Physical activity and activity space in patients with pulmonary fibrosis not prescribed supplemental oxygen.

BACKGROUND: Patients with pulmonary fibrosis (PF) have impaired quality of life, and research suggests that dyspnea and physical activity are primary drivers. As PF progresses, some patients notice the disease "shrinks their worlds". The objective of this study is to describe movement (both physical activity and activity space) in a cohort of patients with PF of various etiologies who have not been prescribed supplemental oxygen (O2). METHODS: Subjects with PF not on supplemental O2 during the day were enrolled from across the U.S. from August 2013 to October 2015. At enrollment, each subject completed questionnaires and, for seven consecutive days, wore an accelerometer and GPS tracker. RESULTS: One hundred ninety-four subjects had a confirmed diagnosis of PF and complete, analyzable GPS data. The cohort was predominantly male (56%), Caucasian (95%) and had idiopathic pulmonary fibrosis (30%) or connective tissue disease related-PF (31%). Subjects walked a median 7497 (interquartile range [IQR] 5766-9261) steps per day. Steps per day were correlated with symptoms and several quality of life domains. In a model controlling for age, body mass index, wrist- (vs. waist) worn accelerometer and percent predicted diffusing capacity (DLCO%), fatigue (beta coefficient = -51.5 ± 11.7, p < 0.0001) was an independent predictor of steps per day (model R2=0.34). CONCLUSIONS: Patients with PF, who have not been prescribed O2 for use during the day, have wide variability in their mobility. Day-to-day physical activity is related to several domains that impact quality of life, but GPS-derived activity space is not. Wearable data collection devices may be used to determine whether and how therapeutic interventions impact movement in PF patients. TRIAL REGISTRATION: NCT01961362 . Registered 9 October, 2013.

Tracking dyspnea up to supplemental oxygen prescription among patients with pulmonary fibrosis.

BACKGROUND: Dyspnea is the hallmark symptom of pulmonary fibrosis. Supplemental oxygen (O2) is prescribed to many patients with pulmonary fibrosis in hopes of alleviating dyspnea and improving physical functioning. We used response data from the University of California San Diego Shortness of Breath Questionnaire (UCSD) which was administered monthly in the context of a longitudinal, observational study to plot a rich trajectory for dyspnea over time in patients with pulmonary fibrosis. We used other data from that study to identify clinical predictors of being prescribed O2 and to provide additional information for how UCSD scores could be used for clinical purposes. METHODS: We used linear mixed-effects models and multivariate Cox proportional hazards to model change in dyspnea scores over time and to identify significant predictors of time-to-O2-prescription among a pool of clinically-meaningful candidate variables. In the longitudinal study, all decisions, including whether or not to prescribe O2, were made by subjects' treating physicians, not members of the research team. RESULTS: One-hundred ninety-four subjects with pulmonary fibrosis completed more than one UCSD or were prescribed O2 at some point during the follow-up period (N = 43). Twenty-eight of the 43 had analyzable, longitudinal data and contribute data to the longitudinal UCSD analyses. All 43 were included in the time-to-O2-prescription analyses. Subjects prescribed O2 had more severe dyspnea at enrollment (38.4 ± 19.6 vs. 22.6 ± 18.7, p < 0.0001) and a steeper increase in UCSD scores over time (slope = 1.18 ± 0.53 vs. 0.24 ± 0.09 points per month, p = 0.02) than subjects not prescribed O2. Controlling for baseline UCSD score and FVC%, subjects with a clinical summary diagnosis of idiopathic pulmonary fibrosis (IPF) were far more likely to be prescribed O2 than subjects with other forms of pulmonary fibrosis (hazard ratio = 4.85, (2.19, 10.74), p < 0.0001). CONCLUSIONS: Baseline dyspnea and rise in dyspnea over time predict timing of O2 prescription. Accounting for disease severity, patients with IPF are more likely than patients with other forms of pulmonary fibrosis to be prescribed O2. UCSD scores provide clinically useful information; frequent administration could yield timely data on changes in disease status in patients with pulmonary fibrosis. TRIAL REGISTRATION: The longitudinal study is registered on ClinicalTrials.gov ( NCT01961362 ). Registered October 9, 2013.

Sarcoidosis-related mortality in the United States from 1988 to 2007.

