Craig E. Daniels

Incidence, Prevalence, and Clinical Course of Idiopathic Pulmonary Fibrosis: A Population-Based Study

BACKGROUND Limited data exist regarding the population-based epidemiology of idiopathic pulmonary fibrosis (IPF). The objective of the study was to describe the trends in the incidence, prevalence, and clinical course of IPF in the community. METHODS We conducted a population-based study of adult patients with IPF in Olmsted County, Minnesota, from 1997 to 2005. Two methods were used to identify IPF cases, as defined by the 2002 American Thoracic Society/European Respiratory Society consensus statement: (1) usual interstitial pneumonia (UIP) on a surgical lung biopsy specimen or a definite UIP pattern on a high-resolution CT image (narrow criteria) and (2) UIP on a surgical lung biopsy specimen or a definite or possible UIP pattern on CT image (broad criteria). RESULTS Of 596 patients screened for the possibility of pulmonary disease or pulmonary fibrosis over 9 years of follow-up, 47 cases had IPF. Of these, 24 met the narrow criteria. The age- and sex-adjusted incidence was 8.8/100,000 and 17.4/100,000 person-years, for narrow and broad criteria, respectively. The age-adjusted incidence was higher in men than in women, and among patients aged 70-79 years. During the study period, the incidence of IPF decreased (P < .001). On December 31, 2005, the age- and sex-adjusted prevalence was 27.9/100,000 and 63/100,000 persons by narrow and broad criteria, respectively. Thirty-seven patients experienced a total of 53 respiratory exacerbations (26 IPF related, 27 non-IPF related), and 34 (72%) patients died. The primary cause of death was IPF related in 16 (47%) patients. Median survival for narrow-criteria and broad-criteria incidence cases was 3.5 and 4.4 years, respectively. CONCLUSIONS The incidence of IPF in Olmsted County decreased over the study period. Nonprimary IPF respiratory exacerbations are as frequent as primary IPF respiratory exacerbations and an important cause of death.

Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis

Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Prior efforts to treat idiopathic pulmonary fibrosis that focused on anti-inflammatory therapy have not proven to be effective. Recent insight suggests that the pathogenesis is mediated through foci of dysregulated fibroblasts driven by profibrotic cytokine signaling. TGF-beta and PDGF are 2 of the most potent of these cytokines. In the current study, we investigated the role of TGF-beta-induced fibrosis mediated by activation of the Abelson (Abl) tyrosine kinase. Our data indicate that fibroblasts respond to TGF-beta by stimulating c-Abl kinase activity independently of Smad2/3 phosphorylation or PDGFR activation. Moreover, inhibition of c-Abl by imatinib prevented TGF-beta-induced ECM gene expression, morphologic transformation, and cell proliferation independently of any effect on Smad signaling. Further, using a mouse model of bleomycin-induced pulmonary fibrosis, we found a significant inhibition of lung fibrosis by imatinib. Thus, Abl family members represent common targets for the modulation of profibrotic cytokine signaling.

Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results.

RATIONALE Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no known efficacious therapy. Imatinib is a tyrosine kinase inhibitor with potential efficacy to treat fibrotic lung disease. OBJECTIVES To investigate the safety and clinical effects of imatinib in patients with IPF. METHODS We studied 119 patients in an investigator-initiated, multicenter, multinational, double-blind clinical trial to receive imatinib or placebo for 96 weeks. MEASUREMENTS AND MAIN RESULTS Over 96 weeks of follow-up, imatinib did not differ significantly from placebo (log rank P = 0.89) for the primary endpoint defined as time to disease progression (10% decline in percent predicted FVC from baseline) or time to death. There was no effect of imatinib therapy on change in FVC at 48, 72, or 96 weeks (P > or = 0.39 at all time points) or change in diffusing capacity of carbon monoxide at 48, 72, or 96 weeks (P > or = 0.26 at all time points). Change in resting Pa(O(2)) favored imatinib therapy at 48 weeks (P = 0.005) but not at 96 weeks (P = 0.074). During the 96-week trial there were 8 deaths in the imatinib group and 10 deaths in the placebo group (log rank test P = 0.64). Thirty-five (29%) patients discontinued the study without reaching the primary endpoint (imatinib, 32%; placebo, 27%; P = 0.51). Serious adverse events (SAEs) were not more common in the imatinib group (imatinib, 18 SAEs in 17 patients; placebo, 19 SAEs in 18 patients). CONCLUSIONS In a randomized, placebo-controlled trial of patients with mild to moderate IPF followed for 96 weeks, imatinib did not affect survival or lung function. Clinical trial registered with www.clinicaltrials.gov (NCT00131274).

