditional treatments fail. However, there is limited information regarding the long-term outcomes of VV-ECMO use as a bridge to lung transplantation in patients with ARDS. This was a retrospective review of an institutional lung transplant database. We included consecutive lung transplant recipients between June 2020 and June 2022. Demographic, clinical, laboratory, treatment data, the outcomes of lung transplantation, and survival were collected and analyzed. Kaplan-Meier and Wilcoxon tests were used to evaluate survival rates. Among the 41 lung transplant recipients for COVID-19-associated ARDS, 25 patients (median age 53 years [IQR, 36-55];11 women [44.0%]) had ECMO bridges and 16 patients (median age 54.5 years [IQR, 52.75 to 63];7 women [43.8%]) did not. For lung transplant recipients with ECMO bridges compared to those without, the median lung allocation scores were 88.1 vs. 74.9 (p<0.001). During transplantation, patients with COVID-19-associated ARDS received transfusions with a median of ten units of packed red blood cells vs. two units in those without ECMO bridges;96.0% vs. 93.8% underwent intraoperative venoarterial ECMO, and the median operative time was 9.5 hrs. vs. 7.8 hrs., respectively. Postoperatively, the rates of primary graft dysfunction grade 3, within 72 hrs., were 44% in the ECMO bridge vs. 0% in those without them. The median duration of intensive care unit stays was 20 days vs. 13 days, and the median post-lung transplant hospitalization duration was 35 days vs. 19.5 days, respectively. After follow-up (median follow-up period: 448 days [IQR, 314-664] in patients with ECMO bridges vs. 417 days [IQR, 389.5-506] in patients without them), one-year survival rates were 78.3% in patients with ECMO bridges and 100.0% in patients without (p=0.06). In this single-center case series of 41 consecutive patients who underwent lung transplantation for COVID-19-associated ARDS, patients on an ECMO bridge showed a more severe cohort. However, there was no significant difference in the overall outcomes between the two groups (p=0.06). [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Right Heart Recovery after Lung Transplantation in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome: A Cohort Study

In patients with COVID-19-associated acute respiratory distress syndrome (ARDS), decreased pulmonary compliance, increased pulmonary vascular resistance and micro pulmonary thrombosis increase the right heart burden, which can lead to right heart failure. However, the impact of lung transplantation for ARDS on the right heart is unclear. Therefore, we evaluated changes in heart function and structural abnormalities with pre- and postoperative transthoracic echocardiography (TTE). This study was a retrospective review of the institutional lung transplantation database from June 2020 to June 2022. Pre- and postoperative TTE were performed, and postoperative TTE beyond 90 days was recorded. Right ventricular (RV) function and size were evaluated and scored. The Wilcoxon signed-rank test was used to compare pre- and postoperative TTE values. During the period, 42 patients underwent lung transplantation for COVID-19-associated ARDS: 10 were excluded (two single-lung, one lobar, one dual-organ transplant, and six patients with missing postoperative TTE data);and 32 were included in the study. TTE was evaluated at a median of 15 days preoperatively (IQR 9.5-30) and 144.5 days postoperatively (IQR 112-210). Pre- and postoperative TTE showed significant changes in mitral A, lateral E', RV estimated systolic pressure (RVSP), RV function and size (Figure 1 and Table 1). In patients with severe right heart dysfunction due to COVID-19-associated ARDS, RV function and structure normalized within a relatively short period after lung transplantation. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Feasibility of Veno-Venous Extracorporeal Membrane Oxygenation Using ProtekDuoTM Cannula Ina Patients with COVID-19-Associated Acute Respiratory Distress Syndrome with Severe Right Heart Dysfunction Before Lung Transplantation