RATIONALE: It has been nearly 20 years since sarcoidosis mortality was examined at the population level in the United States. OBJECTIVES: To examine mortality rates and underlying causes of death among United States decedents with sarcoidosis from 1988-2007. METHODS: We used data from the National Center for Health Statistics to (1) calculate age-adjusted sarcoidosis-associated mortality rates; (2) examine how those rates differ by age, sex, and race and ethnicity; and (3) determine underlying causes of death among sarcoidosis decedents. MEASUREMENTS AND MAIN RESULTS: From 1988-2007, there were 46,450,489 deaths in the United States and 23,679 decedents with sarcoidosis mentioned on their death certificates. Over this time, the age-adjusted, sarcoidosis-related mortality rate increased 50.5% in women and 30.1% in men. The greatest absolute increase in death rates was among non-Hispanic black females. Regardless of sex or race, mortality rates climbed most in decedents 55 years or older. The most common cause of death was sarcoidosis itself. Younger sarcoidosis decedents with pulmonary fibrosis were more likely to be black than white, and younger sarcoidosis decedents were more likely than similarly aged decedents in the general population to have a cardiac cause contribute to death. CONCLUSIONS: From 1988-2007, sarcoidosis-related mortality rates increased significantly, particularly in non-Hispanic black females aged 55 years or older. The underlying cause of death in most patients with sarcoidosis was the disease itself. Among young sarcoidosis decedents, those with pulmonary fibrosis or a cardiac cause contributing to death were more likely to be black than white.

Rheumatoid arthritis-interstitial lung disease-associated mortality.

RATIONALE: Mortality rates from rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are largely unknown. OBJECTIVES: We sought to determine mortality rates from rheumatoid arthritis-associated interstitial lung disease in the United States from 1988 through 2004. METHODS: Using data from the National Center for Health Statistics, we calculated age-adjusted mortality rates from the deaths of persons with rheumatoid arthritis-associated interstitial lung disease, determined the prevalence of interstitial lung disease in all decedents with rheumatoid arthritis, and compared the age and underlying cause of death in these two cohorts of decedents. MEASUREMENTS AND MAIN RESULTS: From 1988 to 2004, there were 39,138,394 deaths in U.S. residents and 162,032 rheumatoid arthritis-associated deaths. Of these deaths, 10,725 (6.6%) met criteria for rheumatoid arthritis-associated interstitial lung. Mortality rates from rheumatoid arthritis fell over the course of this study in both women and men. However, mortality rates from rheumatoid arthritis-associated interstitial lung disease increased 28.3% in women (to 3.1 per million persons in 2004) and declined 12.5% in men (to 1.5 per million persons in 2004). Because the rate of decline in rheumatoid arthritis outpaced rheumatoid arthritis-associated interstitial lung disease in men, the prevalence of rheumatoid arthritis-associated interstitial lung disease increased in both sexes over time. CONCLUSIONS: Clinically significant RA-ILD occurs in nearly 10% of the RA population, and is associated with shortened survival and more severe underlying disease. Whereas overall mortality rates for RA have fallen, those associated with RA-ILD have increased significantly in older age groups.

Development of the ATAQ-IPF: a tool to assess quality of life in IPF.

BACKGROUND: There is no disease-specific instrument to assess health-related quality of life (HRQL) in patients with idiopathic pulmonary fibrosis (IPF). METHODS: Patients' perspectives were collected to develop domains and items for an IPF-specific HRQL instrument. We used item variance and Rasch analysis to construct the ATAQ-IPF (A Tool to Assess Quality of life in IPF). RESULTS: The ATAQ-IPF version 1 is composed of 74 items comprising 13 domains. All items fit the Rasch model. Domains and the total instrument possess acceptable psychometric characteristics for a multidimensional questionnaire. The pattern of correlations between ATAQ-IPF scores and physiologic variables known to be important in IPF, along with significant differences in ATAQ-IPF scores between subjects using versus those not using supplemental oxygen, support its validity. CONCLUSIONS: Patient-centered and careful statistical methodologies were used to construct the ATAQ-IPF version 1, an IPF-specific HRQL instrument. Simple summation scoring is used to derive individual domain scores as well as a total score. Results support the validity of the ATAQ-IPF, and future studies will build on that validity.

Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia.

Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring < or =5 min after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.

Amygdala regulation of immediate-early gene expression in the hippocampus induced by contextual fear conditioning.

The basolateral nuclei of the amygdala (BLA) are thought to modulate memory storage in other brain regions (McGaugh, 2004). We reported that BLA modulates the memory for both an explored context and for contextual fear conditioning. Both of these memories depend on the hippocampus. Here, we examined the hypothesis that the BLA exerts its modulatory effect by regulating the expression of immediate-early genes (IEGs) in the hippocampus. The main findings of these experiments were: (1) Arc activity-regulated cytoskeletal protein (Arc), an immediate-early gene (also termed Arg 3.1) and c-fos mRNA are induced in the hippocampus after a context exposure, or context plus shock experience, but not after an immediate shock; and (2) BLA inactivation with muscimol attenuated the increase in Arc and c-fos mRNA in the hippocampus associated with contextual fear conditioning but did not influence Arc mRNA associated with context exploration. These results support the hypothesis that the amygdala modulates contextual fear memory by regulating expression of IEGs in the hippocampus.

The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories.

The authors used 3-phase context preexposure facilitation methodology to study the contribution of N-methyl-D-aspartate (NMDA) receptors in dorsal hippocampus (DH) and the basal lateral region of the amygdala (BLA) to (a) acquisition of the context memory, (b) retrieval of the context memory, (c) acquisition of context-shock association, and (d) retrieval of the context-shock association. The NMDA receptor antagonist D-2-amino-5 phosphonopentanoic acid (D-AP5) was injected into either the DH or BLA prior to (a) the context preexposure phase, (b) the immediate shock phase, or (c) the test for contextual fear. Antagonizing NMDA receptors in the DH impaired the acquisition of the context memory but did not affect its retrieval or retrieval of the fear memory. Antagonizing NMDA receptors with D-AP5 in the BLA impaired acquisition of the context-shock association but had no effect on the expression of fear. However, both DL-AP5 and L-AP5 reduced the expression of fear when they were injected into the amygdala prior to testing for contextual fear.

Supradural inflammatory soup in awake and freely moving rats induces facial allodynia that is blocked by putative immune modulators.

Facial allodynia is a migraine symptom that is generally considered to represent a pivotal point in migraine progression. Treatment before development of facial allodynia tends to be more successful than treatment afterwards. As such, understanding the underlying mechanisms of facial allodynia may lead to a better understanding of the mechanisms underlying migraine. Migraine facial allodynia is modeled by applying inflammatory soup (histamine, bradykinin, serotonin, prostaglandin E2) over the dura. Whether glial and/or immune activation contributes to such pain is unknown. Here we tested if trigeminal nucleus caudalis (Sp5C) glial and/or immune cells are activated following supradural inflammatory soup, and if putative glial/immune inhibitors suppress the consequent facial allodynia. Inflammatory soup was administered via bilateral indwelling supradural catheters in freely moving rats, inducing robust and reliable facial allodynia. Gene expression for microglial/macrophage activation markers, interleukin-1ß, and tumor necrosis factor-α increased following inflammatory soup along with robust expression of facial allodynia. This provided the basis for pursuing studies of the behavioral effects of 3 diverse immunomodulatory drugs on facial allodynia. Pretreatment with either of two compounds broadly used as putative glial/immune inhibitors (minocycline, ibudilast) prevented the development of facial allodynia, as did treatment after supradural inflammatory soup but prior to the expression of facial allodynia. Lastly, the toll-like receptor 4 (TLR4) antagonist (+)-naltrexone likewise blocked development of facial allodynia after supradural inflammatory soup. Taken together, these exploratory data support that activated glia and/or immune cells may drive the development of facial allodynia in response to supradural inflammatory soup in unanesthetized male rats.

BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration.

The present study examined the modulating effects of an intrahippocampal injection of interleukin-1beta (IL-1beta) on brain-derived neurotrophic factor (BDNF) mRNA expression 0.5, 2, 4, and 6 h following contextual fear conditioning, a task known to increase BDNF mRNA, in rats. Contextual fear conditioning produced a time-dependent increase in BDNF mRNA that varied by region of hippocampus. IL-1beta blocked or reduced these increases in BDNF mRNA in the CA1, CA2, and dentate gyrus regions of the hippocampus, but had no effect in cortical regions. These data support the idea that IL-1beta-produced memory deficits may be mediated via BDNF mRNA reductions in hippocampus.

Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus.

Prior research has revealed that treatments that elevate the level of the pro-inflammatory cytokine IL-1beta in the brain, if given after training, impair contextual but not auditory-cue fear conditioning. The present experiments add to these finding by showing that, (a) IL-1beta exerts its effect on contextual fear conditioning by impairing consolidation processes that support the storage of the memory representation of the context; (b) the dorsal hippocampus is a critical site for the effect of IL-1beta; (c) the effect of IL-1beta cannot be attributed to its effect on glucocorticoid levels; and (d) IL-1beta injected into dorsal hippocampus either, immediately, 3, or 24 h, but not 48 h, after training produces this impairment. At this time the mechanisms responsible for this impairment are not understood, but may involve late-phase protein synthesis processes associated with LTP, because later consolidation processes are being disrupted.

Pulmonary function and survival in idiopathic vs secondary usual interstitial pneumonia.

BACKGROUND: The usual interstitial pneumonia (UIP) pattern of lung injury may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). Our objective was to observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF. METHODS: We used longitudinal data analytic models to compare groups (IPF [n = 321] and CTD-UIP [n = 56]) on % predicted FVC (FVC %) or % predicted diffusing capacity of the lung for carbon monoxide (Dlco %), and we used both unadjusted and multivariable techniques to compare survival between these groups. RESULTS: There were no significant differences between groups in longitudinal changes in FVC % or Dlco % up to diagnosis, or from diagnosis to 10 years beyond (over which time, the mean decrease in FVC % per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, P = .49 for difference; and the mean decrease in Dlco % per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, P = .60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log-rank P = .003) and certain multivariable analyses. CONCLUSIONS: Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF--an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF.

Indwelling supradural catheters for induction of facial allodynia: surgical procedures, application of inflammatory stimuli, and behavioral testing.

Migraine headaches are debilitatingly painful and poorly managed. Facial allodynia is often associated with migraine, and clinical evidence indicates that it is a critical point in migraine progression. That is, if the migraine can be treated prior to the onset of facial allodynia, the migraine can be halted using triptans, whereas if treatment is administered after facial allodynia has begun, the treatment is ineffective. The meninges and the immune cells therein have been implicated in migraine facial pain. Indeed, application of inflammatory mediators over the meninges has been used to study changes in pain responsive neurons in trigeminal complex, and changes in their receptive fields. Much of this research has been carried out in anesthetized rats, which limits the clinical application. Our indwelling supradural catheter model, in which inflammatory mediators can be administered to the meninges in awake and freely moving rats, allows for the assessment of behavioral changes shortly after injection. Following administration of inflammatory soup (histamine, serotonin, bradykinin, and prostaglandin E2) or the immunogenic HIV-1 coat protein gp120 results in reliable periorbital mechanical allodynia. This model provides an additional means to study the neurocircuitry and neuropharmacology of facial allodynia. Here, we describe detailed methods for the placement of the catheter, injection procedures, and assessment of facial allodynia.

Ethnic and racial differences in the presence of idiopathic pulmonary fibrosis at death.

BACKGROUND: In studies of idiopathic pulmonary fibrosis (IPF), whites makeup the vast majority of subjects. Whether ethnic/racial differences in idiopathic pulmonary fibrosis occur in the general population is unknown. METHODS: To compare the presence of IPF between ethnic/racial groups of U.S. decedents from 1989 to 2007 by using the National Center for Health Statistics database. RESULTS: There were 251,058 U.S. decedents with IPF; 87.2% were non-Hispanic whites (White), 5.1% were non-Hispanic African American (black), 5.4% were Hispanic, and 2.2% were from other ethnic/racial groups (other). Whites coded with IPF died older than those in the other groups (77.9 years vs. 72.1 years for blacks, 75.3 years for Hispanics, and 75.6 years for others; p < 0.0001 for all pairwise comparisons). When controlling for age and for sex, compared with whites, both Hispanics and Others were more likely to be coded with IPF (OR = 1.47, 95% CI 1.44-1.49, p < 0.0001 and OR = 1.29, 95% CI 1.26-1.36, p < 0.0001 respectively), while blacks were significantly less likely to be coded with IPF (OR = 0.48, 95% CI 0.47-0.49, p < 0.0001). Among decedents with IPF, Hispanics were more likely, and blacks were less likely, than whites to die from IPF (OR = 1.24, 95% CI 1.20-1.29, p < 0.0001 and OR = 0.91, 95% CI 0.87-0.94, p < 0.0001). CONCLUSION: From 1989 to 2007, black decedents were less-and Hispanics were more-likely than whites to die of/with IPF. Research is needed to determine if genetic differences between ethnic/racial groups explain these findings.

