A Multicenter Retrospective Cohort Study to Characterize Patients Hospitalized With Multisystem Inflammatory Syndrome in Adults and Coronavirus Disease 2019 in the United States, 2020-2021.

BACKGROUND: The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated multisystem inflammatory syndrome in adults (MIS-A) requires distinguishing it from acute coronavirus disease 2019 (COVID-19) and may affect clinical management. METHODS: In this retrospective cohort study, we applied the US Centers for Disease Control and Prevention case definition to identify adults hospitalized with MIS-A at 6 academic medical centers from 1 March 2020 to 31 December 2021. Patients MIS-A were matched by age group, sex, site, and admission date at a 1:2 ratio to patients hospitalized with acute symptomatic COVID-19. Conditional logistic regression was used to compare demographic characteristics, presenting symptoms, laboratory and imaging results, treatments administered, and outcomes between cohorts. RESULTS: Through medical record review of 10 223 patients hospitalized with SARS-CoV-2-associated illness, we identified 53 MIS-A cases. Compared with 106 matched patients with COVID-19, those with MIS-A were more likely to be non-Hispanic black and less likely to be non-Hispanic white. They more likely had laboratory-confirmed COVID-19 ≥14 days before hospitalization, more likely had positive in-hospital SARS-CoV-2 serologic testing, and more often presented with gastrointestinal symptoms and chest pain. They were less likely to have underlying medical conditions and to present with cough and dyspnea. On admission, patients with MIS-A had higher neutrophil-to-lymphocyte ratio and higher levels of C-reactive protein, ferritin, procalcitonin, and D-dimer than patients with COVID-19. They also had longer hospitalization and more likely required intensive care admission, invasive mechanical ventilation, and vasopressors. The mortality rate was 6% in both cohorts. CONCLUSIONS: Compared with patients with acute symptomatic COVID-19, adults with MIS-A more often manifest certain symptoms and laboratory findings early during hospitalization. These features may facilitate diagnosis and management.

Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing.

BACKGROUND: Frontal fibrosing alopecia (FFA) is a scarring alopecia with unclear pathogenesis and a progressive course. The disease has a major impact on patients' quality of life and there is a lack of effective treatment to halt disease progression. METHODS: We profiled lesional and nonlesional scalp biopsies collected in 2017 from patients with FFA (n = 12) compared with scalp biopsies from patients with alopecia areata (AA) (n = 8) and controls (n = 8) to evaluate gene and protein expression, including the primary outcome (CXCL9). We determined significant differences between biomarkers using a two-sided Student's t-test adjusting P-values by false discovery rate. RESULTS: Significant increases were seen in CD8+ cytotoxic T cells, CD11c+ dendritic cells, CD103+ and CD69+ tissue-resident memory T cells in FFA and AA vs. control scalp (P < 0·05), with corresponding significantly upregulated granzyme B mRNA, particularly in FFA (P < 0·01). In AA, cellular infiltrates were primarily concentrated at the bulb, while in FFA these were mainly localized at the bulge. FFA demonstrated significant upregulation of T helper 1/intereferon (IFN) (IFN-γ, CXCL9/CXCL10), the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway (STAT1, JAK3) and fibrosis-related products (vimentin, fibronectin; P < 0·05), with no concomitant downregulation of hair keratins and the T-regulatory marker, forkhead box P3, which were decreased in AA. The stem cell markers CD200 and K15 demonstrated significantly reduced expression only in FFA (P < 0·05). CONCLUSIONS: These data suggest that follicular damage and loss of stem cells in FFA may be mediated through immune attack in the bulge region, with secondary fibrosis and reduced but still detectable stem cells. JAK/STAT-targeting treatments may be able to prevent permanent follicular destruction and fibrosis in early disease stages.

Alopecia areata is characterized by expansion of circulating Th2/Tc2/Th22, within the skin-homing and systemic T-cell populations.

