Cardiac Fibrosis Is a Risk Factor for Severe COVID-19.

Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor ß1 (TGF-ß1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-ß1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-ß1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-ß1 mRNA performed at the time of first medical contact.

Complications after discharge with COVID-19 infection and risk factors associated with development of post-COVID pulmonary fibrosis.

INTRODUCTION: Survivors of COVID-19 infection may develop post-covid pulmonary fibrosis (PCF) and suffer from long term multi-system complications. The magnitude and risk factors associated with these are unknown. OBJECTIVES: We investigated the prevalence and risk factors associated with PCF and other complications in patients discharged after COVID-19 infection. METHODS: Patients had phone assessment 6 weeks post hospital discharge after COVID-19 infection using a set protocol. Those with significant respiratory symptoms were investigated with a CTPA, Pulmonary Function Tests and echocardiogram. Prevalence of myalgia, fatigue, psychological symptoms and PCF was obtained. Risk factors associated with these were investigated. RESULTS: A large number of patients had persistent fatigue (45.1%), breathlessness (36.5%), myalgia (20.5%) and psychological symptoms (19.5%). PCF was seen in 9.5% of the patients and was associated with persistent breathlessness at 6 weeks and inpatient ventilation [adjusted OR 5.02(1.76-14.27) and 4.45(1.27-15.58)] respectively. It was more common in men and in patients with peak CRP >171.5 mg/L, peak WBC count ≥12 × 10 9/L, severe inpatient COVID-19 CXR changes and CT changes. Ventilation was also a risk factor for persisting fatigue and myalgia, the latter was also more common in those with severe cytokine storm and severe COVID-19 inpatient CXR changes. CONCLUSIONS: All the patients discharged after COVID-19 should be assessed using a set protocol by a multidisciplinary team. Patients who had severe COVID-19 infection particularly those who were intubated and who have persistent breathlessness are at risk of developing PCF. They should have a CT Chest and have respiratory follow-up.

Pulmonary fibrosis and its related factors in discharged patients with new corona virus pneumonia: a cohort study.

BACKGROUND: Thousands of Coronavirus Disease 2019 (COVID-19) patients have been discharged from hospitals Persistent follow-up studies are required to evaluate the prevalence of post-COVID-19 fibrosis. METHODS: This study involves 462 laboratory-confirmed patients with COVID-19 who were admitted to Shenzhen Third People's Hospital from January 11, 2020 to April 26, 2020. A total of 457 patients underwent thin-section chest CT scans during the hospitalization or after discharge to identify the pulmonary lesion. A total of 287 patients were followed up from 90 to 150 days after the onset of the disease, and lung function tests were conducted about three months after the onset. The risk factors affecting the persistence of pulmonary fibrosis were identified through regression analysis and the prediction model of the persistence of pulmonary fibrosis was established. RESULTS: Parenchymal bands, irregular interfaces, reticulation and traction bronchiectasis were the most common CT features in all COVID-19 patients. During the 0-30, 31-60, 61-90, 91-120 and > 120 days after onset, 86.87%, 74.40%, 79.56%, 68.12% and 62.03% patients developed with pulmonary fibrosis and 4.53%, 19.61%, 18.02%, 38.30% and 48.98% patients reversed pulmonary fibrosis, respectively. It was observed that Age, BMI, Fever, and Highest PCT were predictive factors for sustaining fibrosis even after 90 days from onset. A predictive model of the persistence with pulmonary fibrosis was developed based-on the Logistic Regression method with an accuracy, PPV, NPV, Sensitivity and Specificity of the model of 76%, 71%, 79%, 67%, and 82%, respectively. More than half of the COVID-19 patients revealed abnormal conditions in lung function after 90 days from onset, and the ratio of abnormal lung function did not differ on a statistically significant level between the fibrotic and non-fibrotic groups. CONCLUSIONS: Persistent pulmonary fibrosis was more likely to develop in patients with older age, higher BMI, severe/critical condition, fever, a longer viral clearance time, pre-existing disease and delayed hospitalization. Fibrosis developed in COVID-19 patients could be reversed in about a third of the patients after 120 days from onset. The pulmonary function of less than half of COVID-19 patients could turn to normal condition after three months from onset. An effective prediction model with an average area under the curve (AUC) of 0.84 was established to predict the persistence of pulmonary fibrosis in COVID-19 patients for early diagnosis.