Severe right heart failure (RHF) is a known complication of pulmonary hypertension, which increases mortality before lung transplantation. The safety and feasibility of venovenous (VV)-extracorporeal oxygenation (ECMO) using ProtekDuoTM (CardiacAssist Inc., Pittsburgh, PA) as a bridge to lung transplantation in severe RHF caused have not been well studied. This study aimed to evaluate the safety and feasibility of VV-ECMO using ProtekDuoTM as a bridge to lung transplantation in patients with severe RHF. This study was a prospective review of the institutional lung transplantation database from June 2020 to June 2022. Patients who underwent lung transplantation with VV-ECMO using ProtekDuoTM for COVID-19 associated acute respiratory distress syndrome (ARDS) were prospectively enrolled;and preoperative and postoperative transthoracic echocardiographic (TTE) data were analyzed. RV function and size were evaluated and scored. The Wilcoxon signed-rank test was used to compare pre- and post-operative TTE values. During the study period, 20 patients underwent lung transplantation for COVID-19-associated ARDS with preoperative VV-ECMO using ProtekDuoTM. TTE was assessed at a median of 15 days preoperatively (IQR, 7.75-31) and 155.5 days postoperatively (IQR, 112-210). Pre and post-operative median RVSP was 45.4 mm Hg (IQR, 29.4-49.0) and 30.0 mm Hg (IQR, 28.0-35.0), p=0.02, and the median mitral valve A was 0.70 cm/s (IQR, 0.70-0.80) and 0.55 cm/s (IQR, 0.50-0.70), p=0.03 (Table1). All patients were hemodynamically stable with active rehabilitation and did not require inotropes or inhaled nitric oxide. VV-ECMO with ProtekDuoTM for patients with COVID-19-associated ARDS before lung transplantation can stabilize patients without significant complications and allows active rehabilitation of patients with severe RHF. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cytomegalovirus Serologic Mismatch Impact Long-Term Outcomes after Lung Transplantation

Cytomegalovirus (CMV) infection is associated with poor outcomes after solid organ transplantation. The long-term impact of donor and recipient CMV serological status on lung transplant outcomes has been considered a risk factor for mortality, which donor CMV-IgG positive-recipient CMV-IgG negative (D+R-) group is a high risk for CMV infection and mortality. However, the risk factors in this group of patients remain unclear. We evaluated the impact of donor and recipient CMV status on long-term outcomes, as well as the risk factors for CMV infection. This was a prospective review of the institutional lung transplantation database from June 2014 to June 2022. Data on patient characteristics, pre-transplantation laboratory values, postoperative outcomes, and CMV infection were collected. All patients received a prophylactic dose of valganciclovir hydrochloride (900 mg once daily) after lung transplantation. The donor positive-recipient CMV-IgG negative group was defined as the CMV-mismatch group. The results were analyzed using the chi-square test, Mann-Whitney U test, t-test, logistic regression analyses, and receiver operating characteristic curve analysis. During the study period, 257 patients underwent lung transplantation. CMV infection was detected in 69 patients (26.8%):25 of 203 (12.3%) in the non-CMV mismatch group and 29 of 54 (53.7%) in the CMV mismatch group (p<0.001). CMV infection occurred 395 days (IQR;264-452) in the entire cohort. In multivariate logistic analysis, COVID-19-associated acute respiratory distress syndrome etiology, lower albumin level, and CMV mismatch were independent factors for CMV infection (COVID-19-related ARDS, OR=3.03, 95% CI=1.20-7.64, p=0.02;albumin [g/dl], OR=0.34, 95% CI=0.16-0.70, p<0.01;CMV mismatch, OR=6.66, 95% CI=2.79-15.9, p<0.001). Receiver operating characteristic curve analysis showed that an albumin of 4.0 g/dl was the cut-off value (area under the curve=0.64) for the risk of CMV infection. In the CMV mismatch group, hemodialysis use after discharge was associated with CMV infection (OR=9.10, 95% CI=1.02-82.4, p=0.04). In patients with CMV mismatch, hemodialysis use was an independent predictor of CMV infection. Further studies are needed to determine the risks and benefits of extending CMV prophylaxis or aggressive CMV treatment, particularly in high-risk groups. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Hypercapnia alters stroma-derived Wnt production to limit ß-catenin signaling and proliferation in AT2 cells.

Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits ß-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize ß-catenin signaling, thereby limiting progenitor function. Constitutive activation of ß-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.