BACKGROUND: Characterizing blood profile of alopecia areata (AA) is important not only for treatment advancements, but also for possibly identifying peripheral biomarkers that will eliminate the need for scalp biopsies. We aimed to compare frequencies of skin homing (CLA+ ) vs systemic (CLA- ) "polar" CD4+ and CD8+ and activated T-cell subsets in AA vs atopic dermatitis (AD) and control blood. METHODS: Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4+ and CD8+ T cells. Inducible co-stimulator molecule (ICOS) and HLA-DR were used to define mid- and long-term T-cell activation. We compared peripheral blood from 32 moderate-to-severe AA adults with 43 moderate-to-severe AD patients and 30 age-matched controls. RESULTS: AA patients had increased CLA+ /CLA- Th2 (P < .007), CLA+ Tc2 (P = .04), and CLA+ Th22 (P < .05) frequencies than controls. Except of CLA- Tc1 cells (P = .03), IFN-γ levels were mostly similar between AA, AD, and controls (P > .1). ICOS and HLA-DR activation were significantly higher in AA than controls (P < .05). T regulatory cells were significantly decreased in AA patients than controls (P < .01) and were correlated with activated CD8+ T cells and with multiple cytokine subsets (P < .05). While Th2 and Tc2 clustered with disease severity, IFN-γ producing cells were linked with AA duration. CONCLUSIONS: Alopecia areata is accompanied by Th2/Tc2 activation in skin-homing and systemic subsets, correlating with disease severity, while IFN-γ is linked to disease chronicity. These data hint for a possible role of diverse T-cells subsets in disease pathogenesis and emphasize the systemic nature of AA supporting the need for systemic therapeutic strategies in severe patients.

Dust mite induces multiple polar T cell axes in human skin.

BACKGROUND: House dust mite/HDM atopy patch test/APT elicits positive reactions in a high fraction of atopic dermatitis/AD and healthy individuals. Experimental systems for new-onset/chronic AD are needed to support rapid therapeutic development, particularly since animal models representing human AD are lacking. While HDM APT has been considered to simulate AD, its suitability to model AD's emerging Th2/Th22 phenotype with Th1 and Th17 components is unknown. OBJECTIVE: To assess whether HDM APT reproduces AD. METHODS: Positive HDM APTs (n = 15) from patients with and without AD were evaluated, using genomic and immunohistochemistry studies, against intrapersonal control skin. RESULTS: APT lesions showed higher T cell and dendritic cell infiltrates vs. CONTROLS: Seven hundred and forty-three up- and 326 downregulated genes were differentially expressed in HDM APT (fold change >2 and false discovery rate < 0.05), with increased expression of Th2, Th9, Th17/Th22 polar cytokines (i.e. IL-5, IL-13, IL-9, IL-17, IL-22). CONCLUSION: While HDM caused significant Th2 skewing, it also illustrated differences in Th2 induction and barrier defects; thus, HDM APT does not fully simulate AD. Given its widespread availability and sensitization rates, HDM may potentially be a useful tool that represents select aspects of AD, psoriasis, or contact dermatitis.

Identification of unique proteomic signatures in allergic and non-allergic skin disease.

BACKGROUND: Atopic dermatitis (AD), psoriasis (PS), and contact dermatitis (CD) are common skin diseases, characterized by barrier disruption and systemic inflammation, with unique epidermal signatures and common inflammatory pathways identified by transcriptomic profiling. This study profiled proteomic signatures in serum from subjects with AD, PS, and CD compared with healthy controls (HC). OBJECTIVE: Identify unique proteomic signatures to distinguish between inflammatory diseases with similar epidermal disruption and overlapping epithelial inflammation. METHODS: Sera from 20 subjects with moderate to severe AD, 10 subjects with CD, 12 subjects with moderate to severe PS, 10 subjects with both AD and CD, and 10 HC with no history of skin disease was analysed using high-throughput proteomic analysis that detects expression of 1129 protein targets. Protein expression was compared between disease and HC, and across diseases for statistical significance (fold change≥1.5 and false discovery rate≤0.05), to identify unique proteomic signatures for each disease. RESULTS: Complement C5A anaphylatoxin (C5A), lipopolysaccharide binding protein (LBP), C-reactive protein (CRP), ILT-4, C-C motif ligand 18 (PARC), and sialic acid-binding Ig-like lectin 14 (SIG14) were significantly modulated in all three diseases compared with HC. We identified unique signatures for AD (Immunoglobulin E (IgE), thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC)), CD (10 proteins), and PS (kynureninase (KYNU)). Proteomic profiling in subjects with both AD and CD identified additional dysregulated proteins compared with subjects with either condition alone, indicating an exacerbated inflammation reaction. CONCLUSIONS AND CLINICAL RELEVANCE: Unique sera proteomic signatures may distinguish between inflammatory skin diseases despite similar epidermal barrier disruption and epithelial inflammation. This may provide insight into disease pathogenesis, diagnosis, and therapeutic intervention in difficult-to-treat subjects.