Type 1 inflammatory endotype relates to low compliance, lung fibrosis, and severe complications in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an acute respiratory disease; approximately 5% of patients developing severe COVID-19. It is known that cytokine release is associated with disease severity, but the relationship between the different clinical phenotypes and inflammatory endotypes is not well understood. OBJECTIVE: This study investigated the association between inflammatory biomarker-based endotypes and severe COVID-19 phenotypes. METHODS: Interleukin (IL) -6, C-reactive protein (CRP), C-X-C motif chemokine (CXCL) 9, IL-18, C-C motif chemokine (CCL) 3, CCL17, IL-10, and vascular endothelial growth factor (VEGF) were measured in 57 COVID-19 patients, and their association with clinical characteristics was examined using a cluster analysis. RESULTS: Significantly higher blood levels of the eight inflammatory markers were noted in patients who developed acute respiratory distress syndrome (ARDS) than in those who did not develop ARDS (non-ARDS). Using a cluster analysis, the patient groups were classified into four clusters, of which two had patients with high IL-6 and CRP levels. In the cluster with high levels of Type 1 (T1) inflammatory markers such as CXCL9 and IL-18, 85% of the patients had ARDS, 65% of the patients developed acute kidney injury (AKI), and 78% of the patients developed pulmonary fibrosis. CONCLUSIONS: In the cluster with high levels of T1 inflammatory markers, the patients frequently suffered from tissue damage, manifested as ARDS and AKI. Our findings identified distinct T1 inflammatory endotypes of COVID-19 and suggest the importance of controlling inflammation by monitoring T1 biomarkers and treating accordingly to limit the severity of the disease.

Lung transplantation for patients with severe COVID-19.

Lung transplantation can potentially be a life-saving treatment for patients with nonresolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with nonresolving COVID-19-associated respiratory failure. We performed single-molecule fluorescence in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single-cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm postmortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single-cell RNA sequencing data from the lungs of patients with late-stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.

Short-Term Consequences of SARS-CoV-2-Related Pneumonia: A Follow Up Study.

The aim of the study was to assess the short-term consequences of SARS-CoV-2-related pneumonia, also in relation to radiologic/laboratory/clinical indices of risk at baseline. This prospective follow-up cohort study included 94 patients with confirmed COVID-19 admitted to a medical ward at the Montichiari Hospital, Brescia, Italy from February 28th to April 30th, 2020. Patients had COVID-19 related pneumonia with respiratory failure. Ninety-four patients out of 193 survivors accepted to be re-evaluated after discharge, on average after 4 months. In » of the patients an evidence of pulmonary fibrosis was detected, as indicated by an altered diffusing capacity of the lung for carbon monoxide (DLCO); in 6-7% of patients the alteration was classified as of moderate/severe degree. We also evaluated quality of life thorough a structured questionnaire: 52% of the patients still lamented fatigue, 36% effort dyspnea, 10% anorexia, 14% dysgeusia or anosmia, 31% insomnia and 21% anxiety. Finally, we evaluated three prognostic indices (the Brixia radiologic score, the Charlson Comorbidity Index and the 4C mortality score) in terms of prediction of the clinical consequences of the disease. All of them significantly predicted the extent of short-term lung involvement. In conclusion, our study demonstrated that SARS-CoV-2-related pneumonia is associated to relevant short-term clinical consequences, both in terms of persistence of symptoms and in terms of impairment of DLCO (indicator of a possible development of pulmonary fibrosis); some severity indices of the disease may predict short-term clinical outcome. Further studies are needed to ascertain whether such manifestations may persist long-term.

Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19.

A compelling body of evidence points to pulmonary thrombosis and thromboembolism as a key feature of COVID-19. As the pandemic spread across the globe over the past few months, a timely call to arms was issued by a team of clinicians to consider the prospect of long-lasting pulmonary fibrotic damage and plan for structured follow-up. However, the component of post-thrombotic sequelae has been less widely considered. Although the long-term outcomes of COVID-19 are not known, should pulmonary vascular sequelae prove to be clinically significant, these have the potential to become a public health problem. In this Personal View, we propose a proactive follow-up strategy to evaluate residual clot burden, small vessel injury, and potential haemodynamic sequelae. A nuanced and physiological approach to follow-up imaging that looks beyond the clot, at the state of perfusion of lung tissue, is proposed as a key triage tool, with the potential to inform therapeutic strategies.

"A Chain Only as Strong as Its Weakest Link": An Up-to-Date Literature Review on the Bidirectional Interaction of Pulmonary Fibrosis and COVID-19.

The COVID-19 pandemic rapidly became a worldwide healthcare emergency affecting millions of people, with poor outcomes for patients with chronic conditions and enormous pressure on healthcare systems. Pulmonary fibrosis (PF) has been cited as a risk factor for a more severe evolution of COVID-19, primarily because its acute exacerbations are already associated with high mortality. We reviewed the available literature on biochemical, pathophysiological, and pharmacological mechanisms of PF and COVID-19 in an attempt to foresee the particular risk of infection and possible evolution of PF patients if infected with SARS-COV-2. We also analyzed the possible role of medication and risk factors (such as smoking) in the disease's evolution and clinical course. We found out that there is a complexity of interactions between coexisting idiopathic pulmonary fibrosis/interstitial lung disease (ILD) and COVID-19 disease. Also, patients recovering from severe COVID-19 disease are at serious risk of developing PF. Smokers seem to have, in theory, a chance for a better outcome if they develop a severe form of COVID-19 but statistically are at much higher risk of dying if they become critically ill.