Lung Transplantation Promotes Survival In Patients with COVID-19 ARDS Who Require Extended Duration of VV ECMO support

Background: Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is increasingly being utilized to manage critical COVID-19 associated ARDS (CCAA) in patients who fail medical optimization and mechanical ventilatory support. The aim of this study was to determine the probability of weaning patients from ECMO over time and whether a subset of patients should be considered for lung transplantation. Additionally, we investigated when lung transplant should be considered after VV ECMO support. Methods: 49 patients with CCAA who required ECMO between January 2020 and September 2021 were investigated. Baseline patient demographics, clinical, laboratory, and follow-up data were compared. The change in probability of ECMO weaning based on duration of ECMO support was studied using a univariate analysis. Additionally, patients who received lung transplantation following VV ECMO for COVID-19 during this same period were studied to compare outcomes to those of patients with only VV ECMO support. Cox proportion hazard analysis was performed to determine predictors of survival in patients who required greater than 28 days of ECMO support. Yuden index was used to determine change in probability of survival with time on ECMO. Results: Of 49 patients, 17 (35%) received lung transplants and 32 (65%) remained on ECMO for >28 days. The probability of weaning patients from ECMO was highest within the first 10 days (60%);beyond 40 days, it was 5.1% (Fig. A). The probability of successfully weaning patients from ECMO significantly decreased over time and ECMO support greater than 28 days (Yuden index, Hazard ratio: 1.09, 95% CI;1.00-1.03) was associated with a significantly increased risk of mortality. Additionally, both survival to hospital discharge (p<0.001, Fig. B) and post-discharge survival (p<0.001, Fig. C) were significantly greater in those who were weaned from ECMO prior to 28 days than those who were weaned after 28 days. In those who could not be weaned from ECMO, lung transplantation (HR:0.47, p<0.01, 95% CI 0.17-0.94), ECMO duration (HR:1.09, p=0.01, 95% CI 1.00-1.03) and higher BUN levels (HR:1.02, p<0.01, 95% CI 1.01- 1.46) prior to ECMO initiation were independent predictors of survival. ECMO support of greater than 8 days was associated with a statistically significant increase in mortality compared to those who received fewer than 8 days of support (Yuden index, HR 1.96, CI 1.06-5.51). Furthermore, the projected survival of patients on ECMO support for greater than 8 days was substantially worse than those requiring fewer than 8 days of support (Fig. C and D). Conclusion: This study suggests that survival and accompanying lung recovery is more probable in patients who require a short duration of ECMO support whereas those who require longer durations, particularly exceeding 28 days, is associated with a lower rate of survival. (Figure Presented).

Hypercapnia Increases ACE2 Protein Expression and Pseudo-SARSCoV- 2 Virus Entry in Airway Epithelial Cells by Augmenting Cellular Cholesterol

Rationale: Individuals with COPD who develop COVID-19 are at increased risk of hospitalization, ICU admission and death. COPD is associated with increased airway epithelial expression of ACE2, the receptor mediating SARS-CoV-2 entry into cells. Hypercapnia commonly develops in advanced COPD and is associated with frequent and potentially fatal pulmonary infections. We previously reported that hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus. Also, global gene expression profiling of primary human bronchial epithelial (HBE) cells showed that elevated CO2 upregulates expression of cholesterol biosynthesis genes, including HMGCS1, and downregulates ATP-binding cassette (ABC) transporters that promote cholesterol efflux. Given that cellular cholesterol is important for entry of viruses into cells, in the current study we assessed the impact of hypercapnia on regulation of cellular cholesterol levels, and resultant effects on expression of ACE2 and entry of Pseudo-SARS-CoV-2 in cultured HBE, BEAS-2B and VERO cells, and airway epithelium of mice. Methods: Differentiated HBE, BEAS-2B or VERO cells were pre-incubated in normocapnia (5% CO2, PCO2 36 mmHg) or hypercapnia (15% CO2, PCO2 108 mmHg), both with normoxia, for 4 days. Expression of ACE2 and sterol regulatory element binding protein 2 (SREPB2), the master regulator of cholesterol synthesis, was assessed by immunoblot or immunofluorescence. Cholesterol was measured in cell lysates by Amplex red assay. Cells cultured in normocapnia or hypercapnia were also infected with Pseudo SARS-CoV-2, a Neon Green reporter baculovirus. For in vivo studies, C57BL/6 mice were exposed to normoxic hypercapnia (10% CO2/21% O2) for 7 days, or air as control, and airway epithelial expression of ACE2, SREBP2, ABCA1, ABCG1 and HMGCS1 was assessed by immunofluorescence. SREBP2 was blocked using the small molecules betulin or AM580, and cellular cholesterol was disrupted using MβCD. Results: Hypercapnia increased expression and activation of SREBP2 and decreased expression of ABC transporters, thereby augmenting epithelial cholesterol levels. Elevated CO2 also augmented ACE2 expression and Pseudo-SARSCoV- 2 entry into epithelial cells in vitro and in vivo. These effects were all reversed by blocking SREBP2 or disrupting cellular cholesterol. Conclusion: Hypercapnia augments cellular cholesterol levels by altering expression of cholesterol biosynthetic enzymes and efflux transporters, leading to increased epithelial expression of ACE2 and entry of Pseudo-SARS-CoV-2 into cells. These findings suggest that ventilatory support to limit hypercapnia or pharmacologic interventions to decrease cellular cholesterol might reduce viral burden and improve clinical outcomes of SARSCoV- 2 infection in advanced COPD and other severe lung diseases.

