Genetic variations in idiopathic pulmonary fibrosis and patient response to pirfenidone.

Background: Genetic variations in Idiopathic Pulmonary Fibrosis (IPF) affect survival and outcomes. Current antifibrotic agents are managed based on the patient's reported side effects, although certain single nucleotide polymorphisms (SNPs) might alter treatment response and survival depending on the antifibrotic administered. This study investigated variations in response and outcomes to pirfenidone based on patients-specific genetic profiles. Methods: Retrospective clinical data were collected from 56 IPF patients and had blood drawn for DNA extraction between 7/2013 and 3/2016, with the last patient followed until 10/2018. Nine SNPs were selected for pharmacogenetic investigation based on prior associations with IPF treatment outcomes or implications for pirfenidone metabolism. Genetic variants were examined in relation to clinical data and treatment outcomes. Results: Of the 56 patients, 38 were males (67.85%). The average age of IPF at diagnosis was 66.88 years. At the initiation of pirfenidone, the average percent predicted FVC was 70.7%, and the average DLCO percent predicted was 50.02% (IQR 40-61%). Among the genetic variants tested, the TOLLIP rs5743890 risk allele was significantly associated with improved survival, with increasing pirfenidone duration. This finding was observed with CC or CT genotype carriers but not for those with the TT genotype (p = 0.0457). Similarly, the TGF-B1 rs1800470 risk allele was also significantly associated with improved survival with longer pirfenidone therapy (p = 0.0395), even though it was associated with disease progression. Conclusion: This pilot study suggests that in IPF patients, the TOLLIP rs5743890 genotypes CC and CT, as well as TGF-B1 rs 1800470 may be associated with increased survival when treated with pirfenidone.

Quantification of Perinodular Emphysema in High-risk Patients Offers No Benefit in Lung Nodule Risk-Stratification of Malignancy Potential.

PURPOSE: Pulmonary nodules, found either incidentally or on lung cancer screening, are common. Evaluating the benign or malignant nature of these nodules is costly in terms of patient risk and expense. The presence of both global and regional emphysema has been linked to increased lung cancer risk. We sought to determine whether the measurement of emphysema directly adjacent to a lung nodule could inform the likelihood of a nodule being malignant. MATERIALS AND METHODS: Within a population of Veterans at high risk for lung cancer, 58 subjects with malignant nodules found on computerized tomographic chest scans were matched by lobe and nodule size to 58 controls. Lung densitometry was measured via determination of the low attenuation area percentage at -950 Hounsfield units (LAA950) and the Hounsfield unit (HU) value at which 15% of lung voxels have a lower lung density (Perc15), at predefined lung volumes that encompassed the nodule to evaluate both perinodular and regional lung fields. The association between measured lung density and malignancy was investigated using conditional logistic regression models, with densitometry measurements used as the primary predictor, adjusting for age alone, or age and computerized tomographic scan characteristics. RESULTS: No significant differences in emphysema measurements between malignant and benign nodules were identified at lung volumes encompassing both perinodular and regional emphysema. Furthermore, emphysema quantification remained stable across lung volumes within individuals. CONCLUSIONS: In this study, quantifying the degree of perinodular or regional emphysema did not offer any benefit in the risk stratification of lung nodules.

Acute exacerbation of interstitial lung disease after procedures.

Interstitial lung disease (ILD) is a category of diffuse parenchymal lung diseases characterized by inflammation and/or fibrosis. The best characterized ILD is idiopathic pulmonary fibrosis (IPF). Acute exacerbation of IPF is a dreaded occurrence with grim prognosis and suboptimal treatment options. There have been recent reports that acute exacerbation can occur in other ILDs (AE-ILD). Of note, some of these acute exacerbations follow lung procedures. This review summarizes the available information on AE-ILD and discusses the procedures reported to cause AE-ILD. We also discuss proposed mechanisms, risk factors, treatment and prognosis. This review should help to inform decision-making about risks versus benefits of procedures that are commonly recommended to diagnose ILD.

Unnecessary antimicrobial use in patients with current or recent Clostridium difficile infection.