Reducing Iatrogenic Risk in Thoracentesis: Establishing Best Practice Via Experiential Training in a Zero-Risk Environment

BACKGROUND We studied the reasons why patients undergoing thoracenteses performed in our outpatient pulmonary clinic had a higher frequency of iatrogenic pneumothorax compared to that in the concurrent radiology practice in our institution, which utilizes ultrasound guidance. We reviewed our practice model and implemented a unique experiential training paradigm in a zero-risk simulation environment to improve efficacy, timeliness, service orientation, and safety. METHODS We retrospectively determined the rate of clinically significant pneumothoraces in our practice (phase I, July 1, 2001, to June 30, 2002). The training system redesign included the following: (1) a designated group of pulmonologist instructors dedicated to treating pleural disease and reducing the number of iatrogenic complications; (2) the use of ultrasound image guidance for all thoracenteses; and (3) structured proficiency and competency standards for proceduralists. Postintervention (phase II) data were prospectively collected (January 2005 to December 2006) and compared with our baseline data. RESULTS The baseline rate of pneumothorax was 8.6% (5 of 58 patients) in our pulmonary practice. Following intervention (phase II), the rate of pneumothorax declined to 1.1% (p = 0.0034). During phase II, the number of thoracenteses performed increased (186 vs 58 per year, respectively; p < 0.05). The iatrogenic pneumothorax rate was stable in the 2 years following intervention (2005, 0.7% [1 of 137 pneumothoraces]; 2006, 1.3% [3 of 226 pneumothoraces]; p > 0.9). Postintervention complications included procedure-related pain (n = 19), cough (n = 4), and hypotension (n = 10). CONCLUSIONS An improvement program that included simulation, ultrasound guidance, competency testing, and performance feedback reduced iatrogenic risk to patients. We recommend application of this process to procedural practices.

Does interstitial lung disease predispose to lung cancer

Purpose of review This review examines the evidence for the causality and pathogenesis of lung cancer associated with interstitial lung disease. Recent findings Although cigarette smoking is the leading cause of lung cancer, several other conditions either predispose to lung cancer or increase the risk of lung cancer in smokers. The evidence supports an increased risk of lung cancer due to specific fibrotic and inflammatory lung diseases (termed interstitial lung diseases), including idiopathic pulmonary fibrosis, systemic sclerosis, and certain pneumoconioses. The potential pathogenetic mechanisms indicate that recurrent injury and inflammation result in genetic alterations that predispose to lung cancer. Summary Idiopathic pulmonary fibrosis, systemic sclerosis, and certain pneumoconioses are associated with an independent increased risk of lung cancer; however, a unifying pathogenetic mechanism to explain the causality of this association has not been described. In addition, the inconsistently reported lung cancer frequencies call attention to the need for prospective studies of good quality.

Pleural Fluid Characteristics of Chylothorax

OBJECTIVE To determine the biochemical parameters of chylous pleural fluids and better inform current clinical practice in the diagnosis of chylothorax. PATIENTS AND METHODS We retrospectively reviewed 74 patients with chylothorax (defined by the presence of chylomicrons) who underwent evaluation during a 10-year period from January 1, 1997, through December 31, 2006. The biochemical parameters and appearance of the fluid assessed during diagnostic evaluation were analyzed. RESULTS The study consisted of 37 men (50%) and 37 women (50%), with a median age of 61.5 years (range, 20-93 years). Chylothorax was caused by surgical procedures in 51%. The chylous pleural fluid appeared milky in only 44%. Pleural effusion was exudative in 64 patients (86%) and transudative in 10 patients (14%). However, pleural fluid protein and lactate dehydrogenase levels varied widely. Transudative chylothorax was present in all 4 patients with cirrhosis but was also seen with other causes. The mean ± SD triglyceride level was 728±797 mg/dL, and the mean ± SD cholesterol value was 66±30 mg/dL. The pleural fluid triglyceride value was less than 110 mg/dL in 10 patients (14%) with chylothorax, 2 of whom had a triglyceride value lower than 50 mg/dL. CONCLUSION Chylothoraces may present with variable pleural fluid appearance and biochemical characteristics. Nonmilky appearance is common. Chylous effusions can be transudative, most commonly in patients with cirrhosis. Traditional triglyceride cutoff values used in excluding the presence of chylothorax may miss the diagnosis in fasting patients, particularly in the postoperative state.