Diagnostic Yield and Complications of Bronchoscopy for Peripheral Lung Lesions. Results of the AQuIRE Registry.

RATIONALE: Advanced bronchoscopy techniques such as electromagnetic navigation (EMN) have been studied in clinical trials, but there are no randomized studies comparing EMN with standard bronchoscopy. OBJECTIVES: To measure and identify the determinants of diagnostic yield for bronchoscopy in patients with peripheral lung lesions. Secondary outcomes included diagnostic yield of different sampling techniques, complications, and practice pattern variations. METHODS: We used the AQuIRE (ACCP Quality Improvement Registry, Evaluation, and Education) registry to conduct a multicenter study of consecutive patients who underwent transbronchial biopsy (TBBx) for evaluation of peripheral lesions. MEASUREMENTS AND MAIN RESULTS: Fifteen centers with 22 physicians enrolled 581 patients. Of the 581 patients, 312 (53.7%) had a diagnostic bronchoscopy. Unadjusted for other factors, the diagnostic yield was 63.7% when no radial endobronchial ultrasound (r-EBUS) and no EMN were used, 57.0% with r-EBUS alone, 38.5% with EMN alone, and 47.1% with EMN combined with r-EBUS. In multivariate analysis, peripheral transbronchial needle aspiration (TBNA), larger lesion size, nonupper lobe location, and tobacco use were associated with increased diagnostic yield, whereas EMN was associated with lower diagnostic yield. Peripheral TBNA was used in 16.4% of cases. TBNA was diagnostic, whereas TBBx was nondiagnostic in 9.5% of cases in which both were performed. Complications occurred in 13 (2.2%) patients, and pneumothorax occurred in 10 (1.7%) patients. There were significant differences between centers and physicians in terms of case selection, sampling methods, and anesthesia. Medical center diagnostic yields ranged from 33 to 73% (P = 0.16). CONCLUSIONS: Peripheral TBNA improved diagnostic yield for peripheral lesions but was underused. The diagnostic yields of EMN and r-EBUS were lower than expected, even after adjustment.

Blood Neutrophil Count and Neutrophil-to-Lymphocyte Ratio for Prediction of Disease Progression and Mortality in Two Independent Systemic Sclerosis Cohorts.

OBJECTIVE: To assess the predictive significance of blood neutrophil count and the ratio between neutrophil and lymphocyte count (neutrophil-to-lymphocyte ratio [NLR]) for disease severity and mortality in systemic sclerosis (SSc). METHODS: Neutrophil and lymphocyte counts were prospectively measured in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) and the Scleroderma Lung Study II (SLS II). Forced vital capacity percent predicted (FVC%) and modified Rodnan skin thickness score (MRSS) were used as surrogate measures for disease severity. Longitudinal analyses were performed using generalized linear mixed models. Cox proportional hazards models evaluated the predictive significance of these cell counts for mortality. RESULTS: Of the 447 SSc patients in the GENISOS cohort at the time of analysis, 377 (84.3%) had available baseline blood neutrophil and lymphocyte counts. Higher baseline neutrophil count and NLR predicted lower serially obtained FVC% (b = -4.74, P = 0.009 and b = -2.68, P = 0.028, respectively) and higher serially obtained MRSS (b = 4.07, P < 0.001 and b = 2.32, P < 0.001, respectively). Longitudinal neutrophil and NLR measurements also significantly correlated with lower concurrently obtained FVC% measurements and higher concurrently obtained MRSS. Baseline neutrophil count and NLR predicted increased risk of long-term mortality, even after adjustment for baseline demographic and clinical factors (hazard ratio [HR] 1.42, P = 0.02 and HR 1.48, P < 0.001, respectively). The predictive significance of higher baseline neutrophil count and NLR for declining FVC% and increased long-term mortality was confirmed in the SLS II. CONCLUSION: Higher blood neutrophil count and NLR are predictive of more severe disease course and increased mortality, indicating that these easily obtainable laboratory studies might be a reflection of pathologic immune processes in SSc.