Clinical Characteristics and Outcomes of Patients With COVID-19-Associated Acute Respiratory Distress Syndrome Who Underwent Lung Transplant.

Importance: Lung transplantation is a potentially lifesaving treatment for patients who are critically ill due to COVID-19-associated acute respiratory distress syndrome (ARDS), but there is limited information about the long-term outcome. Objective: To report the clinical characteristics and outcomes of patients who had COVID-19-associated ARDS and underwent a lung transplant at a single US hospital. Design, Setting, and Participants: Retrospective case series of 102 consecutive patients who underwent a lung transplant at Northwestern University Medical Center in Chicago, Illinois, between January 21, 2020, and September 30, 2021, including 30 patients who had COVID-19-associated ARDS. The date of final follow-up was November 15, 2021. Exposures: Lung transplant. Main Outcomes and Measures: Demographic, clinical, laboratory, and treatment data were collected and analyzed. Outcomes of lung transplant, including postoperative complications, intensive care unit and hospital length of stay, and survival, were recorded. Results: Among the 102 lung transplant recipients, 30 patients (median age, 53 years [range, 27 to 62]; 13 women [43%]) had COVID-19-associated ARDS and 72 patients (median age, 62 years [range, 22 to 74]; 32 women [44%]) had chronic end-stage lung disease without COVID-19. For lung transplant recipients with COVID-19 compared with those without COVID-19, the median lung allocation scores were 85.8 vs 46.7, the median time on the lung transplant waitlist was 11.5 vs 15 days, and preoperative venovenous extracorporeal membrane oxygenation (ECMO) was used in 56.7% vs 1.4%, respectively. During transplant, patients who had COVID-19-associated ARDS received transfusion of a median of 6.5 units of packed red blood cells vs 0 in those without COVID-19, 96.7% vs 62.5% underwent intraoperative venoarterial ECMO, and the median operative time was 8.5 vs 7.4 hours, respectively. Postoperatively, the rates of primary graft dysfunction (grades 1 to 3) within 72 hours were 70% in the COVID-19 cohort vs 20.8% in those without COVID-19, the median time receiving invasive mechanical ventilation was 6.5 vs 2.0 days, the median duration of intensive care unit stay was 18 vs 9 days, the median post-lung transplant hospitalization duration was 28.5 vs 16 days, and 13.3% vs 5.5% required permanent hemodialysis, respectively. None of the lung transplant recipients who had COVID-19-associated ARDS demonstrated antibody-mediated rejection compared with 12.5% in those without COVID-19. At follow-up, all 30 lung transplant recipients who had COVID-19-associated ARDS were alive (median follow-up, 351 days [IQR, 176-555] after transplant) vs 60 patients (83%) who were alive in the non-COVID-19 cohort (median follow-up, 488 days [IQR, 368-570] after lung transplant). Conclusions and Relevance: In this single-center case series of 102 consecutive patients who underwent a lung transplant between January 21, 2020, and September 30, 2021, survival was 100% in the 30 patients who had COVID-19-associated ARDS as of November 15, 2021.

Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries.

BACKGROUND: Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications. METHODS: We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres-including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes-were collected by Northwestern University (Chicago, IL, USA) and analysed. FINDINGS: Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41-51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19. INTERPRETATION: The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients. FUNDING: National Institutes of Health. VIDEO ABSTRACT.

Outcomes after extracorporeal membrane oxygenation support in COVID-19 and non-COVID-19 patients.