Diagnosis of Interstitial Lung Diseases

Interstitial lung diseases (ILDs), a broad heterogeneous group of parenchymal lung disorders, can be classified into those with known and unknown causes. The definitions and diagnostic criteria for several major forms of ILDs have been revised in recent years. Although well over 100 distinct entities of ILDs are recognized, a limited number of disorders, including idiopathic pulmonary fibrosis, sarcoidosis, and connective tissue disease-related ILDs, account for most ILDs encountered clinically. In evaluating patients with suspected ILD, the clinician should confirm the presence of the disease and then try to determine its underlying cause or recognized clinicopathologic syndrome. Clues from the medical history along with the clinical context and radiologic findings provide the initial basis for prioritizing diagnostic possibilities for a patient with ILD. High-resolution computed tomography of the chest has become an invaluable tool in the diagnostic process. A confident diagnosis can sometimes be made on the basis of high-resolution computed tomography and clinical context. Serologic testing can be helpful in selected cases. Histopathologic findings procured through bronchoscopic or surgical lung biopsy are often needed in deriving a specific diagnosis. An accurate prognosis and optimal treatment strategy for patients with ILDs depend on an accurate diagnosis, one guided by recent advances in our understanding of the causes and pathogenetic mechanisms of ILDs.

Autopsy findings in 42 consecutive patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease that commonly results in respiratory failure and death. However, the cause of death in these patients has not previously been fully defined. The current study reviews the clinical records and pathological findings of 42 consecutive patients with IPF who underwent a post mortem at the Mayo Clinic (Rochester, MN, USA) over a 9-yr period, from January 1996 to December 2004. The median (range) age at post mortem for the patients was 74 (46–98 yrs) yrs, which included 25 (60%) males. A total of 31 (74%) patients died in the hospital. The immediate causes of death were reported as: respiratory (64%), cardiovascular (21%), or noncardiopulmonary (14%). Acute exacerbation of IPF was the most common immediate cause of death (29%). Pneumonia, aspiration and drug-induced lung disease were identified as other causes of respiratory death. Evidence of pulmonary hypertension was present in the post mortem of 19 (45%) patients and was the immediate cause of death in two of these patients. The immediate cause of death was clinically unsuspected in five (12%) patients and IPF was diagnosed post mortem in nine (21%) patients. The majority of patients with idiopathic pulmonary fibrosis who had undergone a post mortem were found to have died from respiratory causes. Acute exacerbation of idiopathic pulmonary fibrosis was found to be the most common cause of death whilst death from the gradual progression of idiopathic pulmonary fibrosis was found to be less common.

B-type natriuretic peptide in the assessment of acute lung injury and cardiogenic pulmonary edema

Objective:The role of plasma B-type natriuretic peptide (BNP) in critically ill patients with acute pulmonary edema is controversial. We postulated that a low BNP level would exclude cardiac dysfunction as the principal cause of pulmonary edema and therefore help in the diagnosis of acute lung injury. Design:A retrospective derivation cohort was followed by a prospective validation cohort of consecutive patients with acute pulmonary edema admitted to three intensive care units. BNP was measured within 24 hrs from onset. Critical care experts blinded to BNP results integrated clinical data with the course of disease and response to therapy and served as the reference standard. Setting:Three intensive care units at the tertiary center. Patients:Consecutive critically ill patients with acute pulmonary edema. Interventions:None. Measurements and Main Results:In a derivation cohort of 84 patients, a BNP threshold of ≤250 pg/mL had a specificity of 87% and sensitivity of 48% for the diagnosis of acute lung injury. High specificity of BNP (90%, likelihood ratio of 3.9) was confirmed in a validation cohort of 120 consecutive patients, 52 (43%) of whom had acute lung injury. Notably, 32% of patients with acute lung injury had concomitant cardiac dysfunction. The median time from the onset of pulmonary edema to BNP testing was 3 hrs. The accuracy of BNP (area under receiver operator curve, 0.71) was comparable with pulmonary artery occlusion pressure (area under receiver operator curve, 0.66) and superior to ejection fraction (area under receiver operator curve, 0.60) in subgroups of patients in whom these tests were performed. The accuracy of BNP improved when patients with renal insufficiency were excluded (area under receiver operator curve, 0.82). Conclusion:When measured early after the onset of acute pulmonary edema, a BNP level of <250 pg/mL supports the diagnosis of acute lung injury. The high rate of cardiac and renal dysfunction in critically ill patients limits the discriminative role of BNP. No level of BNP could completely exclude cardiac dysfunction.

The accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic) in the differentiation between transfusion-related acute lung injury and transfusion-related circulatory overload in the critically ill.

BACKGROUND: The diagnostic workup of transfusion‐related acute lung injury (TRALI) requires an exclusion of transfusion‐associated circulatory overload (TACO). Brain natriuretic peptide (BNP) and N‐terminal pro‐brain natriuretic (NT‐pro‐BNP) accurately diagnosed TACO in preliminary studies that did not include patients with TRALI.