Pneumothorax and pneumomediastinum in COVID-19: A case series.

COVID- 19 has become a major pandemic affecting more than 11 million people worldwide. Common radiological manifestations of COVID-19 include peripheral based ground-glass or consolidative opacities; however, pneumothorax and pneumo-mediastinum are very rare manifestations; even more so within patients not on mechanical ventilation. We present a case series of 5 patients with COVID-19 who either presented with or developed spontaneous pneumothorax or pneumo-mediastinum within the course of hospitalization. With the exception of one patient, all other patients developed pneumothorax as a late manifestation in their illness; more than 10 days after initial symptom onset in COVID-19. From within this case series, all patients who developed spontaneous pneumothorax or pneumo-mediastinum during hospitalization subsequently succumbed to the illness. Spontaneous pneumothorax or pneumo-mediastinum may be an important late manifestation in COVID-19; even in spontaneously breathing patients. This may be related to development of cystic changes within the lung parenchyma. Although the clinical relevance of this finding is unknown; in our series, it portended a worse prognosis in the majority of patients.

The Effect of Anti-Scl-70 Antibody Determination Method on Its Predictive Significance for Interstitial Lung Disease Progression in Systemic Sclerosis.

OBJECTIVE: The objective of this study was to assess the predictive significance of anti-Scl-70 (anti-topoisomerase I) antibodies, as determined by three different methods, for decline in forced vital capacity (FVC) within the first year of follow-up in patients with systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS: Patients in the Genetics Versus Environment in Scleroderma Outcome Study cohort who had ILD (verified by imaging) and available FVC% at enrollment, plus 12 to 18 months thereafter, were examined. All patients had a disease duration of 5 years or less at enrollment. The annualized percentage change in FVC% at 1 year follow-up was the outcome variable. Anti-Scl-70 antibodies were determined by passive immunodiffusion (ID) against calf thymus extract, chemiluminescent immunoassay (CIA), and line blot immunoassay (LIA). RESULTS: Ninety-one patients with a mean disease duration of 2.36 years were included. Anti-Scl-70 antibodies by ID predicted a faster rate of FVC% decline (b = -0.06, P = 0.04). None of the other clinical or serological variables significantly predicted ILD progression. Interestingly, anti-Scl-70 antibodies as determined by CIA and LIA were not significant predictors of FVC decline (P = 0.26 and 0.64, respectively). The observed level of agreement between ID and LIA was moderate (κ = 0.568), whereas it was good between ID and CIA (κ = 0.66). CONCLUSION: Anti-Scl-70 antibodies determined by ID predicted faster FVC decline in patients with SSc-related ILD. Notably, both CIA and LIA for the same antibody did not predict rate of FVC decline at their current cutoffs of positivity. The discrepancy observed between anti-Scl-70 antibody assays can have relevant implications for clinical care and trial enrichment strategies in SSc-ILD.

52-Year-Old With Epistaxis, Hemoptysis, Hoarseness, and Weight Loss.

CLINICAL PRESENTATION: A 52-year-old man presented with hemoptysis of 2 weeks' duration. He had been experiencing hoarseness, right-sided pleuritic chest pain, subjective fevers, chills, night sweats, and 10 pounds weight loss for the previous 2 months. He additionally reported severe frontal headaches, nasal congestion, and intermittent epistaxis, which had been present for a year before his current presentation. He had worked in construction and denied tobacco or illicit drug use.

Diagnostic yield of electromagnetic navigational bronchoscopy: A safety net community-based hospital experience in the United States.