OBJECTIVE: To determine the fraction of unnecessary antimicrobial use among patients with current and/or recent Clostridium difficile infection (CDI). DESIGN: Retrospective review from January 2004 through December 2006. SETTING: Minneapolis Veterans Affairs Medical Center (MVAMC). PARTICIPANTS: Patients with new-onset CDI diagnosed at the MVAMC without another CDI diagnosis in the prior 30 days. METHODS: Pharmacy and medical records were reviewed to identify incident CDI cases, non-CDI antimicrobial use during and up to 30 days after completion of CDI treatment, and patient characteristics. Two infectious disease physicians independently assessed non-CDI antimicrobial use, which was classified as unnecessary if not fully indicated. Factors associated with only unnecessary use were identified through univariable and multivariable analysis. RESULTS: Of 246 patients with new-onset CDI, 141 (57%) received non-CDI antimicrobials during and/or after their CDI treatment, totaling 2,147 antimicrobial days and 445 antimicrobial courses. The two reviewers agreed regarding the necessity of antimicrobials in more than 99% of antimicrobial courses (85% initially, 14% after discussion). Seventy-seven percent of patients received at least 1 unnecessary antimicrobial dose, 26% of patients received only unnecessary antimicrobials, and 45% of total non-CDI antimicrobial days included unnecessary antimicrobials. The leading indications for unnecessary antimicrobial use were putative urinary tract infection and pneumonia. Drug classes frequently used unnecessarily were fluoroquinolones and ß-lactams. CONCLUSIONS: Twenty-six percent of patients with recent CDI received only unnecessary (and therefore potentially avoidable) antimicrobials. Heightened awareness and caution are needed when antimicrobial therapy is contemplated for patients with recent CDI.

Antimicrobial use and risk for recurrent Clostridium difficile infection.

BACKGROUND: Although antimicrobial use during and immediately after Clostridium difficile infection (CDI) is discouraged, the frequency and consequences of such use are poorly defined. We sought to determine the frequency of non-CDI antimicrobial therapy during and after treatment for CDI, and the association of such therapy with recurrent disease. METHODS: Retrospective review of all CDI cases at a Veterans Affairs medical center from 2004-2006. Outcomes were non-CDI antimicrobial use during and within 30 days after completing CDI treatment, and recurrent CDI. RESULTS: From 2004 to 2006, new-onset CDI occurred in 249 unique patients. No follow-up information was available for 3 patients, leaving 246 as study subjects. Of these, 141 (57%) received non-CDI antimicrobials, including 61 (25%) who received non-CDI antimicrobials during CDI treatment, and 80 (33%) who received non-CDI antimicrobial therapy after CDI treatment. With adjustment for age, disease severity, duration of CDI treatment, and recent hospital or intensive-care unit stay, receipt of non-CDI antimicrobials after CDI treatment was significantly associated with recurrent CDI (odds ratio [OR] 3.02; 95% confidence interval [CI], 1.66-5.52), compared with no antimicrobial use. Antimicrobial use during CDI treatment was not associated with recurrent CDI (OR 0.79; 95% CI, 0.40-1.52). Neither number of antimicrobial courses nor antimicrobial days was associated with recurrence. CONCLUSIONS: Non-CDI antimicrobial therapy after an episode of CDI is common and is associated with a 3-fold increase in the odds of recurrent disease. The added risk associated with antimicrobial exposure (regardless of duration) should be considered if such therapy is contemplated.

Novel toxic shock syndrome toxin-1 amino acids required for biological activity.

Superantigens interact with T lymphocytes and macrophages to cause T lymphocyte proliferation and overwhelming cytokine production, which lead to toxic shock syndrome. Staphylococcus aureus superantigen toxic shock syndrome toxin-1 is a major cause of menstrual toxic shock syndrome. In general, superantigen-secreting S. aureus remains localized at the vaginal surface, and the superantigen must therefore penetrate the vaginal mucosa to interact with underlying immune cells to cause toxic shock syndrome. A dodecapeptide region (toxic shock syndrome toxin-1 amino acids F119-D130), relatively conserved among superantigens, has been implicated in superantigen penetration of the epithelium. The purpose of this study was to determine amino acids within this dodecapeptide region that are required for interaction with vaginal epithelium. Alanine mutations were constructed in S. aureus toxic shock syndrome toxin-1 amino acids D120 to D130. All mutants maintained superantigenicity, and selected mutants were lethal when given intravenously to rabbits. Toxic shock syndrome toxin-1 induces interleukin-8 from immortalized human vaginal epithelial cells; however, three toxin mutants (S127A, T128A, and D130A) induced low levels of interleukin-8 compared to wild type toxin. When carboxy-terminal mutants (S127A to D130A) were administered vaginally to rabbits, D130A was nonlethal, while S127A and T128A demonstrated delayed lethality compared to wild type toxin. In a porcine ex vivo permeability model, mutant D130A penetrated the vaginal mucosa more quickly than wild type toxin. Toxic shock syndrome toxin-1 residue D130 may contribute to binding an epithelial receptor, which allows it to penetrate the vaginal mucosa, induce interleukin-8, and cause toxic shock syndrome.