BACKGROUND: Veno-venous extracorporeal membrane oxygenation (V-V ECMO) support is increasingly used in the management of COVID-19-related acute respiratory distress syndrome (ARDS). However, the clinical decision-making to initiate V-V ECMO for severe COVID-19 still remains unclear. In order to determine the optimal timing and patient selection, we investigated the outcomes of both COVID-19 and non-COVID-19 patients undergoing V-V ECMO support. METHODS: Overall, 138 patients were included in this study. Patients were stratified into two cohorts: those with COVID-19 and non-COVID-19 ARDS. RESULTS: The survival in patients with COVID-19 was statistically similar to non-COVID-19 patients (p = .16). However, the COVID-19 group demonstrated higher rates of bleeding (p = .03) and thrombotic complications (p < .001). The duration of V-V ECMO support was longer in COVID-19 patients compared to non-COVID-19 patients (29.0 ± 27.5 vs 15.9 ± 19.6 days, p < .01). Most notably, in contrast to the non-COVID-19 group, we found that COVID-19 patients who had been on a ventilator for longer than 7 days prior to ECMO had 100% mortality without a lung transplant. CONCLUSIONS: These findings suggest that COVID-19-associated ARDS was not associated with a higher post-ECMO mortality than non-COVID-19-associated ARDS patients, despite longer duration of extracorporeal support. Early initiation of V-V ECMO is important for improved ECMO outcomes in COVID-19 ARDS patients. Since late initiation of ECMO was associated with extremely high mortality related to lack of pulmonary recovery, it should be used judiciously or as a bridge to lung transplantation.

Bacterial Superinfection Pneumonia in Patients Mechanically Ventilated for COVID-19 Pneumonia.

Rationale: Current guidelines recommend patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia receive empirical antibiotics for suspected bacterial superinfection on the basis of weak evidence. Rates of ventilator-associated pneumonia (VAP) in clinical trials of patients with SARS-CoV-2 pneumonia are unexpectedly low. Objectives: We conducted an observational single-center study to determine the prevalence and etiology of bacterial superinfection at the time of initial intubation and the incidence and etiology of subsequent bacterial VAP in patients with severe SARS-CoV-2 pneumonia. Methods: Bronchoscopic BAL fluid samples from all patients with SARS-CoV-2 pneumonia requiring mechanical ventilation were analyzed using quantitative cultures and a multiplex PCR panel. Actual antibiotic use was compared with guideline-recommended therapy. Measurements and Main Results: We analyzed 386 BAL samples from 179 patients with SARS-CoV-2 pneumonia requiring mechanical ventilation. Bacterial superinfection within 48 hours of intubation was detected in 21% of patients. Seventy-two patients (44.4%) developed at least one VAP episode (VAP incidence rate = 45.2/1,000 ventilator days); 15 (20.8%) initial VAPs were caused by difficult-to-treat pathogens. The clinical criteria did not distinguish between patients with or without bacterial superinfection. BAL-based management was associated with significantly reduced antibiotic use compared with guideline recommendations. Conclusions: In patients with SARS-CoV-2 pneumonia requiring mechanical ventilation, bacterial superinfection at the time of intubation occurs in <25% of patients. Guideline-based empirical antibiotic management at the time of intubation results in antibiotic overuse. Bacterial VAP developed in 44% of patients and could not be accurately identified in the absence of microbiologic analysis of BAL fluid.

Distinctive features of severe SARS-CoV-2 pneumonia.

The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.

Hypercapnia Increases ACE2 Protein Expression and Pseudo-SARS-CoV-2 Virus Entry in Airway Epithelial Cells