INTRODUCTION: Electromagnetic navigational bronchoscopy (ENB) is an excellent tool to diagnose peripheral pulmonary nodules, especially in the setting of emphysema and pulmonary fibrosis. However, most of these procedures are done by interventional pulmonologists and academic tertiary centers under general anesthesia. Studies evaluating the diagnostic utility of this tool in safety-net community hospitals by pulmonologists not formally trained in this technology are lacking. The objective was to evaluate the diagnostic yield of ENB done in such a setting and its associated complications. METHODS: Retrospective chart review of consecutive ENB procedures over 5 years from 2014, since its inception in our institution-a safety-net community based hospital was performed. Multiple variables were analyzed to assess their impact on diagnostic yields. RESULTS: After exclusion criteria were applied, 72 patients with 76 procedures were eventually included within our study, with an overall 1-year diagnostic yield of 80.2%. Sensitivity for malignancy was 73% and negative predictive value of 65%. Primary lung cancer was the most common diagnosis obtained, followed by tuberculosis (TB). The overall complication rates were low, with only 1 patient (1.3%) requiring hospitalization due to pneumothorax needing tube thoracostomy. No deaths or respiratory failures were noted within the cohort. The only significant variable affecting diagnostic yield was forced expiratory volume in 1 s. The presence of emphysema did not affect diagnostic yield. CONCLUSIONS: ENB is safe and feasible with a high diagnostic success rate even when performed by pulmonologists not formally trained in interventional pulmonology in low resource settings under moderate sedation.

Safety and incidence of complications associated with bronchoscopy in an obese population.

INTRODUCTION: The safety of bronchoscopy in obese patients and those with obstructive sleep apnea (OSA) is unclear. Our objective was to evaluate the incidence of complications during bronchoscopy under moderate sedation in obese patients and to assess the impact of OSA, body mass index (BMI), and duration of the procedure. METHODS: We performed a retrospective study in adult patients undergoing bronchoscopy from January 2010 to August 2019. All patients with BMI > 30 kg/m2 were included. Logistic regression analyses were used to identify the factors associated with all-complications and respiratory complications. RESULTS: A total of 345 obese patients were identified. The average BMI in our cohort was 35.3 ± 5.1 kg/m2 . During the pre-procedure risk assessment, 165 (47.8%) patients were labelled as "suspected OSA." The most common doses of sedation given during the bronchoscopies were fentanyl 50 mcg (34.5%) and midazolam 3 mg (33.6%). The incidence of major complications was 0.6% and minor complications were 41.2%. Minor respiratory (22.9%) and cardiac (26.4%) complications were common. No deaths occurred due to bronchoscopy. Factors that were associated with increased respiratory complications were female gender, suspected OSA, and bronchoscopy duration 20-30 minutes and bronchoscopy duration greater than 1 hour. CONCLUSION: Bronchoscopy under moderate sedation performed in obese patients is safe; however, increased risk may exist with females, increased procedure time, and suspected OSA.

Wells Score to Predict Pulmonary Embolism in Patients with Coronavirus Disease 2019.

BACKGROUND: The association between coronavirus disease 2019 (COVID-19) and hypercoagulability has been extensively described, and pulmonary embolism is a recognized complication of COVID-19. Currently, the need for computed tomography pulmonary angiogram (CTPA) relies on the Wells score and serum D-dimer levels. However, because COVID-19 patients have a different thrombotic and inflammatory milieu, the usefulness of the Wells score deserves further exploration for this patient population. We aimed to explore the ability of the Wells score to predict pulmonary embolism in patients with COVID-19. METHODS: In this retrospective study, patients found to have a CTPA and a COVID-19 diagnosis during the same admission were selected for analysis. Age and sex, CTPA results, and associated D-dimer levels were entered in a database. The Wells score sensitivity and specificity were calculated at different values, and the area under the curve of the receiver operating characteristic curve measured. RESULTS: Of 459 patients with COVID-19, 64 had a CTPA and 12 (19%) had evidence of pulmonary embolism. Previous or current evidence of deep vein thrombosis, a Wells score above 4 points, and serum D-dimer levels 5 times above age-adjusted upper normal values were associated with pulmonary embolism. However, only 33% of patients with pulmonary embolism had a Wells score of 4 points or higher. The area under the curve of the receiver operating characteristic showed non-discriminating values (0.54) CONCLUSIONS: Although a Wells score of 4 or more points predicted pulmonary embolism in our cohort, the outcome can be present even with lower scores.

