Patients With Idiopathic Pulmonary Fibrosis Admitted to the ICU With Acute Respiratory Failure-A Reevaluation of the Risk Factors and Outcomes.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) patients admitted to the ICU with acute respiratory failure (ARF) are known to have a poor prognosis. However, the majority of the studies published to date are older and had small sample sizes. Given the advances in ICU care since the publication of these studies, we sought to reevaluate the outcomes and risk factors associated with mortality in these patients. METHODS: Retrospective study using a large multi-center ICU database. We identified 411 unique patients with IPF admitted with ARF between 2014-2015. RESULTS: Of all IPF patients admitted to the ICU with ARF, 81.3% required mechanical ventilation (MV): 48.9% invasive and 32.4% non-invasive alone. The hospital mortality rate was 34.5% for all patients; 48.8% in patients requiring invasive MV, 21.8% in those requiring non-invasive MV and 19.5% with no MV. In multiple regression analyses, age, APACHE score, invasive MV, and hyponatremia at admission were associated with increased mortality whereas post-op status was associated with lower mortality. In patients requiring invasive MV, baseline PaO2/FiO2 ratio was also predictive of mortality. Non-pulmonary organ failures were present in less than 20% of the patients. CONCLUSIONS: Although the overall mortality rate for IPF patients admitted to the ICU with ARF has improved, the mortality rates for patients requiring invasive MV remains high at approximately 50%. Older age, high APACHE score, and low baseline PaO2/FiO2 ratio are factors predictive of increased mortality in this population.

Current Trends in Sepsis-Related Mortality in the United States.

OBJECTIVES: Sepsis is a life-threatening condition and is one of the leading causes of death in the United States. The burden of sepsis-related mortality in the United States in recent years is not well characterized. We sought to describe sepsis-related mortality rates and mortality trends in the United States from 2005 to 2018. DESIGN: Retrospective population-based study. SETTING: We used the Multiple Cause of Death Database available through the Centers for Disease Control and Prevention website. PATIENTS: Decedents with sepsis-related deaths were identified using previously validated International Classification of Diseases codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From 2005 to 2018, 6.7% of decedents had a diagnosis of sepsis. The overall sepsis-related mortality rates remained stable in both males (57 deaths per 100,000) and females (45.1 deaths per 100,000) during this period. Compared with Whites, the sepsis-related mortality rates were higher in Blacks (rate ratio = 1.78), Native Americans (rate ratio = 1.43), and Hispanics (rate ratio = 1.04) and were lower in Asians (rate ratio = 0.73). Sepsis-related mortality rates declined in Blacks, Hispanics, and Asians but increased in Whites and Native Americans. The majority of sepsis-related deaths occurred in the hospital. The percentage of deaths in the nursing home decreased, whereas deaths occurring at home and hospice increased. CONCLUSIONS: From 2005 to 2018, the overall sepsis-related mortality rates were stable, but there were significant racial and gender disparities in mortality trends. Further research is needed to evaluate the genetic and environmental contributors to these differences.

Characteristics and Outcomes of Patients With and Without Type 2 Diabetes Mellitus and Pulmonary Sepsis.

PURPOSE: To date, studies have provided conflicting results regarding the impact of type 2 diabetes mellitus (DM) on sepsis-related outcomes. Our objective is to understand the impact of type 2 DM in bacterial pneumonia and sepsis-related intensive care unit (ICU) outcomes. METHODS: Retrospective study using Multiparameter Intelligent Monitoring in Intensive Care III database. We included 1698 unique patients admitted with sepsis secondary to bacterial pneumonia to the ICU within the time period of 2001 to 2012. RESULTS: The type 2 DM group had an increased incidence of acute kidney injury (67.9% vs 58.1%, P < .01) and need for dialysis compared to the non-DM group. There was no difference in mortality, microbiology, other organ failure, or hospital length of stay between the type 2 DM and non-DM group. Lower admission blood glucose was associated with increased mortality in patients with type 2 DM (49% at ≤120 mg/dL, 35.1% at 121-180 mg/dL, and 32.1% at >180 mg/dL) but not in non-DM patients. Conversely, higher mean glucose during the hospital stay was associated with increased mortality in non-DM patients (24.7% at ≤120 mg/dL, 45.1% at 121-180 mg/dL, and 73.0% at >180 mg/dL) but not in patients with type 2 DM. CONCLUSIONS: Our findings demonstrated that type 2 DM does not increase the overall mortality. Our findings of increased mortality in both type 2 DM patients with lower admission glucose, and non-DM patients with higher mean glucose during the hospital stay needs to be further evaluated. Future studies in regards to this could lead to personalized glucose treatment goals for patients.