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) who develop 2019 coronavirus disease (COVID-19) are at increased risk of hospitalization, intensive care unit admission and death. COPD is associated with increased airway epithelial expression of angiotensin converting enzyme 2 (ACE2), the cell surface receptor to which the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds and which mediates entry of the virus into cells. Hypercapnia, the elevation of CO2 in blood and tissue, commonly develops in advanced COPD and is associated with frequent and potentially fatal pulmonary infections. We previously showed that normoxic hypercapnia alters expression of innate immune genes, including multiple viral response genes, in primary human bronchial epithelial (HBE) cells (Sci Reports 8:13508, 2018). Thus, in the current study, we explored the effect of hypercapnia on expression of ACE2 and uptake of a Pseudo-SARS-CoV-2 baculovirus by airway epithelial cells. Methods: HBE cells (Lonza) differentiated at air-liquid interface or immortalized BEAS-2B cells were pre-incubated in normocapnia (NC, 5% CO2, PCO2 36 mmHg) or normoxic hypercapnia (HC, 15% CO2, PCO2 108 mmHg) for 4 days. ACE2 protein expression was assessed by immunoblot or immunofluorescence (IF). In addition, BEAS-2B cells pre-exposed to NC or HC for 2 days were infected with Pseudo SARS-CoV-2 for an additional 2 days. Pseudo SARS-CoV-2 (Montana Molecular) is a reporter baculovirus whose surface is decorated with SARS-CoV-2 spike protein, and which induces expression of Neon Green protein in the nucleus of host cells 24 h after viral entry. For in vivo studies, C57BL/6 mice were pre-exposed to normoxic hypercapnia (10% CO2/21% O2) for 7 days, or air as control, and ACE2 expression in lung tissue was assessed by IF. Results: Compared to culture in NC, HC increased ACE2 protein expression by ∼4-fold in HBE cells and ∼2.5-fold in BEAS-2B cells. Likewise exposure of mice for 7 days to 10% CO2, as compared to air, markedly increased airway epithelial cell expression of ACE2 (Figure 1). Additionally, culture in HC, as compared to NC, increased Pseudo SARS-CoV-2 entry to BEAS-2B cells. Conclusion: Elevated CO2 increases airway epithelial cell expression of the SARS-CoV-2 receptor, ACE2, in vitro and in vivo. This may lead to a greater burden of SARS-CoV-2 infection in patients with hypercapnia, and in part account for worse clinical outcomes of COVID-19 pneumonia in advanced COPD and other severe lung diseases.

Computed tomography scan abnormalities in patients with post-acute COVID syndrome

Rationale: Patients recovering from COVID-19 infection can have persistent respiratory symptoms. These symptoms are part of a syndrome of prolonged recovery from of COVID-19 which has been termed 'Post-Acute Covid Syndrome (PACS).' Many patients with PACS have been found to have persistent radiographic changes. It is not known whether these radiographic changes represent developing fibrosis, a developing inflammatory process such as organizing pneumonia, or both. In this study we sought to characterize the radiographic changes seen in patients with persistent pulmonary symptoms. Methods: The medical records of patients who presented to the pulmonary clinic at the Comprehensive COVID Center were reviewed. Computed tomography (CT) scans were reviewed if obtained greater than 4 weeks after COVID diagnosis. If multiple CT scans were performed, the most recent scan was included. Radiographic abnormalities were categorized as inflammatory (ground-glass opacities or consolidation), fibrotic (traction bronchiectasis, reticulation, or honeycombing), both, or neither. Results: 33 patients were evaluated. During the acute phase of COVID infection 8 (24%) were admitted to the intensive care unit, 7 (21%) required mechanical ventilation, and 12 (36%) were admitted to the floor. 20 (61%) patients had CT that fit inclusion criteria. Of the 20 CT scans reviewed, 13 (65%) were abnormal. 10 (50%) scans demonstrated evidence of fibrosis, 11 (55%) scans demonstrated inflammatory changes, and 8 (40%) scans demonstrated both fibrosis and inflammatory changes. The average time from COVID diagnosis to recovery CT was 131 days. The average time from COVID diagnosis to scans with signs of fibrosis was 151 days, whereas the average time from COVID diagnosis to scans with inflammatory changes was 127 days. Conclusion: The etiology of persistent dyspnea in PACS is an area of active investigation, and radiographic patterns of injury may suggest underlying pathologic processes. Our study demonstrates abnormal radiographic findings, including evidence of both fibrotic and inflammatory parenchymal changes, in the majority of patients seen with PACS followed greater than 4 months after initial diagnosis. It is unknown if the ground glass opacities or consolidative changes are representative of post infectious organizing injury or fibrosis that is below the level of detection of CT resolution. Further prospective observational studies are warranted to determine if these changes are progressive, or if interventions such as steroids can expedite respiratory symptom recovery in the setting of a post-acute COVID clinic.

