Diagnostic test interpretation and referral delay in patients with interstitial lung disease.

BACKGROUND:Diagnostic delays are common in patients with interstitial lung disease (ILD). A substantial percentage of patients experience a diagnostic delay in the primary care setting, but the factors underpinning this observation remain unclear. In this multi-center investigation, we assessed ILD reporting on diagnostic test interpretation and its association with subsequent pulmonology referral by a primary care physician (PCP). METHODS:A retrospective cohort analysis of patients referred to the ILD programs at UC-Davis and University of Chicago by a PCP within each institution was performed. Computed tomography (CT) of the chest and abdomen and pulmonary function test (PFT) were reviewed to identify the date ILD features were first present and determine the time from diagnostic test to pulmonology referral. The association between ILD reporting on diagnostic test interpretation and pulmonology referral was assessed, as was the association between years of diagnostic delay and changes in fibrotic features on longitudinal chest CT. RESULTS:One hundred and forty-six patients were included in the final analysis. Prior to pulmonology referral, 66% (n = 97) of patients underwent chest CT, 15% (n = 21) underwent PFT and 15% (n = 21) underwent abdominal CT. ILD features were reported on 84, 62 and 33% of chest CT, PFT and abdominal CT interpretations, respectively. ILD reporting was associated with shorter time to pulmonology referral when undergoing chest CT (1.3 vs 15.1 months, respectively; p = 0.02), but not PFT or abdominal CT. ILD reporting was associated with increased likelihood of pulmonology referral within 6 months of diagnostic test when undergoing chest CT (rate ratio 2.17, 95% CI 1.03-4.56; p = 0.04), but not PFT or abdominal CT. Each year of diagnostic delay was associated with a 1.8% increase in percent fibrosis on chest CT. Patients with documented dyspnea had shorter time to chest CT acquisition and pulmonology referral than patients with documented cough and lung crackles. CONCLUSIONS:Determinants of ILD diagnostic delays in the primary care setting include underreporting of ILD features on diagnostic testing and prolonged time to pulmonology referral even when ILD is reported. Interventions to modulate these factors may reduce ILD diagnostic delays in the primary care setting

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 x 10(-5)) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 x 10(-8)). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 x 10(-9)). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression

A 51-Year-Old Man With Unresolved Pulmonary Infiltrates Following Streptococcus&nbsp;pneumoniae Pneumonia

Case presentationA 51-year-old man presented to the clinic 8&nbsp;weeks after a 6-day hospital admission for severe multilobar pneumonia caused by Streptococcus pneumoniae. His productive cough resolved after antibiotics, but he reported persistent dyspnea. He recounted a lifelong history of recurrent sinusitis but no previous episodes of pneumonia. The patient denied fever, weight loss, or tobacco, alcohol, or drug use. He worked as an upholstery craftsman with no work-related exposures. He had no bird or exotic animal exposures, and no history of travel outside Sacramento, California, where he lived. Aside from the recently completed 2-week course of levofloxacin, he was not taking any medications

Investigation of nosocomial SARS-CoV-2 transmission from two patients to healthcare workers identifies close contact but not airborne transmission events.

ObjectiveTo describe the pattern of transmission of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) during 2 nosocomial outbreaks of coronavirus disease 2019 (COVID-19) with regard to the possibility of airborne transmission.DesignContact investigations with active case finding were used to assess the pattern of spread from 2 COVID-19 index patients.SettingA community hospital and university medical center in the United States, in February and March, 2020, early in the COVID-19 pandemic.PatientsTwo index patients and 421 exposed healthcare workers.MethodsExposed healthcare workers (HCWs) were identified by analyzing the electronic medical record (EMR) and conducting active case finding in combination with structured interviews. Healthcare coworkers (HCWs) were tested for COVID-19 by obtaining oropharyngeal/nasopharyngeal specimens, and RT-PCR testing was used to detect SARS-CoV-2.ResultsTwo separate index patients were admitted in February and March 2020, without initial suspicion for COVID-19 and without contact or droplet precautions in place; both patients underwent several aerosol-generating procedures in this context. In total, 421 HCWs were exposed in total, and the results of the case contact investigations identified 8 secondary infections in HCWs. In all 8 cases, the HCWs had close contact with the index patients without sufficient personal protective equipment. Importantly, despite multiple aerosol-generating procedures, there was no evidence of airborne transmission.ConclusionThese observations suggest that, at least in a healthcare setting, most SARS-CoV-2 transmission is likely to take place during close contact with infected patients through respiratory droplets, rather than by long-distance airborne transmission

Circulating Plasma Biomarkers of Survival in Antifibrotic-Treated Patients With Idiopathic Pulmonary Fibrosis.

