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1.
J Pathol Clin Res ; 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960723

RESUMO

Autopsies of patients who have died from COVID-19 have been crucial in delineating patterns of injury associated with SARS-CoV-2 infection. Despite their utility, comprehensive autopsy studies are somewhat lacking relative to the global burden of disease, and very few comprehensive studies contextualize the findings to other fatal viral infections. We developed a novel autopsy protocol in order to perform postmortem examinations on victims of COVID-19 and herein describe detailed clinical information, gross findings, and histologic features observed in the first 16 complete COVID-19 autopsies. We also critically evaluated the role of ancillary studies used to establish a diagnosis of COVID-19 at autopsy, including immunohistochemistry (IHC), in situ hybridization (ISH), and electron microscopy (EM). IHC and ISH targeting SARS-CoV-2 were comparable in terms of the location and number of infected cells in lung tissue; however, nonspecific staining of bacteria was seen occasionally with IHC. EM was unrevealing in blindly sampled tissues. We then compared the clinical and histologic features present in this series to six archival cases of fatal seasonal influenza and six archival cases of pandemic influenza from the fourth wave of the 'Spanish Flu' in the winter of 1920. In addition to routine histology, the inflammatory infiltrates in the lungs of COVID-19 and seasonal influenza victims were compared using quantitative IHC. Our results demonstrate that the clinical and histologic features of COVID-19 are similar to those seen in fatal cases of influenza, and the two diseases tend to overlap histologically. There was no significant difference in the composition of the inflammatory infiltrate in COVID-19 and influenza at sites of acute lung injury at the time of autopsy. Our study underscores the relatively nonspecific clinical features and pathologic changes shared between severe cases of COVID-19 and influenza, while also providing important caveats to ancillary methods of viral detection.

2.
Chest ; 159(4): 1321-1323, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34021989
3.
Clin Chest Med ; 42(2): 251-261, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34024401

RESUMO

Interstitial lung diseases (ILDs) are challenging to diagnose, requiring integration of multiple complex features that are often difficult to interpret. This article reviews a pragmatic approach to ILD diagnosis and classification, focusing on diagnostic tools and strategies that are used to separate different subtypes and identify the most appropriate management. We discuss the evolution of ILD classification and the contemporary approach that integrates routinely used diagnostic tools in a multidisciplinary discussion. We highlight the increasing importance of taking a multipronged approach to ILD classification that reflects the recent emphasis on disease behavior while also considering etiopathogenesis and morphologic features.

7.
Eur Radiol ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33847810

RESUMO

OBJECTIVES: To determine if a quantitative imaging variable (vessel-related structures [VRS]) could identify subjects with a non-IPF diagnosis CT pattern who were highly likely to have UIP histologically. METHODS: Subjects with a multidisciplinary diagnosis of interstitial lung disease including surgical lung biopsy and chest CT within 1 year of each other were included in the study. Non-contrast CT scans were analyzed using the Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) program, which quantifies the amount of various abnormal CT patterns on chest CT. Quantitative data were analyzed relative to pathological diagnosis as well as the qualitative CT pattern. RESULTS: CALIPER-derived volumes of reticulation (p = 0.012), honeycombing (p = 0.017), and VRS (p < 0.001) were associated with a UIP pattern on pathology on univariate analysis but only VRS was associated with a UIP pathology on multivariable analysis (p = 0.013). Using a VRS cut-off of 173 cm3, the sensitivity and specificity for pathological UIP were similar to those for standard qualitative CT assessment (55.9% and 80.4% compared to 60.6% and 80.4%, respectively). VRS differentiated pathological UIP cases in those with a non-IPF diagnosis CT category (p < 0.001) but not in other qualitative CT patterns (typical UIP, probable UIP, and indeterminate for UIP). The rate of pathological UIP in those with VRS greater than 173 cm3 (84.2%) was nearly identical to those who had a qualitative CT pattern of probable UIP (88.9%). CONCLUSIONS: VRS may be an adjunct to CT in predicting pathology in patients with interstitial lung disease. KEY POINTS: • Volume of vessel-related structures (VRS) was associated with usual interstitial pneumonia (UIP) on pathology. • This differentiation arose from those with CT scans with a non-IPF diagnosis imaging pattern. • Higher VRS has similar diagnostic ramifications for UIP as probable UIP, transitively suggesting in patients with high VRS, pathology may be obviated.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33689671

RESUMO

Rationale: Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objective: To identify a predictor using short-term longitudinal changes in gene-expression that forecasts future forced vital capacity (FVC) decline and to characterize involved pathways and cell types. Methods: Seventy-four patients from Correlating Outcomes with biochemical Markers to Estimate Time-progression in IPF (COMET) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months, and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC-predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-seq (PBMC scRNA-seq) data from healthy controls were used as references to characterize cell type compositions from bulk PBMC RNA-seq data that were associated with FVC decline. Results: The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared to a cross-sectional model. The FVC-predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were down- and up-regulated, respectively. Cellular deconvolution using scRNA-seq data identified natural killer (NK) cells as significantly correlated with progression. Conclusions: Serial transcriptomic change predicts future FVC decline. Analysis of cell types involved in the progressor signature supports the novel involvement of NK cells in IPF progression.

