Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injury.

COVID-19 has been a significant public health concern for the last four years; however, little is known about the mechanisms that lead to severe COVID-associated kidney injury. In this multicenter study, we combined quantitative deep urinary proteomics and machine learning to predict severe acute outcomes in hospitalized COVID-19 patients. Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrated predictive power for both discovery and validation set with 87% and 79% accuracy, respectively. These predictive urinary biomarkers were recapitulated in non-COVID acute kidney injury revealing overlapping injury mechanisms. We further combined orthogonal multiomics datasets to understand the mechanisms that drive severe COVID-associated kidney injury. Functional overlap and network analysis of urinary proteomics, plasma proteomics and urine sediment single-cell RNA sequencing showed that extracellular matrix and autophagy-associated pathways were uniquely impacted in severe COVID-19. Differentially abundant proteins associated with these pathways exhibited high expression in cells in the juxtamedullary nephron, endothelial cells, and podocytes, indicating that these kidney cell types could be potential targets. Further, single-cell transcriptomic analysis of kidney organoids infected with SARS-CoV-2 revealed dysregulation of extracellular matrix organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters showed significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. Collectively, these data suggest that extracellular matrix degradation and adhesion-associated mechanisms could be a main driver of COVID-associated kidney injury and severe outcomes.

Greater executive dysfunction in patients post-COVID-19 compared to those not infected.

BACKGROUND: A number of patients post-coronavirus disease-19 (COVID-19) report cognitive impairment (CI), even months after acute infection. We aimed to assess if COVID-19 is associated with increased incidence of CI in comparison to controls. METHODS: We analyzed data from the Mount Sinai Health System Post-COVID-19 Registry in New York City, a prospective cohort of patients post-COVID-19 ≥18 years of age and non-infected controls. CI was defined by scores ≥ 1.0 standard deviation below population norms, and was assessed using well-validated measures of attention, working memory, processing speed, executive functioning/cognitive flexibility, language, learning, and memory. Logistic regression models assessed odds for CI in each domain in patients post-COVID-19 vs. controls after adjusting for potential confounders. In exploratory analyses, we assessed odds for CI by site of acute COVID-19 care as a proxy for disease severity. FINDINGS: 417 patients post-COVID-19 and 151 controls (mean age 49 years, 63% female, 21% Black, 17% Latinx) were included. In adjusted analyses, patients were significantly more likely than controls to have CI in executive functioning (odds ratio [OR]: 2.19; 95% confidence interval [CI]: 1.03 to 4.67), particularly those treated in outpatient (OR: 2.22; 95% CI: 1.02 to 4.82) and inpatient hospital (OR: 3.59; 95% CI: 1.27 to 10.16) settings. There were no significant associations between CI in other domains and history of COVID-19 or site of acute care. INTERPRETATION: Patients post-COVID-19 have greater odds of executive dysfunction, suggesting that focused cognitive screening may be prudent, even in those with mild to moderate disease. Studies should explore the pathophysiology and potential treatments for CI in this population. FUNDING: This work was funded by the Icahn School of Medicine at Mount Sinai.

PAP Adherence and Nasal Resistance. A Randomized Controlled Trial of CPAPflex versus CPAP in World Trade Center Responders.

Rationale: Continuous positive airway pressure (CPAP) adherence is often poor in obstructive sleep apnea (OSA) and may be influenced by nasal resistance. CPAP with a reduction of expiratory pressure (CPAPflex) may reduce discomfort in those with high nasal resistance and improve adherence in this subgroup.Objectives: To evaluate the association of positive airway pressure (PAP) treatment adherence to nasal resistance and examine if CPAPflex improves adherence over CPAP in subjects with high nasal resistance.Methods: A randomized double-blind crossover trial of 4 weeks each of CPAPflex versus CPAP in subjects exposed to World Trade Center dust with OSA stratified by nasal resistance, measured by 4-Phase Rhinomanometry.Results: Three hundred seventeen subjects with OSA (mean, apnea-hypopnea index with 4% O2 desaturation for hypopnea = 17 ± 14/h) were randomized. Overall, PAP adherence was poor, but adherence to CPAP (n = 239; mean hours per night [95% confidence interval (CI)]), 1.97 h (1.68 to 2.26) was greater than adherence to CPAPflex (n = 249; 1.65 h [1.39 to 1.91]; difference of 0.31 h [0.03; 0.6]; P < 0.05). Contrary to our hypothesis there was no correlation between nasal resistance and adherence to CPAP (r = 0.098; P = not significant) or CPAPflex (r = 0.056; P = not significant). There was no difference in adherence between CPAP and CPAPflex (mean Δ hours [95% CI]) in subjects with low resistance (0.33 h [-0.10 to 0.76]) or high nasal resistance (0.26 h [-0.14 to 0.66]). No significant differences were observed in any of the secondary outcomes between PAP modes.Conclusions: Contrary to expectations, our data do not show better adherence to CPAPflex than to CPAP in subjects with high or low nasal resistance and do show clinically insignificant better adherence overall with CPAP.Clinical trial registered with www.clinicaltrials.gov (NCT01753999).