Predictive factors for success of awake proning in hypoxemic respiratory failure secondary to COVID-19: A retrospective cohort study.

BACKGROUND: Awake prone positioning has been recommended as an adjunctive measure in spontaneously breathing patients with hypoxemic respiratory failure during the COVID-19 pandemic. It remains uncertain as to how long this should be implemented, what variables to follow and who would be the ideal candidates for this adjunctive therapy. METHODS: A retrospective chart review of patients admitted from April to August 2020 within our institution with multifocal pneumonia and hypoxemic respiratory failure secondary to COVID-19 who underwent awake-proning for at least 3 hours was conducted. RESULTS: Improvement in respiratory parameters including ROX (SpO2/Fio2/ Respiratory Rate) indices and inflammatory markers within 4 days of institution of awake proning predicted a higher chance for success of this strategy in preventing need for mechanical ventilation. Moreover, benefits of awake proning were limited to patients with mild to moderate ARDS. CONCLUSIONS: Awake prone positioning can be safely performed with improvement in oxygenation. However, its institution may be beneficial only in patients with mild to moderate ARDS and requires careful evaluation of respiratory parameters and serum inflammatory markers to avoid a delay in endotracheal intubation and consequent increase in mortality rates.

E-Cigarette or Vaping Product-Associated Lung Injury: A Review.

Since its introduction in the US market in 2007, the use of electronic nicotine delivery systems, colloquially referred to as e-cigarettes or "vaping" products, has increased substantially, particularly among high school children and young men. With the legalization of marijuana within multiple states in the United States and thus, coincident change in the public perception of its risk, the availability of multiple tetrahydrocannabinol (the psychoactive agent in marijuana)- and cannabidiol (a nonpsychogenic agent in marijuana)- containing vaping products has also increased tremendously. Since March 2019, there has been an ongoing epidemic of acute lung injury secondary to the use of e-cigarettes, with over 2600 cases and 60 deaths reported all over the United States; the term e-cigarette- or vaping product-associated lung injury is used. E-cigarette- or vaping product-associated lung injury is defined by the 1) presence of pulmonary infiltrates in imaging; 2) use of electronic nicotine delivery systems within the previous 90 days; and 3) absence of other possible causes such as infection, cardiac, neoplastic, or rheumatologic causes. A significant proportion of patients hospitalized with e-cigarette- or vaping product-associated lung injury have required admission in the intensive care unit, with mechanical ventilation needed in up to one-third of patients. Corticosteroids, supportive care, and further avoidance of vaping products remain the cornerstone of treatment. Although generally associated with an excellent prognosis, older patients and patients with underlying cardiac and pulmonary conditions are at risk for higher mortality and morbidity. This review article aims to describe e-cigarette- or vaping product-associated lung injury, its pathogenesis, clinical and radiological manifestations, and management.

A 35-Year-Old Woman With Progressive Dyspnea and Cough.

CASE PRESENTATION: A 35-year-old woman with no known medical history presented to the ED with complaints of progressive dyspnea for several months. The patient also reported episodic cough with yellow to green sputum production. She denied fever, chills, weight loss, or hemoptysis. She also denied any history of previous lung diseases in her family. She denied any history of tobacco or recreational drug use or any exposures. She was originally from El Salvador and immigrated to the United States approximately 3 years earlier. She was evaluated in El Salvador at age 15 for "lung issues" but had never received a formal diagnosis.

Clinical, radiology, pathologic patterns and outcomes of vaping related pulmonary injury in a single institution; A case series.

Since March 2019, E-cigarette or Vaping product associated lung injury (EVALI) has become an ongoing epidemic with more 2600 cases reported in the span of a few months in the United States. EVALI is defined as acute lung injury that develops secondary to the use of e-cigarettes or vaping products within the previous 90 days after exlusion of other possible inciting factors. Vitamin E acetate is believed to play a significant role in its pathogenesis. Treatment involves use of corticosteroids and further avoidance of these products. We describe a case series of 8 patients with EVALI, their clinical course and outcomes. All patients showed an excellent response to corticosteroids. In our experience, prognosis of EVALI is excellent, with complete resolution of symptoms in patients who followed up at 8 weeks.