Utility of a Molecular Classifier as a Complement to High-Resolution Computed Tomography to Identify Usual Interstitial Pneumonia.

Rationale: Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A "molecular diagnosis of UIP" in transbronchial lung biopsy, the Envisia Genomic Classifier, accurately predicted histopathologic UIP.Objectives: We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern.Methods: Ninety-six patients who had diagnostic lung pathology as well as a transbronchial lung biopsy for molecular testing with Envisia Genomic Classifier were included in this analysis. The classifier results were scored against reference pathology. UIP identified on high-resolution computed tomography (HRCT) as documented by features in local radiologists' reports was compared with histopathology.Measurements and Main Results: In 96 patients, the Envisia Classifier achieved a specificity of 92.1% (confidence interval [CI],78.6-98.3%) and a sensitivity of 60.3% (CI, 46.6-73.0%) for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology, with a sensitivity of 34.0% (CI, 21.5-48.3%) and a specificity of 96.9% (CI, 83.8-100%). In conjunction with HRCT patterns of UIP, the Envisia Classifier results identified 24 additional patients with UIP (sensitivity 79.2%; specificity 90.6%).Conclusions: In 96 patients with suspected interstitial lung disease, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an interstitial lung disease (especially IPF) diagnosis without the need for a surgical lung biopsy.

Home-based overnight transcutaneous capnography/pulse oximetry for diagnosing nocturnal hypoventilation associated with neuromuscular disorders.

OBJECTIVE: To determine the utility of home-based, unsupervised transcutaneous partial pressure of carbon dioxide (tc-Pco(2)) monitoring/oxygen saturation by pulse oximetry (Spo(2)) for detecting nocturnal hypoventilation (NH) in individuals with neuromuscular disorders. DESIGN: Retrospective case series analyzed consecutively. SETTING: Multidisciplinary neuromuscular respiratory failure (NMRF) clinic at an academic institution. PARTICIPANTS: Subjects (N=35, 68.6% men; mean age, 46.9y) with spinal cord injury (45.7%) or other neuromuscular disorders underwent overnight tests with tc-Pco(2)/Spo(2) monitoring. Fifteen (42.9%) were using nocturnal ventilatory support, either bilevel positive airway pressure (BiPAP) or tracheostomy ventilation (TV). INTERVENTIONS: A respiratory therapist brought a calibrated tc-Pco(2)/Spo(2) monitor to the patient's home and provided instructions for data collection during the subject's normal sleep period. Forced vital capacity (FVC), body mass index (BMI), and exhaled end-tidal Pco(2) (ET-Pco(2)) were recorded at a clinic visit before monitoring. MAIN OUTCOME MEASURES: Detection of NH (tc-Pco(2) ≥50mmHg for ≥5% of monitoring time). Data were also analyzed to determine whether nocturnal oxygen desaturation (Spo(2) ≤88% for ≥5% of monitoring time), FVC, BMI, or daytime ET-Pco(2) could predict the presence of NH. RESULTS: NH was detected in 18 subjects (51.4%), including 53.3% of those using BiPAP or TV. NH was detected in 43.8% of ventilator-independent subjects with normal daytime ET-Pco(2) (present for 49.4%±31.5% [mean ± SD] of the study period), and in 75% of subjects with an elevated daytime ET-Pco(2) (present for 92.3%±8.7% of the study period). Oxygen desaturation, BMI, and FVC were poor predictors of NH. Only 3 attempted monitoring studies failed to produce acceptable results. CONCLUSIONS: Home-based, unsupervised monitoring with tc-Pco(2)/Spo(2) is a useful method for diagnosing NH in NMRF.

The Role of Genetic Testing in Pulmonary Fibrosis: A Perspective From the Pulmonary Fibrosis Foundation Genetic Testing Work Group.

Patients with familial pulmonary fibrosis represent a subset of patients with pulmonary fibrosis in whom inherited gene variation predisposes them to disease development. In the appropriate setting, genetic testing allows for personalized assessment of disease, recognition of clinically relevant extrapulmonary manifestations, and assessing susceptibility in unaffected relatives. However currently, the use of genetic testing is inconsistent, partly because of the lack of guidance regarding high-yield scenarios in which the results of genetic testing can inform clinical decision-making. To address this, the Pulmonary Fibrosis Foundation commissioned a genetic testing work group comprising pulmonologists, geneticists, and genetic counselors from the United States to provide guidance on genetic testing in patients with pulmonary fibrosis. This CHEST special feature presents a concise review of these proceedings and reviews pulmonary fibrosis susceptibility, clinically available genetic testing methods, and clinical scenarios in which genetic testing should be considered.

Increasing development in the surroundings of U.S. National Park Service holdings jeopardizes park effectiveness.