9.
Chest ; 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33621598

RESUMO

BACKGROUND: Inhalational exposures are increasingly recognized as contributing factors in interstitial lung disease (ILD). However, the characteristics of both exposures and exposed patients are not well understood. We hypothesized that domestic and occupational inhalational exposures would be common and associated with differences in demographics, clinical characteristics, and transplant-free survival in patients with all forms of ILD. RESEARCH QUESTION: What is the prevalence of inhalational exposures across all ILD diagnoses, and are these exposures associated with differences in demographics, clinical characteristics, and transplant-free survival? STUDY DESIGN AND METHODS: Patients from a tertiary ILD clinic underwent an interview designed to capture inhalational exposures including occupational, home, hobbies, and tobacco. Demographic and survival data were collected from the electronic medical record. Survival analysis was performed using Cox regression to compare exposed vs unexposed patients and adjusted for gender, age, physiology score and smoking. RESULTS: One hundred and fifty-six patients seen between May and October 2018 were analyzed. Patients had a wide variety of multidisciplinary diagnoses, with a minority of patients with hypersensitivity pneumonitis (14%). One hundred and one patients (65%) had potentially relevant inhalational exposures. More men than women had a history of any exposure (82% vs 51%; P < .001), occupational exposure (66% vs 14%, P < .001), and multiple exposures (56% vs 26%, P < .001), respectively. White race was associated with bird and hobby exposure. Patients with any exposure had worse transplant-free survival (unadjusted hazard ratio, 2.58; 95% CI, 1.13-5.92; P = .025), but this was not statistically significant after adjustment (hazard ratio, 1.82; 95% CI, 0.77-4.27; P = .17). INTERPRETATION: A standardized interview revealed most patients across all types of ILD had potentially relevant inhalational exposures. Exposures were markedly different based on demographics and were associated with worse transplant-free survival, but this survival difference was not significant after multivariable adjustment. Identification and avoidance of exposures represent actionable targets in ILD management.

10.
J Clin Med ; 9(11)2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33238466

RESUMO

This study aimed to determine diagnostic and prognostic differences in major forms of interstitial lung disease using quantitative CT imaging. A retrospective study of 225 subjects with a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF), interstitial pneumonia with autoimmune features (IPAF), connective tissue disease (CTD), or chronic hypersensitivity pneumonitis (cHP) was conducted. Non-contrast CT scans were analyzed using the Computer Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) program. Resulting data were analyzed statistically using ANOVA and Student's t-test. Univariate, multivariable, and receiver operating characteristic analyses were conducted on patient mortality data. CALIPER analysis of axial distribution on CT scans in those with IPF demonstrated greater peripheral volumes of reticulation than either CTD (p = 0.033) or cHP (p = 0.007). CTD showed lower peripheral ground-glass opacity than IPF (p = 0.005) and IPAF (p = 0.004). Statistical analysis of zonal distributions revealed reduced lower zone ground-glass opacity in cHP than IPF (p = 0.044) or IPAF (p = 0.018). Analysis of pulmonary vascular-related structure (VRS) volume by diagnosis indicated greater VRS volume in IPF compared to CTD (p = 0.003) and cHP (p = 0.003) as well as in IPAF compared to CTD (p = 0.007) and cHP (p = 0.007). Increased reticulation (p = 0.043) and ground glass opacity (p = 0.032) were predictive of mortality on univariate analysis. Increased pulmonary VRS volume was predictive of mortality (p < 0.001) even after multivariate analysis (p = 0.041). Quantitative CT imaging revealed significant differences between ILD diagnoses in specific CT findings in axial and, to a lesser degree, zonal distributions. Increased pulmonary VRS volume seems to be associated with both diagnosis and survival.

11.
Blood Adv ; 4(19): 4873-4886, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33035329

RESUMO

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.