Connective Tissue Disease-Related Interstitial Lung Disease: Prevalence, Patterns, Predictors, Prognosis, and Treatment.

Interstitial lung disease is a common pulmonary manifestation of connective tissue diseases and results in significant morbidity and mortality. Although all connective tissue diseases are linked by underlying autoimmunity, there is significant variability in the presentation and clinical course of interstitial lung disease associated with the different types of connective tissue diseases. In this paper, we review the prevalence, patterns, predictors, and prognosis of interstitial lung disease secondary to the most common forms of connective tissue diseases. We have also highlighted the available evidence regarding treatment options for interstitial lung disease due to different connective tissue diseases.

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed.

Murine models of pulmonary arterial hypertension (PAH) that recapitulate the plexiform and obliterative arteriopathy seen in PAH patients and help in defining the molecular mechanisms involved are missing. Herein, we investigated whether intersectin-1s (ITSN) deficiency and prolonged lung expression of an ITSN fragment with endothelial cell (EC) proliferative potential (EHITSN), present in the lungs of PAH animal models and human patients, induce formation of plexiform/obliterative lesions and defined the molecular mechanisms involved. ITSN-deficient mice (knockout/heterozygous and knockdown) were subjected to targeted lung delivery of EHITSN via liposomes for 20 days. Immunohistochemistry and histological and morphometric analyses revealed a twofold increase in proliferative ECs and a 1.35-fold increase in proliferative α-smooth muscle actin-positive cells in the lungs of ITSN-deficient mice, transduced with the EHITSN relative to wild-type littermates. Treated mice developed severe medial wall hypertrophy, intima proliferation, and various forms of obliterative and plexiform-like lesions in pulmonary arteries, similar to PAH patients. Hemodynamic measurements indicated modest increases in the right ventricular systolic pressure and right ventricle hypertrophy. Transcriptional and protein assays of lung tissue indicated p38MAPK-dependent activation of Elk-1 transcription factor and increased expression of c-Fos gene. This unique murine model of PAH-like plexiform/obliterative arteriopathy induced via a two-hit pathophysiological mechanism without hypoxia provides novel druggable targets to ameliorate and, perhaps, reverse the EC plexiform phenotype in severe human PAH.

Intersectin-1s deficiency in pulmonary pathogenesis.

Intersectin-1s (ITSN-1s), a multidomain adaptor protein, plays a vital role in endocytosis, cytoskeleton rearrangement and cell signaling. Recent studies have demonstrated that deficiency of ITSN-1s is a crucial early event in pulmonary pathogenesis. In lung cancer, ITSN-1s deficiency impairs Eps8 ubiquitination and favors Eps8-mSos1 interaction which activates Rac1 leading to enhanced lung cancer cell proliferation, migration and metastasis. Restoring ITSN-1s deficiency in lung cancer cells facilitates cytoskeleton changes favoring mesenchymal to epithelial transformation and impairs lung cancer progression. ITSN-1s deficiency in acute lung injury leads to impaired endocytosis which leads to ubiquitination and degradation of growth factor receptors such as Alk5. This deficiency is counterbalanced by microparticles which, via paracrine effects, transfer Alk5/TGFßRII complex to non-apoptotic cells. In the presence of ITSN-1s deficiency, Alk5-restored cells signal via Erk1/2 MAPK pathway leading to restoration and repair of lung architecture. In inflammatory conditions such as pulmonary artery hypertension, ITSN-1s full length protein is cleaved by granzyme B into EHITSN and SH3A-EITSN fragments. The EHITSN fragment leads to pulmonary cell proliferation via activation of p38 MAPK and Elk-1/c-Fos signaling. In vivo, ITSN-1s deficient mice transduced with EHITSN plasmid develop pulmonary vascular obliteration and plexiform lesions consistent with pathological findings seen in severe pulmonary arterial hypertension. These novel findings have significantly contributed to understanding the mechanisms and pathogenesis involved in pulmonary pathology. As demonstrated in these studies, genetically modified ITSN-1s expression mouse models will be a valuable tool to further advance our understanding of pulmonary pathology and lead to novel targets for treating these conditions.

Impact of End-Stage Renal Disease and Acute Kidney Injury on ICU Outcomes in Patients With Sepsis.

PURPOSE: To report the characteristics and outcomes of patients with sepsis in the intensive care unit (ICU) with end-stage renal disease (ESRD) and acute kidney injury (AKI) compared to patients with nonkidney injury (non-KI). METHODS: Retrospective study of all patients with sepsis admitted to the ICU of a university hospital within a 12-month time period. Data were obtained from the University Health Consortium database and a chart review of the electronic medical records. RESULTS: We identified 39 cases of ESRD, 106 cases of AKI, and 103 cases of non-KI. Intensive care unit mortality was 15.4% for ESRD, 30.2% for AKI, and 13.6% for non-KI ( P < .01). Hospital mortality was 20.5% for ESRD, 32.1% for AKI, and 13.6% for non-KI ( P < .01). Early AKI and late AKI had an ICU mortality of 24.4% versus 50% ( P <.01), hospital mortality of 26.8% versus 50% ( P = .03), ICU length of stay (LOS) of 3 and 6 days ( P = .04), and hospital LOS of 7 and 12.5 days ( P <.01), respectively. CONCLUSION: Patients with sepsis having AKI have a higher mortality rate than those with ESRD and non-KI. Hospital and ICU mortality rates for patients with ESRD were similar to non-KI patients. Late AKI compared to early AKI had a higher mortality and longer LOS.

Rac1-mediated cytoskeleton rearrangements induced by intersectin-1s deficiency promotes lung cancer cell proliferation, migration and metastasis.

BACKGROUND: The mechanisms involved in lung cancer (LC) progression are poorly understood making discovery of successful therapies difficult. Adaptor proteins play a crucial role in cancer as they link cell surface receptors to specific intracellular pathways. Intersectin-1s (ITSN-1s) is an important multidomain adaptor protein implicated in the pathophysiology of numerous pulmonary diseases. To date, the role of ITSN-1s in LC has not been studied. METHODS: Human LC cells, human LC tissue and A549 LC cells stable transfected with myc-ITSN-1s construct (A549 + ITSN-1s) were used in correlation with biochemical, molecular biology and morphological studies. In addition scratch assay with time lapse microscopy and in vivo xenograft tumor and mouse metastasis assays were performed. RESULTS: ITSN-1s, a prevalent protein of lung tissue, is significantly downregulated in human LC cells and LC tissue. Restoring ITSN-1s protein level decreases LC cell proliferation and clonogenic potential. In vivo studies indicate that immunodeficient mice injected with A549 + ITSN-1s cells develop less and smaller metastatic tumors compared to mice injected with A549 cells. Our studies also show that restoring ITSN-1s protein level increases the interaction between Cbl E3 ubiquitin ligase and Eps8 resulting in enhanced ubiquitination of the Eps8 oncoprotein. Subsequently, downstream unproductive assembly of the Eps8-mSos1 complex leads to impaired activation of the small GTPase Rac1. Impaired Rac1 activation mediated by ITSN-1s reorganizes the cytoskeleton (increased thick actin bundles and focal adhesion (FA) complexes as well as collapse of the vimentin filament network) in favor of decreased LC cell migration and metastasis. CONCLUSION: ITSN-1s induced Eps8 ubiquitination and impaired Eps8-mSos1 complex formation, leading to impaired activation of Rac1, is a novel signaling mechanism crucial for abolishing the progression and metastatic potential of LC cells.

Interstitial lung disease hospitalizations, outcomes, and costs in the United States from 2008 to 2018.

BACKGROUND: Interstitial lung diseases (ILD) are associated with frequent hospitalizations, however, limited studies have evaluated the hospitalization rates and outcomes. STUDY DESIGN AND METHODS: We extracted hospitalization data for ILD patients using the National Inpatient Sample Database. Regression models were used to assess trends in hospitalizations and outcomes. RESULTS: There were 345,063 hospitalizations with a principal diagnosis of ILD from 2008 to 2018. Hospitalization rates were higher in females, older age groups, and those living in rural areas. Rates were lower in those with income levels at or above the median and in the western U.S. Of those hospitalized, 5.1 % died, and ∼37 % required skilled nursing facility/home health. Deaths were lower among females and in those with Medicaid and private insurance. Rates were higher in the older age groups, those with median and above income levels, and those living in medium/small metro and rural areas. The overall hospitalization rate decreased by ∼23 % during this period. The percentage of deaths remained stable (except in rural hospitals) during this period. The average length of stay (LOS) was 5.5 days. The average hospital cost was $10,438 which increased by ∼38 %. INTERPRETATION: Hospitalizations for ILD have been decreasing, however, the death percentage has been stable. The LOS has remained stable, but hospital costs have been increasing. We identified differences in ILD hospitalization rates and outcomes/costs based on patient and hospital characteristics. Identifying the causes for these differences would be important in reducing health disparities in ILD patients. CLINICAL TRIAL REGISTRATION: n/a.

Acute hemorrhagic leukoencephalopathy associated with influenza A (H1N1) virus.

BACKGROUND: Acute hemorrhagic leukoencephalopathy (AHLE) is a rare condition associated with H1N1. In this condition the infection triggers an autoimmune response which results in perivascular demyelination and hemorrhage in the brain parenchyma. METHODS: We report a case of a patient who developed brain edema and herniation as a result of AHLE. RESULTS: A 27-year-old presented to a community hospital with fever, dyspnea, and malaise and was found to have H1N1-associated pneumonia. Despite treatment he progressed to acute respiratory distress syndrome and required mechanical ventilation. Due to failure on conventional ventilation, he was transferred to our hospital and was placed on high-frequency oscillatory ventilation. He was showing improvement until day 6 of transfer to our hospital when he was suddenly noted to have a rise in his blood pressure followed by hypotension. The following morning he was noted to have non-reactive pupils and was declared brain dead. Autopsy of the brain was consistent with AHLE. CONCLUSIONS: This case emphasizes the importance of awareness of this disease. The non-specific signs and symptoms, and the use of sedatives, make diagnosis challenging in the early stages of this disease. If suspected early, appropriate imaging can aid in the diagnosis. Treatment with immunosuppressive agents and plasmapheresis may prevent rapid progression and death. This is the first published case of AHLE in association with H1N1 that has been confirmed pathologically.

A Cross-Sectional Survey of Pulmonologists Working at Non-ILD Centers in the United States.

The purpose of this cross-sectional short report study was to evaluate the perception of pulmonologist working in noninterstitial lung disease centers on challenges (COE) encountered in daily practice. Results of this survey revealed that only 40% of their patients are referred to an ILD COE, out of 69% who have access to an ILDCOE. Of these patients who were referred, the perceived benefits were rated high when it comes to having an accurate diagnosis.

The prevalence and burden of interstitial lung diseases in the USA.

Interstitial lung diseases (ILDs) are a significant contributor to disability and deaths in the USA. The prevalence and deaths from ILDs have increased but when adjusted for age, have been stable since 2010. https://bit.ly/3IDlZrg.

Assessing population interest in interstitial lung diseases in the USA using Google Trends.

Google Trends is a useful tool for evaluating the public interest in interstitial lung diseases (ILD). The interest in ILD is much lower compared to lung cancer although both conditions are associated with significant morbidity and mortality. https://bit.ly/38QzPce.

The association of lung cancer with pulmonary fibrosis.

In this study using a large database of US decedents, the overall presence of lung cancer was lower in those with idiopathic pulmonary fibrosis compared to those without idiopathic pulmonary fibrosis https://bit.ly/30d6dC4.

Sepsis-Related Mortality Rates and Trends Based on Site of Infection.

Sepsis is defined as life-threatening organ dysfunction triggered by an underlying infection. A recent study noted that the overall sepsis-related mortality rate in the United States is stable. In this study, we evaluated the sepsis-related mortality rates and trends associated with the three most common sites of infection. DESIGN: Retrospective population-based study. SETTING: Multiple Cause of Death (MCOD) database available through the Centers for Disease Control and Prevention website. PATIENTS: Decedents with sepsis-related deaths and the source of sepsis were identified using previously validated International Classification of Diseases codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From 2004 to 2018, using the MCOD, the age-adjusted mortality rate per 1,000,000 population from pulmonary sepsis was 111.8, from abdominal sepsis was 46.7, and from genitourinary sepsis was 52. Mortality rates from all three sites increased. Males had a higher mortality rate from pulmonary sepsis and abdominal sepsis and lower mortality rate from genitourinary sepsis. Black and Native American decedents had the highest mortality rates from all three sepsis sites. Compared with White decedents, Hispanic decedents had a higher mortality rate from pulmonary sepsis but lower rate from genitourinary sepsis. Asian decedents had the lowest mortality rates from abdominal and genitourinary sepsis but similar mortality rates from pulmonary sepsis as White decedents. The mortality rate increased in White and Native American decedents for all three sepsis sites, whereas in Hispanic decedents only abdominal and genitourinary sites increased, and in Black and Asian decedents only abdominal sepsis rates increased. CONCLUSIONS: Despite the overall stable sepsis-related mortality rates, the rates secondary to pulmonary, abdominal, and genitourinary sepsis are increasing in both sexes and all age groups. This is likely due to improved identification/documentation of a site of infection in patients with sepsis. We noted significant racial variation in mortality rates/trends, which should be considered in future studies.

Mortality differences in pulmonary fibrosis among the most populated states in the United States.

BACKGROUND: Recent studies suggest that the mortality rate of pulmonary fibrosis (PF) in the U.S. is decreasing. However, the mortality trends and demographic differences of PF among the states have not been evaluated. OBJECTIVE: To evaluate PF-related mortality rates and trends in the nine most populated states in the U.S. METHODS: Population-based study using the Multiple Cause of Death Database available through the Centers for Disease Control and Prevention website. PF-related deaths were identified using ICD codes. RESULTS: From 2004 to 2018, average annual mortality rates ranged from being the lowest in New York (110.8 per 1,000,000) to the highest in North Carolina (195.3 per 1,000,000). The mortality rates showed a decline in the majority of the states and were stable in the other states. The most significant declines were in California and Michigan. The average mortality rates in males were higher than females in all the states (rate ratio ranged from 1.56 in Texas to 1.81 in New York) and the decline in the mortality rates was more pronounced compared to males in most states. The mortality rates in Blacks were lower compared to Whites in all the states (rate ratio ranged from 0.47 in New York to 0.69 in Ohio) and the decline in the mortality rates over the period was more significant than in Whites. CONCLUSIONS: There is substantial variation in mortality rates and mortality trends between states and different demographics. Further studies are needed to evaluate the environmental factors, diagnostic accuracy, and coding practices contributing to these differences.

Rheumatoid Arthritis and Associated Interstitial Lung Disease: Mortality Rates and Trends.

Rationale: The burden of rheumatoid arthritis (RA) and RA-associated interstitial lung disease (RA-ILD) in recent years has not been well characterized. Objectives: In this study, we sought to describe RA- and RA-ILD-related mortality rates and trends in the United States from 2005 to 2018, stratified by demographics. Methods: We used the Multiple Cause of Death Database available through the Centers for Disease Control and prevention website, which contains data of all deceased U.S. residents. RA- and RA-ILD-related deaths were identified using International Classification of Diseases, 10th Revision, codes. We examined the age-adjusted mortality rates and trends stratified by demographics. Results: RA- and RA-ILD-related mortality rates were higher in women and older age groups. However, the prevalence of ILD was higher in male decedents with RA compared with female decedents with RA (13.3% vs. 8.7%). RA-related mortality rates were the highest in Native American individuals followed by White individuals. Compared with White individuals, Hispanic individuals had lower RA-related mortality rates but higher RA-ILD-related mortality rates. Overall RA-related mortality rates per 1,000,000 population members decreased from 30.6 in 2005 to 22.2 in 2018. RA-related mortality rates declined in both sexes, all races, and all age groups. However, RA-ILD-related mortality rates remained stable in both sexes, all races, and all age groups except for the group aged 65 to 84 years, in which the rates declined. Conclusions: The overall RA-related mortality rates are decreasing; however, RA-ILD-related mortality rates remain stable except in the group aged 65-84 years. This would suggest that therapies for RA and improvement in the management of other comorbidities have improved the overall outcomes in patients with RA but have had limited effect in the subgroup of patients with RA-ILD.

Mortality Trends of Idiopathic Pulmonary Fibrosis in the United States From 2004 Through 2017.

BACKGROUND: The burden of idiopathic pulmonary fibrosis (IPF)-related mortality in the United States in recent years is not well characterized. RESEARCH QUESTION: What are the trends in IPF-related mortality rates in the United States from 2004 through 2017? STUDY DESIGN AND METHODS: We used the Multiple Cause of Death Database available through the Centers for Disease Control and Prevention website, which contains data from all deceased US residents. IPF-related deaths were identified using International Classification of Diseases, 10th revision, codes. We examined annual trends in age-adjusted mortality rates stratified by age, sex, race, and state of residence. We also evaluated trends in place of death and underlying cause of death. RESULTS: From 2004 through 2017, the age-adjusted mortality decreased by 4.1% in men (from 75.5 deaths/1,000,000 in 2004 to 72.4 deaths/1,000,000 in 2017) and by 13.4% in women (from 46.3 deaths/1,000,000 in 2004 to 40.1 deaths/1,000,000 in 2017). This overall decrease was driven mainly by a decline in IPF-related mortality in patients younger than 85 years. The decreasing trend also was noted in all races except White men, in whom the rate remained stable. The most common cause of death was pulmonary fibrosis. The percentage of deaths occurring in the inpatient setting and nursing homes decreased, whereas the percentage of deaths occurring at home and hospice increased. INTERPRETATION: From 2004 through 2017, the IPF age-adjusted mortality rates decreased. This may be explained partly by a decline in smoking in the United States, but further research is needed to evaluate other environmental and genetic contributors.

The characteristics and outcomes of patients with idiopathic pulmonary fibrosis admitted to the ICU with acute respiratory failure.

BACKGROUND: To date, studies have provided conflicting results regarding the outcomes of patients with Idiopathic Pulmonary Fibrosis (IPF) admitted to the ICU with acute respiratory failure (ARF). OBJECTIVE: To understand the characteristics and outcomes of these patients. METHODS: Retrospective study using a large single-center ICU database. We identified 48 unique patients with IPF admitted for ARF from 2001-2012. RESULTS: The most common causes of ARF were IPF exacerbation and pneumonia. The overall hospital mortality rate was 43.8% and was 56.7% in those who required invasive mechanical ventilation (IMV). In patients requiring IMV for IPF exacerbation, the mortality rate was 81.3%. In multiple regression analysis, the presence of diabetes mellitus was associated with decreased mortality whereas the need for IMV was associated with increased mortality. CONCLUSIONS: Although the overall mortality rate for IPF patients with ARF has improved, the need for IMV due to IPF exacerbations is associated with increased mortality.