The Association between Health Conditions in World Trade Center Responders and Sleep-Related Quality of Life and Sleep Complaints.

Background: World Trade Center (WTC) dust-exposed subjects have multiple comorbidities that affect sleep. These include obstructive sleep apnea (OSA), chronic rhinosinusitis (CRS), gastroesophageal-reflux disorder (GERD) and post-traumatic stress disorder (PTSD). We examined the impact of these conditions to sleep-related outcomes. Methods: Demographics, co-morbidities and symptoms were obtained from 626 WTC (109F/517M), 33⁻87years, BMI = 29.96 ± 5.53 kg/m²) subjects. OSA diagnosis was from a 2-night home sleep test (ARESTM). Subjective sleep quality, sleep-related quality of life (QOL, Functional Outcomes of Sleep Questionnaire), excessive daytime sleepiness (Epworth Sleepiness Scale), sleep duration and sleep onset and maintenance complaints were assessed. Results: Poor sleep quality and complaints were reported by 19⁻70% of subjects and average sleep duration was 6.4 h. 74.8% of subjects had OSA. OSA diagnosis/severity was not associated with any sleep-related outcomes. Sleep duration was lower in subjects with all conditions (p < 0.05) except OSA. CRS was a significant risk factor for poor sleep-related QOL, sleepiness, sleep quality and insomnia; PTSD for poor sleep-related QOL and insomnia; GERD for poor sleep quality. These associations remained significant after adjustment for, age, BMI, gender, sleep duration and other comorbidities. Conclusions: Sleep complaints are common and related to several health conditions seen in WTC responders. Initial interventions in symptomatic patients with both OSA and comorbid conditions may need to be directed at sleep duration, insomnia or the comorbid condition itself, in combination with intervention for OSA.

Chronic Rhinosinusitis Is an Independent Risk Factor for OSA in World Trade Center Responders.

BACKGROUND: Many respiratory conditions have been attributed to toxic dust and fume exposure in World Trade Center (WTC) rescue and recovery workers, who frequently report symptoms of OSA. We examined the prevalence of new-onset OSA and tested if the prevalence and severity of OSA are related to the presence of chronic rhinosinusitis (CRS). METHODS: A total of 601 subjects (83% men; age, 33-87 years; BMI, 29.9 ± 5.5 kg/m2) enrolled in the WTC Health Program, excluding those with significant pre-September 11, 2001, snoring or prior CRS, underwent two nights of home sleep testing. OSA was defined as Apnea Hypopnea Index 4% ≥ 5 events/h or respiratory disturbance index of ≥ 15 events/h. CRS was assessed using nasal symptom questionnaires. RESULTS: The prevalence of OSA was 75% (25% no OSA, 46% mild OSA, 19% moderate OSA, and 10% severe OSA), and the prevalence of CRS was 43.5%. Compared with no CRS, new and worsening CRS was a significant risk factor for OSA with an OR of 1.80 (95% CI, 1.18-2.73; P = .006) unadjusted and 1.76 (95% CI, 1.08-2.88; P = .02) after adjustment for age, BMI, sex, gastroesophageal reflux disorder, and alcohol use. CONCLUSIONS: The high prevalence of OSA in WTC responders was not explained fully by obesity and sex. Possible mechanisms for the elevated risk of OSA in subjects with CRS include increased upper airway inflammation and/or elevated nasal/upper airway resistance, but these need confirmation.

Severe Obstructive Sleep Apnea Is Associated with Alterations in the Nasal Microbiome and an Increase in Inflammation.

RATIONALE: Obstructive sleep apnea (OSA) is associated with recurrent obstruction, subepithelial edema, and airway inflammation. The resultant inflammation may influence or be influenced by the nasal microbiome. OBJECTIVES: To evaluate whether the composition of the nasal microbiota is associated with obstructive sleep apnea and inflammatory biomarkers. METHODS: Two large cohorts were used: 1) a discovery cohort of 472 subjects from the WTCSNORE (Seated, Supine and Post-Decongestion Nasal Resistance in World Trade Center Rescue and Recovery Workers) cohort, and 2) a validation cohort of 93 subjects rom the Zaragoza Sleep cohort. Sleep apnea was diagnosed using home sleep tests. Nasal lavages were obtained from cohort subjects to measure: 1) microbiome composition (based on 16S rRNA gene sequencing), and 2) biomarkers for inflammation (inflammatory cells, IL-8, and IL-6). Longitudinal 3-month samples were obtained in the validation cohort, including after continuous positive airway pressure treatment when indicated. MEASUREMENTS AND MAIN RESULTS: In both cohorts, we identified that: 1) severity of OSA correlated with differences in microbiome diversity and composition; 2) the nasal microbiome of subjects with severe OSA were enriched with Streptococcus, Prevotella, and Veillonella; and 3) the nasal microbiome differences were associated with inflammatory biomarkers. Network analysis identified clusters of cooccurring microbes that defined communities. Several common oral commensals (e.g., Streptococcus, Rothia, Veillonella, and Fusobacterium) correlated with apnea-hypopnea index. Three months of treatment with continuous positive airway pressure did not change the composition of the nasal microbiota. CONCLUSIONS: We demonstrate that the presence of an altered microbiome in severe OSA is associated with inflammatory markers. Further experimental approaches to explore causal links are needed.