Protected areas are cornerstones of biodiversity conservation, but they are in danger of becoming islands in a sea of human dominated landscapes. Our question was if protected areas may even foster development in their surroundings because they provide amenities that attract development, thus causing the isolation of the ecosystems they were designed to protect. Our study analyzed historic aerial photographs and topographical maps to reconstruct road development and building growth within and around Indiana Dunes and Pictured Rocks National Lakeshores in the U.S. Great Lakes region from 1938 to 2005, and to estimate the effects of park creation in 1966 on changes in landscape patterns. Historic U.S. census housing density data were used as a baseline to compare observed changes to. Our results showed that park establishment was effective in reducing and stopping the fragmenting impact of development within park boundaries. However, increased amenity levels following park establishment led to enhanced development in the surroundings of both parks. In the extreme case of Indiana Dunes, building density outside the park increased from 45 to 200buildings/km(2) and road density almost doubled from 3.6 to 6.6km/km(2) from 1938 to 2005. Development rates of change were much higher than in the broader landscape, particularly after park establishment. The potential amenity effect was up to 9500 new buildings in the 3.2-km zone around Indiana Dunes between 1966 and 2005. For Pictured Rocks the absolute effect was smaller but up to 70% of the observed building growth was potentially due to amenity effects. Our findings highlight the need for conservation planning at broader scales, incorporating areas beyond the boundaries of protected areas.

Diagnosing fibrotic lung disease: when is high-resolution computed tomography sufficient to make a diagnosis of idiopathic pulmonary fibrosis?

Idiopathic pulmonary fibrosis (IPF), a progressive and fatal diffuse parenchymal lung disease, is defined pathologically by the pattern of usual interstitial pneumonia (UIP). Unfortunately, a surgical lung biopsy cannot be performed in all patients due to comorbidities that may significantly increase the morbidity and mortality of the procedure. High-resolution computed tomography (HRCT) has been put forth as a surrogate to recognize pathological UIP. The quality of the HRCT impacts the ability to make a diagnosis of UIP and varies based on the centre performing the study and patient factors. The evaluation of the HRCT includes assessing the distribution and predominance of key radiographical findings, such as honeycomb, septal thickening, traction bronchiectasis and ground glass attenuation lesions. The combination of the pattern and distribution is what leads to a diagnosis and associated confidence level. HRCT features of definite UIP (subpleural, basal predominant honeycomb with septal thickening, traction bronchiectasis and ground glass attenuation lesions) have a high specificity for the UIP pathological pattern. In such cases, surgical lung biopsy can be avoided. There are caveats to using the HRCT to diagnose IPF in isolation as a variety of chronic pulmonary interstitial diseases may progress to a UIP pattern. Referral centres with experience in diffuse parenchymal lung disease that have multidisciplinary teams encompassing clinicians, radiologists and pathologists have the highest level of agreement in diagnosing IPF.

Possible UIP pattern on high-resolution computed tomography is associated with better survival than definite UIP in IPF patients.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease of unknown etiology. Inter-society consensus guidelines on IPF diagnosis and management outline radiologic patterns including definite usual interstitial pneumonia (UIP), possible UIP, and inconsistent with UIP. We evaluate these diagnostic categories as prognostic markers among patients with IPF. METHODS: Included subjects had biopsy-proven UIP, a multidisciplinary team diagnosis of IPF, and a baseline high-resolution computed tomography (HRCT). Thoracic radiologists assigned the radiologic pattern and documented the presence and extent of specific radiologic findings. The outcome of interest was lung transplant-free survival. RESULTS: IPF patients with a possible UIP pattern on HRCT had significantly longer Kaplan-Meier event-free survival compared to those with definite UIP pattern (5.21 and 3.57 years, respectively, p = 0.002). In a multivariable Cox proportional hazards model adjusted for baseline age, gender, %-predicted FVC, and %-predicted DLCO via the GAP Stage, extent of fibrosis (via the traction bronchiectasis score) and ever-smoker status, possible UIP pattern on HRCT (versus definite UIP) was associated with reduced hazard of death or lung transplant (HR = 0.42, CI 95% 0.23-0.78, p = 0.006). CONCLUSIONS: Radiologic diagnosis categories outlined by inter-society consensus guidelines is a widely-reported and potentially useful prognostic marker in IPF patients, with possible UIP pattern on HRCT associated with a favorable prognosis compared to definite UIP pattern, after adjusting for relevant covariates.

