Shelley L. Schmidt

Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema

The composite physiologic index (CPI) was derived to represent the extent of fibrosis on high-resolution computed tomography (HRCT), adjusting for emphysema in patients with idiopathic pulmonary fibrosis (IPF). We hypothesised that longitudinal change in CPI would better predict mortality than forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (DL,CO) in all patients with IPF, and especially in those with combined pulmonary fibrosis and emphysema (CPFE). Cox proportional hazard models were performed on pulmonary function data from IPF patients at baseline (n = 321), 6 months (n = 211) and 12 months (n = 144). Presence of CPFE was determined by HRCT. A five-point increase in CPI over 12 months predicted subsequent mortality (HR 2.1, p = 0.004). At 12 months, a 10% relative decline in FVC, a 15% relative decline in DL,CO or an absolute increase in CPI of five points all discriminated median survival by 2.1 to 2.2 yrs versus patients with lesser change. Half our cohort had CPFE. In patients with moderate/severe emphysema, only a 10% decline in FEV1 predicted mortality (HR 3.7, p = 0.046). In IPF, a five-point increase in CPI over 12 months predicts mortality similarly to relative declines of 10% in FVC or 15% in DL,CO. For CPFE patients, change in FEV1 was the best predictor of mortality.

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

Summary:  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.

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.

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.

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.

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 patients home and provided instructions for data collection during the subjects 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.

Clinical year in review I: interstitial lung disease, occupational and environmental lung disease, education of residents and fellows, and pediatrics.

Telomeres are repeated short sequences at the end of chromosomes that protect the genetically encoded information of the chromosomes from erosion after repeated mitoses (1). The telomerase enzyme is responsible for maintaining telomere integrity. Telomere lengths in normal blood leukocytes are known to shorten with increasing age, from 11 kilobases at birth to about 6 kilobases at 90 years of age. There are known consequences of telomere erosion: cellular senescence and apoptosis, and chromosomal instability leading to aberrant chromosomal fusions. In 2005, mutations in the gene for telomerase reverse transcriptase (TERT) were associated with chronic, human disease for the first time: aplastic anemia (2). Heterozygous mutations in the TERT gene impaired telomerase activity, leading to significantly shorter telomeres in those patients with bone marrow failure compared with age-matched control subjects. In 2007, telomerase mutations were identified in patients with familial idiopathic pulmonary fibrosis (IPF) and also in adult-onset pulmonary fibrosis (3, 4). To further understand the association of telomere lengths and pulmonary fibrosis phenotypes, Diaz de Leon and colleagues studied clinical characteristics and telomere lengths of 134 individuals with known heterozygous TERT mutations from 21 unrelated families (5). They found that 40% of the TERT mutation carriers (mean age, 51 yr) had a diagnosis of pulmonary fibrosis. There was an age-dependent pulmonary fibrosis phenotype: from zero cases in those less than 40 years of age to 60% of men aged 60 or older. Most cases were consistent with IPF: 74% had a radiographic pattern and 86% had a pathologic pattern consistent with usual interstitial pneumonia. In conclusion, there is a subset of age-dependent pulmonary fibrosis that is likely caused by germline mutations in telomerase reverse transcriptase, which results in short telomere lengths.

Clinical Year in Review I Interstitial Lung Disease, Pulmonary Vascular Disease and Venous Thromboembolism, Diagnostic Imaging, and Lung Cancer

The differentiation between idiopathic pulmonary fibrosis (IPF) and non-IPF idiopathic interstitial pneumonias (IIP) is clinically relevant, as the prognosis and response to therapy is different (1). For patients without a definite usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) scan, a surgical lung biopsy is needed to establish diagnosis (2–4). Unfortunately, a surgical lung biopsy is not possible in all patients due to severity of disease and/or other co-morbid diseases. These patients are typically excluded from clinical trials and the approach to treatment and prediction of prognosis is often unclear. Fell and colleagues sought to determine if there was a combination of clinical and HRCT characteristics that could predict a diagnosis of IPF, confirmed by surgical lung biopsy, for patients that lacked a definitive HRCT diagnosis (5). A total of 664 patients were retrospectively reviewed from the University of Michigan Interstitial Lung Disease database. HRCT scans were scored by radiologists blinded to final diagnosis using a semiquantitative score from 0–5 for interstitial and ground glass infiltrates (6). Patients were excluded if they did not have a surgical lung biopsy, lacked pulmonary function studies and/or HRCT within 6 months of biopsy, did not have idiopathic disease (i.e., connective tissue disease), or did not have a consensus diagnosis (n 5 421). An additional 108 patients were excluded as their HRCT showed a definite pattern of usual interstitial pneumonia (UIP). The final study group comprised patients with IPF (n 5 97), nonspecific interstitial pneumonia (n 5 19), hypersensitivity pneumonia (n 5 9), respiratory bronchiolitis interstitial lung disease/desquamative interstitial pneumonia (n 5 9), and cryptogenic organizing pneumonia (n 5 1). Univariate logistic regression analysis for the prediction of IPF identified increasing age (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.06–1.16, per year) and total HRCT interstitial score (OR, 17.20; 95% CI, 5.41–54.70) as predictors of IPF. Increased ground glass on HRCT predicted the absence of IPF (OR, 0.61; 95% CI, 0.43–0.87). Pulmonary function, sex, six-minute-walk test desaturation, or distance walked were not predictive. The investigators derived a probability of IPF score as Score 5 [(0.084 3 age 1 2.346 3 HRCT interstitial score – 3.31)/5.856]. This score could be used to estimate the probability of IPF (Table1). This study highlighted the relationship between increased age and even modest amounts of fibrosis on HRCT and the diagnosis of IPF. The study is limited by the high prevalence of IPF in the patients studied. Further prospective validation of these data is required before altering the current diagnostic algorithm for patients with suspected IPF.