Comparison of two home sleep testing devices with different strategies for diagnosis of OSA.

PURPOSE: Home sleep testing devices are being widely used in diagnosis/screening for obstructive sleep apnea (OSA). We examined differences in OSA metrics obtained from two devices with divergent home monitoring strategies, the Apnea Risk Evaluation System (ARES™, multiple signals plus forehead reflectance oximetry) and the Nonin WristOx2™ (single channel finger transmission pulse oximeter), compared to differences from night-night variability of OSA. METHODS: One hundred fifty-two male/26 female subjects (BMI = 30.3 ± 5.6 kg/m2, age = 52.5 ± 8.9 years) were recruited without regard to OSA symptoms and simultaneously wore both ARES™ and Nonin WristOx2™ for two nights (n = 351 nights). Automated analysis of the WristOx2 yielded oxygen desaturation index (ODIOx2, ≥4% O2 dips/h), and automated analysis with manual editing of ARES™ yielded AHI4ARES (apneas + hypopneas with ≥4% O2 dips/h) and RDIARES (apneas + hypopneas with ≥4% O2 dips/h or arousal surrogates). Baseline awake oxygen saturation, percent time < 90% O2 saturation (%time < 90%O2Sat), and O2 signal loss were compared between the two methods. RESULTS: Correlation between AHI4ARES and ODIOx2 was high (ICC = 0.9, 95% CI = 0.87-0.92, p < 0.001, bias ± SD = 0.7 ± 6.1 events/h). Agreement values for OSA diagnosis (77-85%) between devices were similar to those seen from night-to-night variability of OSA using a single device. Awake baseline O2 saturation was significantly higher in the ARES™ (96.2 ± 1.6%) than WristOx2™ (92.2 ± 2.1%, p < 0.01). There was a significantly lower %time < 90%O2Sat reported by the ARES™ compared to WristOx2 (median (IQR) 0.5 (0.0, 2.6) vs. 2.1 (0.3, 9.7), p < 0.001), and the correlation was low (ICC = 0.2). CONCLUSIONS: OSA severity metrics predominantly dependent on change in oxygen saturation and metrics used in diagnosis of OSA (AHI4 and ODI) correlated well across devices tested. However, differences in cumulative oxygen desaturation measures (i.e., %time < 90%O2Sat) between the devices suggest that caution is needed when interpreting this metric particularly in populations likely to have significant hypoxia.

Orexin-A is Associated with Increases in Cerebrospinal Fluid Phosphorylated-Tau in Cognitively Normal Elderly Subjects.

STUDY OBJECTIVES: To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. METHODS: Subjects were recruited from multiple community sources for National Institutes of Health supported studies on normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. RESULTS: Levels of orexin-A, amyloid beta 42 (Aß42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 ± 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Aß42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P-Tau and were not influenced by other clinical or sleep characteristics that were available. CONCLUSIONS: Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT01962779.

A comparison of CPAP and CPAPFLEX in the treatment of obstructive sleep apnea in World Trade Center responders: study protocol for a randomized controlled trial.

BACKGROUND: Following the World Trade Center disaster, a large number of individuals involved in rescue and recovery activity were exposed to significant amounts of dust, and reported symptoms of chronic nasal and sinus inflammation. An unusually high prevalence of obstructive sleep apnea (OSA) has also been observed in this World Trade Center Responder population. This project aims to examine the relationship between nasal pathology and OSA. Our hypothesis is that increased nasal resistance due to nasal inflammation predisposes to OSA in this population. Continuous Positive Airway Pressure (CPAP) is the standard therapy for OSA but despite its efficacy has poor adherence. Subjects with high nasal resistance may have greater difficulty in tolerating this therapy than those who do not have high nasal resistance. Reduction of excess expiratory positive pressure by the modality known as Cflex(™) during Continuous Positive Airway Pressure therapy (CPAP(Flex)) has been suggested to improve comfort without compromising efficacy. We will compare CPAP to CPAP(Flex) in subjects with OSA. STUDY DESIGN: Subjects with new onset habitual snoring will be screened for OSA using home sleep studies and rhinomanometry will be used to determine nasal resistance. In 400 subjects with OSA we will perform a randomized double blind cross-over study comparing CPAP to CPAP(flex), and relate nasal resistance to adherence to CPAP therapy. DISCUSSION: This is the first multicenter trial designed to test the hypothesis that adherence to CPAP therapy relates to nasal resistance and CPAP(Flex) will improve adherence to CPAP in those subjects with high nasal resistance. We anticipate the following results from this trial: 1. Increased nasal resistance is associated with decreased adherence to CPAP therapy. 2. Use of CPAP(Flex) improves adherence with CPAP therapy in subjects with high nasal resistance, but not in those with low nasal resistance. 3. The benefit of CPAP(Flex) on adherence is greatest when offered at CPAP therapy initiation rather than as a "rescue" therapy in subjects with high nasal resistance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01753999, Date: 12 December 2012.