Local and systemic responses to SARS-CoV-2 infection in children and adults.

It is not fully understood why COVID-19 is typically milder in children1-3. Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.

Transcranial Doppler Ultrasound Evidence of Active Cerebral Embolization in COVID-19.

OBJECTIVE: To report six consecutive patients with confirmed coronavirus disease-2019 (COVID-19) who underwent Transcranial Doppler (TCD) ultrasonography evaluation for cerebral microemboli in the setting of suspected or confirmed acute ischemic stroke. METHODS: Patient data were obtained from medical records from Northwestern Memorial Hospital, Chicago, IL between May and June 2020. All patients with confirmed COVID-19 who underwent clinical TCD ultrasonography for microemboli detection were included. RESULTS: A total of eight TCD studies were performed in six patients with COVID-19 (4 men and 2 women, median age 65±5), four with confirmed ischemic stroke and two with refractory encephalopathy. Microemboli were detected in three male patients, two patients had suffered a confirmed ischemic stroke and one who developed prolonged encephalopathy. Microemboli of varying intensity were identified in multiple vascular territories in two patients, and microemboli persisted despite therapeutic anticoagulation in a third patient. Of the three patients without evidence of microemboli on TCD ultrasonography, two patients had suffered a confirmed ischemic stroke, while one remained with refractory encephalopathy. CONCLUSIONS: TCD ultrasonography for microemboli detection identified three patients with confirmed COVID-19 with evidence of cerebral arterial microemboli, including one who was therapeutically anticoagulated. TCD ultrasonography provides a non-invasive method for evaluating cerebral microemboli in patients with COVID-19 and may be useful in assessing response to treatment in cases with suspected or confirmed disorders of hypercoagulability. Further studies investigating the prevalence of cerebral microemboli and associated risk factors are needed to characterize their pathogenic mechanism and guide therapeutic interventions in hospitalized COVID-19 patients.

Impact of healthcare system strain on the implementation of ICU sedation practices and encephalopathy burden during the early COVID-19 pandemic.

The COVID-19 pandemic posed unprecedented challenges to healthcare systems worldwide, particularly in managing critically ill patients requiring mechanical ventilation early in the pandemic. Surging patient volumes strained hospital resources and complicated the implementation of standard-of-care intensive care unit (ICU) practices, including sedation management. The objective of this study was to evaluate the impact of an evidence-based ICU sedation bundle during the early COVID-19 pandemic. The bundle was designed by a multi-disciplinary collaborative to reinforce best clinical practices related to ICU sedation. The bundle was implemented prospectively with retrospective analysis of electronic medical record data. The setting was the ICUs of a single-center tertiary hospital. The patients were the ICU patients requiring mechanical ventilation for confirmed COVID-19 between March and June 2020. A learning health collaborative developed a sedation bundle encouraging goal-directed sedation and use of adjunctive strategies to avoid excessive sedative administration. Implementation strategies included structured in-service training, audit and feedback, and continuous improvement. Sedative utilization and clinical outcomes were compared between patients admitted before and after the sedation bundle implementation. Quasi-experimental interrupted time-series analyses of pre and post intervention sedative utilization, hospital length of stay, and number of days free of delirium, coma, or death in 21 days (as a quantitative measure of encephalopathy burden). The analysis used the time duration between start of the COVID-19 wave and ICU admission to identify a "breakpoint" indicating a change in observed trends. A total of 183 patients (age 59.0 ± 15.9 years) were included, with 83 (45%) admitted before the intervention began. Benzodiazepine utilization increased for patients admitted after the bundle implementation, while agents intended to reduce benzodiazepine use showed no greater utilization. No "breakpoint" was identified to suggest the bundle impacted any endpoint measure. However, increasing time between COVID-19 wave start and ICU admission was associated with fewer delirium, coma, and death-free days (ß = - 0.044 [95% CI - 0.085, - 0.003] days/wave day); more days of benzodiazepine infusion (ß = 0.056 [95% CI 0.025, 0.088] days/wave day); and a higher maximum benzodiazepine infusion rate (ß = 0.079 [95% CI 0.037, 0.120] mg/h/wave day). The evidence-based practice bundle did not significantly alter sedation utilization patterns during the first COVID-19 wave. Sedation practices deteriorated and encephalopathy burden increased over time, highlighting that strategies to reinforce clinical practices may be hindered under conditions of extreme healthcare system strain.

Advances in the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis.

Similarly to idiopathic pulmonary fibrosis (IPF), other interstitial lung diseases can develop progressive pulmonary fibrosis (PPF) characterized by declining lung function, a poor response to immunomodulatory therapies, and early mortality. The pathophysiology of disordered lung repair involves common downstream pathways that lead to pulmonary fibrosis in both IPF and PPF. The antifibrotic drugs, such as nintedanib, are indicated for the treatment of IPF and PPF, and new therapies are being evaluated in clinical trials. Clinical, radiographic, and molecular biomarkers are needed to identify patients with PPF and subgroups of patients likely to respond to specific therapies. This article reviews the evidence supporting the use of specific therapies in patients with IPF and PPF, discusses agents being considered in clinical trials, and considers potential biomarkers based on disease pathogenesis that might be used to provide a personalized approach to care.

Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study.

