Ventilatory Support in Patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the novel coronavirus disease 2019 (COVID-19) pandemic, which spread throughout the world. Acute hypoxemic respiratory failure is the most dangerous complication of COVID-19 pneumonia. To date, no specific therapeutic drugs or vaccines have been proven efficacious. Ventilatory support is still a significant challenge for physicians facing COVID-19. The mechanisms underlying hypoxemia in those patients are not fully understood, but a new physiopathology model has been proposed. Oxygen therapy should be delivered to patients with mild to moderate hypoxemia. More severe patients could benefit from other treatments (high-flow nasal cannula, noninvasive ventilation or intubation, and invasive ventilation). Given the rapid evolution of COVID-19, there has been a paucity of the high-quality data that typically inform clinical practice guidelines from professional societies, and a worldwide consensus is still lacking. This chapter aims to illustrate the potentials of ventilatory support as therapeutic options for adult and pediatric patients affected by COVID-19 pneumonia.

Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series.

There are no definitive therapies for patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Therefore, new therapeutic strategies are needed to improve clinical outcomes, particularly in patients with severe disease. This case series explores the safety and effectiveness of intravenous allogeneic cardiosphere-derived cells (CDCs), formulated as CAP-1002, in critically ill patients with confirmed coronavirus disease 2019 (COVID-19). Adverse reactions to CAP-1002, clinical status on the World Health Organization (WHO) ordinal scale, and changes in pro-inflammatory biomarkers and leukocyte counts were analyzed. All patients (n = 6; age range 19-75 years, 1 female) required ventilatory support (invasive mechanical ventilation, n = 5) with PaO2/FiO2 ranging from 69 to 198. No adverse events related to CAP-1002 administration were observed. Four patients (67%) were weaned from respiratory support and discharged from the hospital. One patient remains mechanically ventilated as of April 28th, 2020; all survive. A contemporaneous control group of critically ill COVID-19 patients (n = 34) at our institution showed 18% overall mortality at a similar stage of hospitalization. Ferritin was elevated in all patients at baseline (range of all patients 605.43-2991.52 ng/ml) and decreased in 5/6 patients (range of all patients 252.89-1029.90 ng/ml). Absolute lymphocyte counts were low in 5/6 patients at baseline (range 0.26-0.82 × 103/µl) but had increased in three of these five patients at last follow-up (range 0.23-1.02 × 103/µl). In this series of six critically ill COVID-19 patients, intravenous infusion of CAP-1002 was well tolerated and associated with resolution of critical illness in 4 patients. This series demonstrates the apparent safety of CAP-1002 in COVID-19. While this initial experience is promising, efficacy will need to be further assessed in a randomized controlled trial.

Protein biomarkers of disease progression in patients with systemic sclerosis associated interstitial lung disease.

Systemic sclerosis is a rare connective tissue disease; and interstitial lung disease (SSc-ILD) is associated with significant morbidity and mortality. There are no clinical, radiologic features, nor biomarkers that identify the specific time when patients are at risk for progression at which the benefits from treatment outweigh the risks. Our study aimed to identify blood protein biomarkers associated with progression of interstitial lung disease in patients with SSc-ILD using an unbiased, high-throughput approach. We classified SSc-ILD as progressive or stable based on change in forced vital capacity over 12 months or less. We profiled serum proteins by quantitative mass spectrometry and analyzed the association between protein levels and progression of SSc-ILD via logistic regression. The proteins associated with at a p value of < 0.1 were queried in the ingenuity pathway analysis (IPA) software to identify interaction networks, signaling, and metabolic pathways. Through principal component analysis, the relationship between the top 10 principal components and progression was evaluated. Unsupervised hierarchical clustering with heatmapping was done to define unique groups. The cohort consisted of 72 patients, 32 with progressive SSc-ILD and 40 with stable disease with similar baseline characteristics. Of a total of 794 proteins, 29 were associated with disease progression. After adjusting for multiple testing, these associations did not remain significant. IPA identified five upstream regulators that targeted proteins associated with progression, as well as a canonical pathway with a higher signal in the progression group. Principal component analysis showed that the ten components with the highest Eigenvalues represented 41% of the variability of the sample. Unsupervised clustering analysis revealed no significant heterogeneity between the subjects. We identified 29 proteins associated with progressive SSc-ILD. While these associations did not remain significant after accounting for multiple testing, some of these proteins are part of pathways relevant to autoimmunity and fibrogenesis. Limitations included a small sample size and a proportion of immunosuppressant use in the cohort, which could have altered the expression of inflammatory and immunologic proteins. Future directions include a targeted evaluation of these proteins in another SSc-ILD cohort or application of this study design to a treatment naïve population.

Cell-Type-Specific Immune Dysregulation in Severely Ill COVID-19 Patients.

Recent studies have demonstrated immunologic dysfunction in severely ill coronavirus disease 2019 (COVID-19) patients. We use single-cell RNA sequencing (scRNA-seq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMCs) from healthy (n = 3) and COVID-19 patients with moderate disease (n = 5), acute respiratory distress syndrome (ARDS, n = 6), or recovering from ARDS (n = 6). Our data reveal transcriptomic profiles indicative of defective antigen presentation and interferon (IFN) responsiveness in monocytes from ARDS patients, which contrasts with higher responsiveness to IFN signaling in lymphocytes. Furthermore, genes involved in cytotoxic activity are suppressed in both natural killer (NK) and CD8 T lymphocytes, and B cell activation is deficient, which is consistent with delayed viral clearance in severely ill COVID-19 patients. Our study demonstrates that COVID-19 patients with ARDS have a state of immune imbalance in which dysregulation of both innate and adaptive immune responses may be contributing to a more severe disease course.