Comparing ecmo characteristics and outcomes among COVID-19 and non-COVID-19 patients at a tertiary academic medical center

Rationale: Coronavirus disease 2019 (COVID-19) can cause severe respiratory failure that worsens despite maximal medical management. When to initiate extracorporeal membrane oxygenation (ECMO) and how to manage these patients on ECMO is not clear. Here, we present our experience with venovenous ECMO to support patients with COVID-19 and compare it to historic patients supported with VV-ECMO for other causes of respiratory failure. Methods: Patients admitted to our tertiary academic medical center in 2019 and 2020 who received VV ECMO support were included in this retrospective chart review. We examined patients with and without COVID-19 infection. We placed COVID-19 patients on ECMO who failed supportive care with mechanical ventilation using a high PEEP low tidal volume strategy, prone positioning, and neuromuscular blockade. Data analysis were done in Excel and Prism. Non-parametric data were compared with unpaired, two-tailed Mann-Whitney tests. Results: ECMO was provided to 26 COVID-19 patients and 38 patients without COVID-19. Median (interquartile range) age of COVID-19 patients was 49.5 (40.5-56.25), compared with non-COVID-19 patients: 53.5 (30.5-60.25), p=0.28. COVID-19 patients had a significantly higher BMI: 32 (30.1-35.9) vs. 26.4 (23.6-29.4), p<0.001. There were 27% female COVID-19 patients compared with 37% female non-COVID patients (p=0.43). COVID-19 patients had similar PaO2:FiO2 ratios as non-COVID patients on day of cannulation: 74 (69-112) vs 78 (60-205), p=0.65. COVID-19 patients had longer ventilator duration pre-cannulation (not including time spent intubated at outside hospitals prior to transfer to our center)-1.9 (1.4-7.0) days vs 0.7 (-.2-1.0) days, p<0.001. COVID patients spent more days on ECMO compared with non-COVID patients: 20.7 (7.3-36.5) vs. 11.5 (3.8-26.8), p=0.14. Twelve (46%) of the COVID-19 ECMO patients died, compared with 9 (25%) of the non-COVID ECMO patients, p=0.10. Conclusions: In patients with severe SARS-CoV-2 pneumonia induced ARDS who fail maximal supportive therapy with mechanical ventilation, outcomes are similar or worse than patients historically receiving VV ECMO support for respiratory failure. These findings highlight the need to determine the optimal timing of ECMO initiation and management in patients with severe SARS-CoV-2 pneumonia.

The use of transthoracic echocardiography in patients with persistent respiratory symptoms post COVID-19 illness

Rationale: Acute Coronavirus-19 infection has implications beyond that of primary alveolar injury. Many case reports and autopsy series highlight pulmonary endothelial microvascular dysfunction, thrombosis, and venous thromboembolism as outcomes of acute coronavirus-19 illness. It is uncertain whether persistent symptoms of dyspnea after COVID-19 infection may signal an increased likelihood of fibrotic lung disease, pulmonary vascular dysfunction, or both. Here, we describe the incidence of post COVID-19 surveillance for right ventricular (RV) dysfunction in a cohort enriched for persistent symptoms after infection. Methods: We reviewed the records of patients referred to a Comprehensive COVID Center at a large urban academic medical center. Manual chart abstraction was used to collect demographic and clinical data during both acute and recovery phases of illness. Computed tomography scans (CT), transthoracic echocardiography, and laboratory data were obtained as part of clinical care. Strain images were captured as part of clinical practice, utilizing TomTec software. Patient were enrolled in a registry approved by the institutional review board. Results: Over the course of six weeks, 33 patients were referred to the pulmonary COVID recovery clinic for persistent shortness of breath or cough. Of the 33 patients evaluated, 20 (61%) were evaluated with diagnostic computed tomography scans and 13 (39%) with transthoracic echo imaging during their recovery phase marked by persistent symptoms. 3 of the 13 (23%) patients with transthoracic echos had evidence of RV dysfunction as determined by right ventricular free wall strain (> -20%) or tricuspid annular plane systolic excursion (<16mm). These three patients did not have concomitant echocardiographic evidence of LV dysfunction (depressed left ventricular ejection fraction or increased left ventricular global longitudinal strain). None of the patients with RV dysfunction had venous thromboembolic events during acute illness, and 2 of the 3 were managed in the intensive care unit (ICU) both of which have evidence of fibrosis on recovery CT scans. Conclusion Transthoracic echocardiography should be considered in post COVID recovery patients with persistent limitations of dyspnea. The noticeable frequency of abnormal right ventricular function, in the presence of normal left ventricular function, may suggest an increased signal of right ventricular dysfunction secondary to chronic pulmonary microvascular disease or complications of restrictive lung physiology after COVID viral pneumonia. These findings warrant further review in larger cohorts with particular attention to the post ICU population.