Ranolazine, a late inward sodium current and fatty acid oxidation inhibitor, may improve right ventricular (RV) function in pulmonary arterial hypertension (PAH); however, the safety and efficacy of ranolazine in humans with PAH is unknown. Therefore, we sought to (1) determine whether ranolazine is safe and well tolerated in PAH and (2) explore ranolazine's effect on symptoms, exercise capacity, RV structure and function, and hemodynamic characteristics. We therefore conducted a 3-month, prospective, open-label pilot study involving patients with symptomatic PAH (n = 11) and echocardiographic evidence of RV dysfunction. We evaluated the safety and tolerability of ranolazine and compared symptoms, exercise capacity, exercise bicycle echocardiographic parameters, and invasive hemodynamic parameters between baseline and 3 months of ranolazine therapy using paired t tests. Of the 11 patients enrolled, one discontinued ranolazine therapy due to a drug-drug interaction after 3 days of therapy. All 10 of the remaining patients continued therapy for 3 months, and 8 (80%) of 10 completed all study tests. After 3 months, ranolazine administration was safe and associated with improvement in functional class (P = 0.0013), reduction in RV size (P = 0.015), improved RV function (improvement in RV strain during exercise at 3 months; P = 0.037), and a trend toward improved exercise time and exercise watts on bicycle echocardiography (P = 0.06 and 0.01, respectively). Ranolazine was not associated with improvement in invasive hemodynamic parameters. In conclusion, in a pilot study involving PAH, ranolazine therapy was safe and well tolerated, and it resulted in improvement in symptoms and echocardiographic parameters of RV structure and function but did not alter invasive hemodynamic parameters. ClinicalTrials.gov Identifier: NCT01174173.

Early stage lung cancer detection in systemic sclerosis does not portend survival benefit: a cross sectional study.

BACKGROUND: Systemic Sclerosis (SSc) is a rare connective tissue disorder associated with an increased risk of malignancy including lung cancer. METHODS: A single center review of all cases of lung cancer in patients with SSc was conducted. Clinical, radiographic, and detailed pathologic data was collected. Risk factors were compared with our center's SSc Registry. Cancer characteristics were compared with the National Cancer Institute SEER Cancer Statistics (NCI SEER) data. RESULTS: 17 cases were identified; the majority were females (82%) with the lung cancers diagnosed after the onset of SSc (88%). Tobacco use was identified in 65% of cases. Serologic testing showed 50% of cases were Scl-70 positive. Twelve cases had radiographic evidence of SSc lung involvement, however only 6 had restrictive physiology on pulmonary function testing. Thirteen cases had pulmonary nodules preceding lung cancer. Thirteen of the cancers were adenocarcinoma. Ten underwent molecular mutational profiling: 2/8 had KRAS mutation and 1/10 had EGFR mutation. More of the non-small cell lung cancers were diagnosed at localized disease (56%) than in the NCI SEER database. However, 5 years survival among the stage I cases was 25% versus an expected survival of 54%. CONCLUSIONS: The high proportion of adenocarcinomas seen in our study is different from that reported in the literature. Lung cancers were diagnosed at an early stage, likely due to our center's practice of radiographic screening for SSc associated lung involvement, however this did not confer a survival advantage. A high proportion of patients who developed lung cancer had interstitial lung disease.

Right heart structural changes are independently associated with exercise capacity in non-severe COPD.

BACKGROUND: Pulmonary hypertension (PH) occurs frequently and results in functional limitation in advanced COPD. Data regarding the functional consequence of PH in less severe COPD are limited. Whether echocardiographic evidence of right sided heart pathology is associated with functional outcomes in patients with non-severe COPD is unknown. METHODS: We evaluated pulmonary function, six minute walk distance, and echocardiography in 74 consecutive patients with non-severe COPD. We performed multivariable linear regression to evaluate the association between right heart echocardiographic parameters and six minute walk distance adjusting for lung function, age, sex, race, and BMI. MAIN RESULTS: The mean six minute walk distance was 324±106 meters. All subjects had preserved left ventricular (LV) systolic function (LV ejection fraction 62.3%±6.1%). 54.1% had evidence of some degree of diastolic dysfunction. 17.6% of subjects had evidence of right ventricular enlargement and 36.5% had right atrial enlargement. In univariate analysis RV wall thickness (ß = -68.6; p = 0.002), log right atrial area (ß = -297.9; p = 0.004), LV mass index (ß = -1.3; p = 0.03), E/E' ratio (ß = -5.5; p = 0.02), and degree of diastolic dysfunction (ß = -42.8; p = 0.006) were associated with six minute walk distance. After adjustment for co-variables, the associations between right atrial area (log right atrial area ß = -349.8; p = 0.003) and right ventricular wall thickness (ß = -43.8; p = 0.04) with lower six minute walk distance remained significant independent of forced expiratory volume in one second (FEV1). LV mass index, E/E' ratio, and degree of diastolic dysfunction were not independent predictors of six minute walk distance. CONCLUSION: In patients with non-severe COPD right sided cardiac structural changes are associated with lower six minute walk distance independent of lung function. These findings may indicate that echocardiographic evidence of pulmonary hypertension is present in patients with non-severe COPD and has important functional consequences.