Idiopathic Pulmonary Fibrosis: Gender-Age-Physiology Index Stage for Predicting Future Lung Function Decline.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disease with variable course. The Gender-Age-Physiology (GAP) Index and staging system uses clinical variables to stage mortality risk. It is unknown whether clinical staging predicts future decline in pulmonary function. We assessed whether the GAP stage predicts future pulmonary function decline and whether interval pulmonary function change predicts mortality after accounting for stage. METHODS: Patients with idiopathic pulmonary fibrosis (N = 657) were identified retrospectively at three tertiary referral centers, and baseline GAP stages were assessed. Mixed models were used to describe average trajectories of FVC and diffusing capacity of the lung for carbon monoxide (Dlco). Multivariable Cox proportional hazards models were used to assess whether declines in pulmonary function ≥ 10% in 6 months predict mortality after accounting for GAP stage. RESULTS: Over a 2-year period, GAP stage was not associated with differences in yearly lung function decline. After accounting for stage, a 10% decrease in FVC or Dlco over 6 months independently predicted death or transplantation (FVC hazard ratio, 1.37; Dlco hazard ratio, 1.30; both, P ≤ .03). Patients with GAP stage 2 with declining pulmonary function experienced a survival profile similar to patients with GAP stage 3, with 1-year event-free survival of 59.3% (95% CI, 49.4-67.8) vs 56.9% (95% CI, 42.2-69.1). CONCLUSIONS: Baseline GAP stage predicted death or lung transplantation but not the rate of future pulmonary function decline. After accounting for GAP stage, a decline of ≥ 10% over 6 months independently predicted death or lung transplantation.

The antibacterial innate immune response by the mosquito Aedes aegypti is mediated by hemocytes and independent of Gram type and pathogenicity.

Previous mosquito studies showed that the hemocyte-mediated innate immune response against Gram- Escherichia coli is phagocytosis, but against Gram+ Micrococcus sp., is melanization. We examined the immune responses mounted by Aedes aegypti towards Gram- Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhimurium, and Gram+ Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus epidermidis. Using light microscopy, electron microscopy, and survival analysis, this investigation conclusively shows that the factors governing phagocytic vs. melanization responses are complex and independent of bacterial Gram type and pathogenicity. These data provide further evidence that hemocytes are central to the immune response against prokaryotes.

Rapid phagocytosis and melanization of bacteria and Plasmodium sporozoites by hemocytes of the mosquito Aedes aegypti.

Mosquitoes are vectors of many deadly and debilitating pathogens. In the current study, we used light and electron microscopies to study the immune response of Aedes aegypti hemocytes to bacterial inoculations, Plasmodium gallinaceum natural infections, and latex bead injections. After challenge, mosquitoes mounted strong phagocytic and melanization responses. Granulocytes phagocytosed bacteria singly or pooled them inside large membrane-delimited vesicles. Phagocytosis of bacteria, Plasmodium sporozoites, and latex beads was extensive; we estimated that individual granulocytes have the capacity to phagocytose hundreds of bacteria and thousands of latex particles. Oenocytoids were also seen to internalize bacteria and latex particles, although infrequently and with low capacity. Besides phagocytosis, mosquitoes cleared bacteria and sporozoites by melanization. Interestingly, the immune response toward 2 species of bacteria was different; most Escherichia coli were phagocytosed, but most Micrococcus luteus were melanized. Similar to E. coli, most Plasmodium sporozoites were phagocytosed. The immune response was rapid; phagocytosis and melanization of bacteria began as early as 5 min after inoculation. The magnitude and speed of the cellular response suggest that hemocytes, acting in concert with the humoral immune response, are the main force driving the battle against foreign invaders.

Predicting pulmonary fibrosis disease course from past trends in pulmonary function.

BACKGROUND: The clinical course of idiopathic pulmonary fibrosis (IPF) is characterized by progressive decline in lung function and eventual mortality. We sought to determine if future declines in pulmonary function, mortality, or both can be predicted from prior trends in pulmonary function tests (PFTs). METHODS: Data from 1981 to 2008 on 4,431 PFTs and mortality were analyzed from 734 subjects with IPF. The Kaplan-Meier method was used for mortality analyses. Mixed models were used to describe longitudinal pulmonary function dynamics, since PFTs were observed at varying time points from baseline. RESULTS: During the first year of follow-up, 135 subjects (73%) had stable FVC while 50 subjects (37%) showed a decline in FVC. During months 12 to 24 (1-2 years after diagnosis), a stable FVC occurred with the same frequency among both subjects whose FVC had declined during year 1 and whose FVC had remained stable (84.0% and 80.7%, respectively; P=.59). Among subjects alive at the end of year 1, those with a stable FVC were more likely to be alive at the end of year 2 than those whose FVC declined (hazard ratio [HR], 0.91 [95% CI, 0.87-0.94] and HR, 0.71 [95% CI, 0.62-0.78], respectively). CONCLUSIONS: PFT decline predicts early mortality, but not future declines in physiology, regardless of time since diagnosis.