BackgroundA number of circulating plasma biomarkers have been shown to predict survival in patients with idiopathic pulmonary fibrosis (IPF), but most were identified before the use of antifibrotic (AF) therapy in this population. Because pirfenidone and nintedanib have been shown to slow IPF progression and may prolong survival, the role of such biomarkers in AF-treated patients is unclear.Research questionTo determine whether plasma concentration of cancer antigen 125 (CA-125), C-X-C motif chemokine 13 (CXCL13), matrix metalloproteinase 7 (MMP7), surfactant protein D (SP-D), chitinase-3-like protein-1 (YKL-40), vascular cell adhesion protein-1 (VCAM-1), and osteopontin (OPN) is associated with differential transplant-free survival (TFS) in AF-exposed and nonexposed patients with IPF.Study design and methodsA pooled, multicenter, propensity-matched analysis of IPF patients with and without AF exposure was performed. Optimal thresholds for biomarker dichotomization were identified in each group using iterative Cox regression. Longitudinal biomarker change was assessed in a subset of patients using linear mixed regression modeling. A clinical-molecular signature of IPF TFS was then derived and validated in an independent IPF cohort.ResultsThree hundred twenty-five patients were assessed, of which 68 AF-exposed and 172 nonexposed patients were included after propensity matching. CA-125, CXCL13, MMP7, YKL-40, and OPN predicted differential TFS in AF-exposed patients but at higher thresholds than in AF-nonexposed individuals. Plasma biomarker level generally increased over time in nonexposed patients but remained unchanged in AF-exposed patients. A clinical-molecular signature predicted decreased TFS in AF-exposed patients (hazard ratio [HR], 5.91; 95%&nbsp;CI, 2.25-15.5; P&nbsp;&lt; .001) and maintained this association in an independent AF-exposed cohort (HR, 3.97; 95%&nbsp;CI, 1.62-9.72; P&nbsp;= .003).InterpretationMost plasma biomarkers assessed predicted differential TFS in AF-exposed patients with IPF, but at higher thresholds than in nonexposed patients. A clinical-molecular signature of IPF TFS may provide a reliable predictor of outcome risk in AF-treated patients but requires additional research for optimization and validation

Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis

BackgroundProgressive fibrosing interstitial lung disease (ILD) is characterised by parenchymal scar formation, leading to high morbidity and mortality. The ability to predict this phenotype remains elusive. We conducted a proteomic analysis to identify novel plasma biomarkers of progressive fibrosing ILD and developed a proteomic signature to predict this phenotype.MethodsRelative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform in patients with connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, or unclassifiable ILD who provided research blood draws at the University of California (discovery cohort) and the University of Texas (validation cohort). Univariable logistic regression was used to identify individual biomarkers associated with 1-year ILD progression, defined as death, lung transplant, or 10% or greater relative forced vital capacity (FVC) decline. A proteomic signature of progressive fibrosing ILD was then derived with use of machine learning in the University of California cohort and validated in the University of Texas cohort.FindingsThe discovery cohort comprised 385 patients (mean age 63·6 years, 59% female) and the validation cohort comprised 204 patients (mean age 60·7 years, 61% female). 31 biomarkers were associated with progressive fibrosing ILD in the discovery cohort, with 17 maintaining an association in the validation cohort. Validated biomarkers showed a consistent association with progressive fibrosing ILD irrespective of ILD clinical diagnosis. A proteomic signature comprising 12 biomarkers was derived by machine learning and validated in the University of Texas cohort, in which it had a sensitivity of 0·90 and corresponding negative predictive value of 0·91, suggesting that approximately 10% of patients with a low-risk proteomic signature would experience ILD progression in the year after blood draw. Those with a low-risk proteomic signature experienced an FVC change of +85·7 mL (95% CI 6·9 to 164·4) and those with a high-risk signature experienced an FVC change of -227·1 mL (-286·7 to -167·5). A theoretical clinical trial restricted to patients with a high-risk proteomic signature would require 80% fewer patients than one designed without regard to proteomic signature.Interpretation17 plasma biomarkers of progressive fibrosing ILD were identified and showed consistent associations across ILD subtypes. A proteomic signature of progressive fibrosing ILD could enrich clinical trial cohorts and avoid the need for antecedent progression when defining progressive fibrosing ILD for clinical trial enrolment.FundingNational Heart Lung and Blood Institute

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P &lt; 5 × 10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P &lt; 5 × 10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 × 10-9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression