Asbestos and Iron.

Theories of disease pathogenesis following asbestos exposure have focused on the participation of iron. After exposure, an open network of negatively charged functional groups on the fiber surface complexes host metals with a preference for iron. Competition for iron between the host and the asbestos results in a functional metal deficiency. The homeostasis of iron in the host is modified by the cell response, including increased import to correct the loss of the metal to the fiber surface. The biological effects of asbestos develop in response to and are associated with the disruption of iron homeostasis. Cell iron deficiency in the host following fiber exposure activates kinases and transcription factors, which are associated with the release of mediators coordinating both inflammatory and fibrotic responses. Relative to serpentine chrysotile, the clearance of amphiboles is incomplete, resulting in translocation to the mesothelial surface of the pleura. Since the biological effect of asbestos is dependent on retention of the fiber, the sequestration of iron by the surface, and functional iron deficiency in the cell, the greater clearance (i.e., decreased persistence) of chrysotile results in its diminished impact. An inability to clear asbestos from the lower respiratory tract initiates a host process of iron biomineralization (i.e., asbestos body formation). Host cells attempt to mobilize the metal sequestered by the fiber surface by producing superoxide at the phagosome membrane. The subsequent ferrous cation is oxidized and undergoes hydrolysis, creating poorly crystalline iron oxyhydroxide (i.e., ferrihydrite) included in the coat of the asbestos body.

Interstitial lung abnormalities and interstitial lung diseases associated with cigarette smoking in a rural cohort undergoing surgical resection.

BACKGROUND: Cigarette smoking is a risk factor for interstitial lung abnormalities (ILAs) and interstitial lung diseases (ILDs). Investigation defining the relationships between ILAs/ILDs and clinical, radiographic, and pathologic findings in smokers have been incomplete. Employing a cohort undergoing surgical resection for lung nodules/masses, we (1) define the prevalence of ILAs/ILDs, (2) delineate their clinical, radiographic and pathologic predictors, and (3) determine their associations with mortality. METHODS: Patients undergoing resection of lung nodules/masses between 2017 and 2020 at a rural Appalachian, tertiary medical center were retrospectively investigated. Predictors for ILAs/ILDs and mortality were assessed using multivariate logistic regression analysis. RESULTS: In the total study cohort of 352 patients, radiographic ILAs and ILDs were observed in 35.2% and 17.6%, respectively. Among ILA patterns, subpleural reticular changes (14.8%), non-emphysematous cysts, centrilobular (CL) ground glass opacities (GGOs) (8% each), and mixed CL-GGO and subpleural reticular changes (7.4%) were common. ILD patterns included combined pulmonary fibrosis emphysema (CPFE) (3.1%), respiratory bronchiolitis (RB)-ILD (3.1%), organizing pneumonitis (2.8%) and unclassifiable (4.8%). The group with radiographic ILAs/ILDs had a significantly higher proportion of ever smokers (49% vs. 39.9%), pack years of smoking (44.57 ± 36.21 vs. 34.96 ± 26.22), clinical comorbidities of COPD (35% vs. 26.5%) and mildly reduced diffusion capacity (% predicated 66.29 ± 20.55 vs. 71.84 ± 23). Radiographic centrilobular and paraseptal emphysema (40% vs. 22.2% and 17.6% vs. 9.6%, respectively) and isolated traction bronchiectasis (10.2% vs. 4.2%) were associated with ILAs/ILDs. Pathological variables of emphysema (34.9% vs. 18.5%), any fibrosis (15.9% vs. 4.6%), peribronchiolar metaplasia (PBM, 8% vs. 1.1%), RB (10.3% vs. 2.5%), and anthracosis (21.6% vs. 14.5%) were associated with ILAs/ILDs. Histologic emphysema showed positive correlations with any fibrosis, RB, anthracosis and ≥ 30 pack year of smoking. The group with ILAs/ILDs had significantly higher mortality (9.1% vs. 2.2%, OR 4.13, [95% CI of 1.84-9.25]). CONCLUSIONS: In a rural cohort undergoing surgical resection, radiographic subclinical ILAs/ILDs patterns were highly prevalent and associated with ever smoking and intensity of smoking. The presence of radiographic ILA/ILD patterns and isolated honeycomb changes were associated with increased mortality. Subclinical ILAs/ILDs and histologic fibrosis correlated with clinical COPD as well as radiographic and pathologic emphysema emphasizing the co-existence of these pulmonary injuries in a heavily smoking population.

Outcomes of Idiopathic Pulmonary Fibrosis Improve with Obesity: A Rural Appalachian Experience.

OBJECTIVES: Obesity can be an independent predictor of fibrosis in tissues, including the liver, heart, and skin. We evaluated a rural Appalachian cohort of idiopathic pulmonary fibrosis (IPF) for its relation to obesity. METHODS: Using American Thoracic Society 2018 diagnostic guidelines, an IPF cohort was systematically identified at an Appalachian academic medical center (2015-2019). The cohort was categorized in subgroups of body mass index (BMI) <30 or BMI ≥30 kg/m2. Demographics, clinical variables, and treatment details were collected retrospectively and evaluated for their associations with obesity. RESULTS: In our IPF cohort (N = 138), a usual interstitial pneumonia pattern was less prevalent in the obese group (n = 49) relative to the nonobese group (69% vs 85%, respectively). The obese group was younger (mean age 73.27 ± 9.12 vs 77.97 ± 9.59 years) and had a higher prevalence of hypertension (90% vs 72%), hyperlipidemia (83% vs 68%), diabetes mellitus (47% vs 25%), sleep-disordered breathing (47% vs 25%), chronic pain disorders (28% vs 15%), and deep vein thrombosis (19% vs 7%). An increased proportion of obese-IPF patients was seen at a tertiary or an interstitial lung disease center, with more surgical lung biopsies performed and incident diagnosis (ie, within 6 months of presentation) assigned. Only a minority of patients underwent lung transplantation (3.6%), all of them from the obese-IPF subgroup. Approximately 30% of the total IPF cohort died, with a lower mortality observed in the obese group (35% vs 20%, P = 0.017). An increasing BMI predicted a better survival in the total IPF cohort (BMI 25-29.9, 20-24.9, and <20 had mortality rates of 20%, 47%, and 75%, respectively; P < 0.001). CONCLUSIONS: Our study represents a first known effort to develop an IPF cohort in a rural Appalachian region. Although they shared an increased burden of comorbidities, the obese subgroup showed less advanced fibrosis with a lower mortality rate relative to nonobese subgroup, suggesting a potential "obesity paradox" in IPF. The study findings significantly advance our understanding of challenges posed by IPF in a rural population that also suffers from an alarming rate of obesity. We highlight the need for the multidisciplinary management of these patients and prospective studies to better define this complex relation.

Echocardiography-Defined Pulmonary Hypertension in Multiple Myeloma: Risk Factors and Impact on Outcomes.

OBJECTIVES: Survival of patients with multiple myeloma (MM) has improved as a result of therapeutic advances. There is evidence that some patients with MM develop pulmonary hypertension (PH). The objective of this study was to identify risk factors of echocardiographic PH and its impact on outcomes of patients with MM. METHODS: We conducted a retrospective study of patients with MM (N = 359) diagnosed between 2000 and 2011 within the Geisinger Medical Center. Chart review was conducted on the subgroup of patients who underwent a transthoracic echocardiogram within 2 years of being diagnosed as having MM. RESULTS: A total of 34% of patients (N = 123/359) underwent transthoracic echocardiogram and 32% (N = 39/123) had echocardiography-defined PH. PH was significantly associated with older age (70.5 vs 65.3 years; P = 0.019), greater left atrial diameter (4.0 vs 3.7 cm; P = 0.025), and a trend toward decreased renal function. PH was not associated with myeloma-specific features. Fewer patients with PH underwent hematopoietic stem cell transplantation compared with those without PH (10% vs 30%; P = 0.018). There was no significant difference in survival between the PH and non-PH groups (P = 0.2775). CONCLUSIONS: Echocardiography-defined PH was found in a sizeable minority of our MM cohort. Although the specific etiology of PH can be determined only through a prospective clinical evaluation, including right heart catheterization, our results suggest that PH in patients with MM is secondary to left heart disease and perhaps impaired renal function. Patients with PH were significantly less likely to undergo hematopoietic stem cell transplantation. Future studies should assess the etiology of PH, its impact on treatment decisions, and prognosis of patients with MM.

Cigarette Smoking, and Blood Monocyte Count Correlate with Chronic Lung Injuries and Mortality.

Background: Cigarette smoking (CS)-related monocytosis contributes to the development of chronic lung injuries via complex mechanisms. We aim to determine correlations between measures of CS and monocytes, their capacities to predict chronic lung diseases, and their associations with mortality. Methods: A single-center retrospective study of patients undergoing surgical resection for suspected lung nodules/masses was performed. CS was quantified as cigarettes smoked per day (CPD), duration of smoking, composite pack years (CPY), current smoking status, and smoking cessation years. A multivariate logistic regression analysis was performed. Results: Of 382 eligible patients, 88% were ever smokers. In this group, 45% were current smokers with mean CPD of 27.2±40.0. CPY and duration of smoking showed positive linear correlations with percentage monocyte count. Physiologically, CPY was associated with progressive obstruction, hyperinflation, and reduced diffusion capacity (DLCO). Across the quartiles of smoking, there was an accumulation of radiologic and histologic abnormalities. Anthracosis and emphysema were associated with CPD, while lung cancer, respiratory bronchiolitis (RB), emphysema, and honeycombing were statistically related to duration of smoking. Analysis using consecutive CPY showed associations with lung cancer (≥10 and <30), fibrosis (≥20 and <40), RB (≥50), anthracosis and emphysema (≥10 and onwards). Percentage monocytes correlated with organizing pneumonia (OP), fibrosis, and emphysema. The greater CPY increased mortality across the groups. Significant predictors of mortality included percentage monocyte, anemia, GERD, and reduced DLCO. Conclusion: Indices of CS and greater monocyte numbers were associated with endpoints of chronic lung disease suggesting a participation in pathogenesis. Application of these easily available metrics may support a chronology of CS-induced chronic lung injuries. While a relative lesser amount of smoking can be associated with lung cancer and fibrosis, greater CPY increases the risk for emphysema. Monocytosis predicted lung fibrosis and mortality. Duration of smoking may serve as a better marker of monocytosis and associated chronic lung diseases.

Peribronchiolar Metaplasia: A Marker of Cigarette Smoke-Induced Small Airway Injury in a Rural Cohort.

Background: Peribronchiolar metaplasia (PBM) is considered a reaction to injury characterized by the proliferation of bronchiolar epithelium into immediately adjacent alveolar walls. While an association of PBM with diffuse interstitial lung diseases has been recognized, the clinical significance of PBM remains uncertain. Methods: A cohort (n = 352) undergoing surgical resection of a lung nodule/mass in a rural area was retrospectively reviewed. Multivariate logistic regression analysis was performed to determine the association of PBM with clinical, physiological, radiographic, and histologic endpoints. Results: In the total study cohort, 9.1% were observed to have PBM as a histologic finding in resected lung tissue (n = 32). All but one of these patients with PBM were ever-smokers with a median of 42 pack years. Clinical COPD was diagnosed in two-thirds of patients with PBM. Comorbid gastroesophageal reflux disease (GERD) was significantly associated with PBM. All patients with PBM demonstrated radiologic and histologic evidence of emphysema. Measures of pulmonary function were not impacted by PBM. Mortality was not associated with the histologic observation of PBM. In a logistic regression model, centrilobular-ground glass opacity interstitial lung abnormality and traction bronchiectasis on the CT scan of the chest and histologic evidence of fibrosis, desquamative interstitial pneumonia and anthracosis all strongly predicted PBM in the cohort. Conclusion: A constellation of radiologic and histologic smoking-related abnormalities predicted PBM in study cohort. This confirms a co-existence of lung tissue responses to smoking including PBM, emphysema, and fibrosis. Acknowledging the physiologically "silent" nature of small airway dysfunction on pulmonary function testing, our findings support PBM as a histologic marker of small-airway injury associated with cigarette smoking.

Cigarette Smoke Particle-Induced Lung Injury and Iron Homeostasis.

It is proposed that the mechanistic basis for non-neoplastic lung injury with cigarette smoking is a disruption of iron homeostasis in cells after exposure to cigarette smoke particle (CSP). Following the complexation and sequestration of intracellular iron by CSP, the host response (eg, inflammation, mucus production, and fibrosis) attempts to reverse a functional metal deficiency. Clinical manifestations of this response can present as respiratory bronchiolitis, desquamative interstitial pneumonitis, pulmonary Langerhans' cell histiocytosis, asthma, pulmonary hypertension, chronic bronchitis, and pulmonary fibrosis. If the response is unsuccessful, the functional deficiency of iron progresses to irreversible cell death evident in emphysema and bronchiectasis. The subsequent clinical and pathological presentation is a continuum of lung injuries, which overlap and coexist with one another. Designating these non-neoplastic lung injuries after smoking as distinct disease processes fails to recognize shared relationships to each other and ultimately to CSP, as well as the common mechanistic pathway (ie, disruption of iron homeostasis).

Metals in air pollution particles decrease whole-blood coagulation time.

The mechanism underlying procoagulative effects of air pollution particle exposure is not known. The authors tested the postulate that (1) the water-soluble components of an air pollution particle could affect whole-blood coagulation time and (2) metals included in this fraction were responsible for this effect. Exposure to the water-soluble fraction of particulate matter (PM), at doses as low as 50 ng/ml original particle, significantly diminished the whole-blood coagulation time. Inclusion of deferoxamine prolonged coagulation time following the exposures to the water-soluble fraction, whereas equivalent doses of ferroxamine had no effect. Except for nickel, all metal sulfates shortened the whole-blood coagulation time. Iron and zinc were two metals with the greatest capacity to reduce the coagulation time, with an effect observed at 10 ng/ml. Finally, in contrast to the anticoagulants citrate and EDTA, their iron complexes were found to be procoagulative. The authors conclude that metals in the water-soluble fraction of air pollution particles decrease whole-blood coagulation time. These metals can potentially contribute to procoagulative effects observed following human exposures to air pollution particles.

Refractory Paraneoplastic Diarrhea Secondary to Adenocarcinoma of the Lung: A Case Report and Literature Review.

Paraneoplastic diarrhea is a commonly described complication of gastrointestinal tract or endocrine malignancies. It is an extremely rare complication of lung adenocarcinoma, with only one previously reported case in the literature. A 46-year-old female with newly diagnosed stage IVb lung adenocarcinoma presented to our intensive care unit in hypovolemic shock with symptoms suggestive of diabetes insipidus (DI) as well as profuse large volume watery diarrhea. Exhaustive serological and microbiological workup revealed the diarrhea to be paraneoplasitc in nature. This case represents the second known case of paraneoplastic diarrhea secondary to lung adenocarcinoma. Clinicians should be aware of this rare phenomenon.

Emerging Risk Profile of Lung Cancer Therapy: Diffuse Alveolar Hemorrhage from Osimertinib.

Osimertinib is an oral epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used primarily in the treatment of metastatic non-small cell lung cancer. It is usually well tolerated with less than 5% of patients developing significant pulmonary toxicity from the medication, typically within the first few months after initiation. Previously reported pulmonary adverse reactions include pneumonitis (nonspecific interstitial pneumonia or other forms of acute interstitial process), fleeting asymptomatic infiltrates on imaging, and eosinophilic pneumonia. We present an interesting case of a 65-year-old female with recurrent metastatic adenocarcinoma of the lung, treated with Osimertinib for 4 months, who developed a previously unreported toxicity of diffuse alveolar hemorrhage (DAH) requiring mechanical ventilatory support.

Derivation and Validation of a Prognostic Model to Predict 6-Month Mortality in an Intensive Care Unit Population.

RATIONALE: Identification of terminally ill patients in the intensive care unit (ICU) would facilitate decision making and timely palliative care. OBJECTIVES: To develop and validate a patient-specific integrated prognostic model to predict 6-month mortality in medical ICU patients. METHODS: A longitudinal prospective cohort study of temporally split samples of 1,049 consecutive medical ICU patients in a tertiary care hospital was performed. For each patient, we collected demographic data, Acute Physiology and Chronic Health Evaluation III score, Charlson comorbidity index, intensivist response to a surprise question (SQ; "Would I be surprised if this patient died in the next 6 months?") on admission, and vital status at 6 months. RESULTS: Between November 2013 and May 2015, derivation and validation cohorts of 500 and 549 consecutive patients were studied to develop a multivariate logistic regression model. In the multivariate logistic regression model, Charlson comorbidity index (P = 0.033), Acute Physiology and Chronic Health Evaluation III score (P < 0.001), and SQ response (P < 0.001) were predictors of vital status at 6 months. The odds of dying within 6 months were significantly higher when the SQ was answered "no" than when it was answered "yes" (odds ratio, 7.29; P < 0.001). The c-statistic for the derivation and validation cohorts were 0.832 (95% confidence interval, 0.795-0.870) and 0.84 (95% confidence interval, 0.806-0.875), respectively. CONCLUSIONS: Our integrated prognostic model, which includes the SQ, has strong discrimination and calibration to predict 6-month mortality in medical ICU patients. This model can aid clinicians in identifying ICU patients who may benefit from the integration of palliative care into their treatment.

Iron, human growth, and the global epidemic of obesity.

Iron is an essential nutrient utilized in almost every aspect of cell function and its availability has previously limited life. Those same properties which allow iron to function as a catalyst in the reactions of life also present a threat via generation of oxygen-based free radicals. Accordingly; life exists at the interface of iron-deficiency and iron-sufficiency. We propose that: (1) human life is no longer positioned at the limits of iron availability following several decades of fortification and supplementation and there is now an overabundance of the metal among individuals of many societies; (2) this increased iron availability exerts a positive effect on growth by targeting molecules critical in regulating the progression of the cell cycle; there is increased growth in humans provided greater amounts of this metal; and indices of obesity can positively correlate with body stores of iron; and (3) diseases of obesity reflect this over-abundance of iron. Testing potential associations between iron availability and both obesity and obesity-related diseases in populations will be difficult since fortification and supplementation is so extensively practiced.

Lung injury after cigarette smoking is particle related.

The specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking are yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure to and retention of particles produced during smoking and 2) the biological effects of particles associated with cigarette smoking share a single mechanism of injury with all particles. Smoking one cigarette exposes the human respiratory tract to between 15,000 and 40,000 µg particulate matter; this is a carbonaceous product of an incomplete combustion. There are numerous human exposures to other particles, and these vary widely in composition, absolute magnitude, and size of the particle. Individuals exposed to all these particles share a common clinical presentation with a loss of pulmonary function, increased bronchial hyperresponsiveness, pathologic changes of emphysema and fibrosis, and comorbidities, including cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and cancers. Mechanistically, all particle exposures produce an oxidative stress, which is associated with a series of reactions, including an activation of kinase cascades and transcription factors, release of inflammatory mediators, and apoptosis. If disease associated with cigarette smoking is recognized to be particle related, then certain aspects of the clinical presentation can be predicted; this would include worsening of pulmonary function and progression of pathological changes and comorbidity (eg, emphysema and carcinogenesis) after smoking cessation since the particle is retained in the lung and the exposure continues.

MRT letter: Auto-fluorescence by human alveolar macrophages after in vitro exposure to air pollution particles.

Macrophages from smokers demonstrate an increased auto-fluorescence. Similarly, auto-fluorescence follows in vitro exposure of macrophages to cigarette smoke condensate (i.e., the particulate fraction of cigarette smoke). The composition of particles in cigarette smoke can be comparable to air pollution particles. We tested the postulate that macrophages exposed to air pollution particles could demonstrate auto-fluorescence. Healthy nonsmoking and healthy smoking volunteers (both 18-40 years of age) underwent fiberoptic bronchoscopy with bronchoalveolar lavage and alveolar macrophages isolated. Macrophages were incubated at 37 degrees C in 5% CO(2) with either PBS or 100 microg/mL particle for both 1 and 24 h. Particles included a residual oil fly ash, Mt. St. Helens volcanic ash, and ambient air particles collected from St. Louis, Missouri and Salt Lake City, Utah. At the end of incubation, 50 microL of the cell suspension was cytocentrifuged and examined at modes for viewing fluorescein isothiocyanate (FITC) and rhodamine fluorescence. Both emission source air pollution particles demonstrated FITC and rhodamine auto-fluorescence at 1 and 24 h, but the signal following incubation of the macrophages with oil fly ash appeared greater. Similarly, the ambient particles were associated with auto-fluorescence by the alveolar macrophages and this appeared to be dose-dependent. We conclude that exposure of macrophages to air pollution particles can be associated with auto-fluorescence in the FITC and rhodamine modes.