Age-associated mortality in immune challenged mosquitoes (Aedes aegypti) correlates with a decrease in haemocyte numbers.

Mosquitoes vector pathogens. One aspect that has been overlooked in mosquito-pathogen relationships is the effect of host age on immune competence. Here, we show that there is age-associated mortality following immune challenge with Escherichia coli. This mortality correlates with a decrease in haemocyte numbers (blood cells) and a decreased ability to kill E. coli. Although the number of haemocytes decreases, the available haemocytes retain their phagocytic ability regardless of age, and we estimate that individual granulocytes can phagocytose approximately 1500 E. coli. Moreover, transcription profiles for cecropin, defensin and gambicin in E. coli challenged mosquitoes do not change with age, indicating that the increased susceptibility is not attributed to fewer humoral antimicrobial peptides. These results suggest that a contributing factor for the age-associated mortality is the decrease in circulating haemocytes, which reduces the overall phagocytic capacity of mosquitoes. To our knowledge, this is the first report detailing an age-associated decline in the immunological capabilities of mosquitoes following challenge with an infectious agent. These data also call for caution in the analysis and interpretation of experimental results when mosquito age has not been closely monitored. Lastly, a model for haemocyte function is presented.

Hemocyte-mediated phagocytosis and melanization in the mosquito Armigeres subalbatus following immune challenge by bacteria.

Mosquitoes are important vectors of disease. These insects respond to invading organisms with strong cellular and humoral immune responses that share many similarities with vertebrate immune systems. The strength and specificity of these responses are directly correlated to a mosquito's ability to transmit disease. In the current study, we characterized the hemocytes (blood cells) of Armigeres subalbatus by morphology (ultrastructure), lectin binding, enzyme activity, immunocytochemistry, and function. We found four hemocyte types: granulocytes, oenocytoids, adipohemocytes, and thrombocytoids. Granulocytes contained acid phosphatase activity and bound the exogenous lectins Helix pomatia agglutinin, Galanthus nivalis lectin, and wheat germ agglutinin. Following bacteria inoculation, granulocytes mounted a strong phagocytic response as early as 5 min postexposure. Bacteria also elicited a hemocyte-mediated melanization response. Phenoloxidase, the rate-limiting enzyme in the melanization pathway, was present exclusively in oenocytoids and in many of the melanotic capsules enveloping bacteria. The immune responses mounted against different bacteria were not identical; gram(-) Escherichia coli were predominantly phagocytosed and gram(+) Micrococcus luteus were melanized. These studies implicate hemocytes as the primary line of defense against bacteria.

Long-term outcome of nonsurgical candidates with medically refractory localization-related epilepsy.

PURPOSE: Epilepsy surgery can result in complete seizure remission rates of upto 80% in patients with mesial temporal sclerosis and unilateral seizures. The seizure-free rate after surgery for patients with extratemporal nonlesional epilepsy has ranged between 30% and 40%. Some patients with medically refractory localization-related epilepsy cannot be offered surgical resection because of inadequate localization of the epileptogenic zone, documentation of bilateral ictal onsets, or functionally important areas of cortex that prohibit resection. The short-term rate of complete remission with medications in temporal lobe epilepsy is poor. Less is known about remission rates in patients who are not surgical candidates. In this study, we evaluated the outcome of medical treatment in patients with medically refractory partial epilepsy who were evaluated for possible epilepsy surgery but deemed to be inadequate surgical candidates. METHODS: A retrospective chart review and telephone survey with a self-rating questionnaire were completed for all patients who underwent epilepsy surgery evaluation but were not ultimately offered surgical treatment at the University of Michigan from 1990 through 1998. We assessed changes in seizure frequency and type, imaging characteristics, ictal recordings, interim medication history, and subjective changes in quality of life. RESULTS: Thirty-four subjects were available for follow-up study, at an average of >4 years after surgical evaluation. A significant reduction in seizure frequency was noted at the time of follow-up compared with that at the time of surgical evaluation. Of patients, 21% achieved seizure remission and remained seizure free for an average of 2.5 years. Four of the seven seizure-free patients attributed their remission to new antiepileptic drugs (AEDs). On a global self-rating item, 15 of 34, or 44%, felt more or much more satisfied with their lives, and 41% felt their quality of life was stable. CONCLUSIONS: A surprisingly large number of patients we surveyed, with refractory partial epilepsy not eligible for surgical management, reported reduced seizure frequency at follow-up, and 21% were seizure free. Our findings suggest that the long-term prognosis in patients with refractory partial epilepsy who are not surgical candidates may be more positive than might be generally expected.