14.
Eur Respir J ; 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32675203

RESUMO

Interstitial pneumonia with autoimmune features (IPAF) characterises individuals with interstitial lung disease (ILD) and features of connective tissue disease (CTD) who fail to satisfy CTD criteria. Inclusion of myositis-specific antibodies (MSAs) in the IPAF criteria has generated controversy, as these patients also meet proposed criteria for an anti-synthetase syndrome. Whether MSAs and myositis associated antibodies (MAA) identify phenotypically distinct IPAF subgroups remains unclear.A multi-center, retrospective investigation was conducted to assess clinical features and outcomes in patients meeting IPAF criteria stratified by the presence of MSAs and MAAs. IPAF subgroups were compared to cohorts of patients with idiopathic inflammatory myopathy-ILD (IIM-ILD), idiopathic pulmonary fibrosis (IPF) and non-IIM CTD-ILDs. The primary endpoint assessed was three-year transplant-free survival. Two hundred sixty-nine patients met IPAF criteria, including 35 (13%) with MSAs and 65 (24.2%) with MAAs. Survival was highest among patients with IPAF-MSA and closely approximated those with IIM-ILD. Survival did not differ between IPAF-MAA and IPAF without MSA/MAA cohorts. Usual interstitial pneumonia (UIP) morphology was associated with differential outcome risk, with IPAF patients with non-UIP morphology approximating survival observed in non-IIM CTD-ILDs. MSAs, but not MAAs identified a unique IPAF phenotype characterised by clinical features and outcomes similar to IIM-ILD. UIP morphology was a strong predictor of outcome in others meeting IPAF criteria. Because IPAF is a research classification without clear treatment approach, these findings suggest MSAs should be removed from the IPAF criteria and such patients should be managed as an IIM-ILD.

15.
Chest ; 158(4): 1701-1712, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32450237

RESUMO

BACKGROUND: OSA, a common comorbidity in interstitial lung disease (ILD), could contribute to a worsened course if untreated. It is unclear if adherence to CPAP therapy improves outcomes. RESEARCH QUESTION: Does adherence to CPAP therapy improve outcomes in patients with concurrent interstitial lung disease and OSA? STUDY DESIGN AND METHODS: We conducted a 10-year retrospective observational multicenter cohort study, assessing adult patients with ILD who had undergone polysomnography. Subjects were categorized based on OSA severity into no/mild OSA (apnea-hypopnea index score < 15) or moderate/severe OSA (apnea-hypopnea index score ≥ 15). All subjects prescribed and adherent to CPAP were deemed to have treated OSA. Cox regression models were used to examine the association of OSA severity and CPAP adherence with all-cause mortality risk and progression-free survival (PFS). RESULTS: Of 160 subjects that met inclusion criteria, 131 had OSA and were prescribed CPAP. Sixty-six patients (41%) had no/mild untreated OSA, 51 (32%) had moderate/severe untreated OSA, and 43 (27%) had treated OSA. Subjects with no/mild untreated OSA did not differ from those with moderate/severe untreated OSA in mean survival time (127 ± 56 vs 138 ± 93 months, respectively; P = .61) and crude mortality rate (2.9 per 100 person-years vs 2.9 per 100 person-years, respectively; P = .60). Adherence to CPAP was not associated with improvement in all-cause mortality risk (hazard ratio [HR], 1.1; 95% CI, 0.4-2.9; P = .79) or PFS (HR, 0.9; 95% CI, 0.5-1.5; P = .66) compared with those that were nonadherent or untreated. Among subjects requiring supplemental oxygen, those adherent to CPAP had improved PFS (HR, 0.3; 95% CI, 0.1-0.9; P = .03) compared with nonadherent or untreated subjects. INTERPRETATION: Neither OSA severity nor adherence to CPAP was associated with improved outcomes in patients with ILD except those requiring supplemental oxygen.

16.
Chest ; 158(4): 1526-1534, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32450241

RESUMO

BACKGROUND: A 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 QUESTION: To 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 METHODS: A 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. RESULTS: Three 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% CI, 2.25-15.5; P < .001) and maintained this association in an independent AF-exposed cohort (HR, 3.97; 95% CI, 1.62-9.72; P = .003). INTERPRETATION: Most 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.

17.
Am J Respir Crit Care Med ; 201(5): 564-574, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710517

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated three new genome-wide significant (P < 5 × 10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.


Assuntos
Fibrose Pulmonar Idiopática/genética , Idoso , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cinesina/genética , Masculino , Pessoa de Meia-Idade , Medição de Risco , Transdução de Sinais , Fuso Acromático , Serina-Treonina Quinases TOR/metabolismo
20.
Respir Res ; 20(1): 253, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718645

RESUMO

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.


Assuntos
Diagnóstico Tardio/tendências , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/fisiopatologia , Encaminhamento e Consulta/tendências , Tempo para o Tratamento/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Testes Diagnósticos de Rotina/métodos , Testes Diagnósticos de Rotina/tendências , Feminino , Humanos , Doenças Pulmonares Intersticiais/terapia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória/métodos , Testes de Função Respiratória/tendências , Estudos Retrospectivos
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