Differences in Clinical Characteristics and Outcomes Between Men and Women With Idiopathic Pulmonary Fibrosis: A Multicenter Retrospective Cohort Study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with a male predominance. Prior data suggest that male sex is associated with disease progression and survival. The basis for this sex difference is unknown. RESEARCH QUESTION: Are there differences in clinical disease characteristics and outcomes between men and women with IPF? STUDY DESIGN AND METHODS: Two tertiary care center IPF cohorts were pooled to analyze sex differences in outcomes of time to lung transplantation or death. Predictors of outcome that were analyzed included age, FVC % predicted, diffusion capacity for carbon monoxide (Dlco) % predicted, BMI, smoking history, and respiratory variables of cough, phlegm, and need for supplemental oxygen. The associations of these factors with mortality were estimated by sex and then compared using tests for interaction. RESULTS: There were a total of 1,263 patients in the pooled cohort with follow-up data; approximately 71% of the patients were men. Male sex was independently associated with higher risk for death or lung transplantation after adjusting for age, FVC % predicted, and Dlco % predicted (hazard ratio for men, 1.4; 95% CI, 1.2-1.7; P < .001). Older age, lower Dlco % predicted, and presence of cough or phlegm were negatively associated with transplant-free survival in men but not in women, but only the association for cough differed statistically by sex (interaction P = .007). INTERPRETATION: Male sex is associated with worse transplant-free survival in IPF. Cough may be a sex-specific predictor of survival in this population.

Cell type-specific immune dysregulation in severely ill COVID-19 patients.

Coronavirus disease 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury called acute respiratory distress syndrome (ARDS) that causes progressive respiratory failure requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients. To further delineate the dysregulated immune response driving more severe clinical course from SARS-CoV-2 infection, we used single-cell RNA sequencing (scRNAseq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) from hospitalized COVID-19 patients having mild disease (n = 5), developing ARDS (n = 6), and recovering from ARDS (n = 6). Our data demonstrated an overwhelming inflammatory response with select immunodeficiencies within various immune populations in ARDS patients. Specifically, their monocytes had defects in antigen presentation and deficiencies in interferon responsiveness that contrasted the higher interferon signals in lymphocytes. Furthermore, cytotoxic activity was suppressed in both NK and CD8 lymphocytes whereas B cell activation was deficient, which is consistent with the delayed viral clearance in severely ill COVID-19 patients. Finally, we identified altered signaling pathways in the severe group that suggests immunosenescence and immunometabolic changes could be contributing to the dysfunctional immune response. Our study demonstrates that COVID-19 patients with ARDS have an immunologically distinct response when compared to those with a more innocuous disease course and show a state of immune imbalance in which deficiencies in both the innate and adaptive immune response may be contributing to a more severe disease course in COVID-19.

Pre-existing traits associated with Covid-19 illness severity.

IMPORTANCE: Certain individuals, when infected by SARS-CoV-2, tend to develop the more severe forms of Covid-19 illness for reasons that remain unclear. OBJECTIVE: To determine the demographic and clinical characteristics associated with increased severity of Covid-19 infection. DESIGN: Retrospective observational study. We curated data from the electronic health record, and used multivariable logistic regression to examine the association of pre-existing traits with a Covid-19 illness severity defined by level of required care: need for hospital admission, need for intensive care, and need for intubation. SETTING: A large, multihospital healthcare system in Southern California. PARTICIPANTS: All patients with confirmed Covid-19 infection (N = 442). RESULTS: Of all patients studied, 48% required hospitalization, 17% required intensive care, and 12% required intubation. In multivariable-adjusted analyses, patients requiring a higher levels of care were more likely to be older (OR 1.5 per 10 years, P<0.001), male (OR 2.0, P = 0.001), African American (OR 2.1, P = 0.011), obese (OR 2.0, P = 0.021), with diabetes mellitus (OR 1.8, P = 0.037), and with a higher comorbidity index (OR 1.8 per SD, P<0.001). Several clinical associations were more pronounced in younger compared to older patients (Pinteraction<0.05). Of all hospitalized patients, males required higher levels of care (OR 2.5, P = 0.003) irrespective of age, race, or morbidity profile. CONCLUSIONS AND RELEVANCE: In our healthcare system, greater Covid-19 illness severity is seen in patients who are older, male, African American, obese, with diabetes, and with greater overall comorbidity burden. Certain comorbidities paradoxically augment risk to a greater extent in younger patients. In hospitalized patients, male sex is the main determinant of needing more intensive care. Further investigation is needed to understand the mechanisms underlying these findings.

Risk factors for the development of idiopathic pulmonary fibrosis: A review.

PURPOSE OF REVIEW: Idiopathic pulmonary fibrosis (IPF) is an invariably progressive disease. Current treatment options simply slow disease progression and better therapeutic options are needed. We aimed to review emerging literature on risk factors associated with the development of IPF. RECENT FINDINGS: There is increasing data to support the role of intrinsic risk factors (e.g. genetics, aging, sex, lung microbiome), co-morbidities (e.g. gastroesophageal reflux, obstructive sleep apnea, diabetes mellitus, herpes virus infection), and extrinsic risk factors (e.g. cigarette smoking, environmental exposures, air pollution) in IPF development. These risk factors may independently increase susceptibility for IPF or act in a synergistic fashion to contribute to increased risk for disease development. SUMMARY: Various risk factors have been identified in IPF development that fit within the current paradigm of disease pathogenesis. Further investigation in to these risk factors may help us better understand the pathophysiology of IPF and may guide future therapeutic interventions.