Increased risk of pulmonary embolism among US decedents with sarcoidosis from 1988 to 2007.

BACKGROUND: A recently published report from the United Kingdom suggested an association between sarcoidosis and pulmonary embolism (PE). We sought to examine whether this association was present among US decedents with sarcoidosis. METHODS: We used data from the National Center for Health Statistics to investigate the association between sarcoidosis and PE among US decedents from 1988 to 2007. RESULTS: From 1988 to 2007, there were 46,450,489 deaths in the United States and 23,679 decedents with sarcoidosis mentioned on their death certificates. Among these, 602 (2.54%) had PE mentioned on their death certificates, compared with only 1.13% of the background population (P < .0001 for comparison). The association between sarcoidosis and PE was significant regardless of gender (OR, 2.07; 95% CI, 1.80-2.39; P < .0001 for men and OR, 1.76; 95% CI, 1.59-1.96; P ≤ .0001 for women) or race (OR, 1.57; 95% CI, 1.41-1.76; P < .0001 for blacks and OR, 1.87; 95% CI, 1.63-2.14; P < .0001 for whites). Among decedents with sarcoidosis, there was no difference in risk of PE between men and women (2.30% vs 2.54%, χ(2) = 1.32, P = .25) or between blacks and whites (2.60% vs 2.23%, χ(2) = 3.09, P = .08). The association between sarcoidosis and PE held regardless of age. CONCLUSIONS: Using death certificate data from 1988 to 2007, we detected an association between sarcoidosis and PE regardless of gender, race, or age. Further investigation is needed to decipher the mechanisms of this apparent association.

A novel method for modeling facial allodynia associated with migraine in awake and freely moving rats.

Migraine is a neurovascular disorder that induces debilitating headaches associated with multiple symptoms including facial allodynia, characterized by heightened responsivity to normally innocuous mechanical stimuli. It is now well accepted that immune activation and immune-derived inflammatory mediators enhance pain responsivity, including the trigeminal system. Nociceptive ("pain" responsive) trigeminal nerves densely innervate the cranial meninges. We have recently proposed that the meninges may serve as a previously unidentified, key interface between the peripheral immune system and the CNS with potential implications for understanding underlying migraine mechanisms. Our focus here is the development of a model for facial allodynia associated with migraine. We developed a model wherein an indwelling catheter is placed between the skull and dura, allowing immunogenic stimuli to be administered over the dura in awake and freely moving rats. Since the catheter does not contact the brain itself, any proinflammatory cytokines induced following manipulation derive from resident or recruited meningeal immune cells. While surgery alone does not alter immune activation markers, TNF or IL6 mRNA and/or protein, it does decrease gene expression and increase protein expression of IL-1 at 4 days after surgery. Using this model we show the induction of facial allodynia in response to supradural administration of either the HIV glycoprotein gp120 or inflammatory soup (bradykinin, histamine, serotonin, and prostaglandin E2), and the induction of hindpaw allodynia in our model after inflammatory soup. This model allows time- and dose-dependent assessment of the relationship between changes in meningeal inflammation and corresponding exaggerated pain behaviors.

Assessing dyspnea and its impact on patients with connective tissue disease-related interstitial lung disease.

RATIONALE: Dyspnea is the cardinal symptom in patients with any type of interstitial lung disease (ILD); however, there are limited data on dyspnea among patients with connective tissue disease-related ILD (i.e., CTD-ILD). OBJECTIVES: To explore the utility of two dyspnea instruments (the University of California San Diego Shortness of Breath Questionnaire [UCSD] and the Dyspnea-12 [D-12]) and use their scores to examine the impact of dyspnea on the lives of patients with CTD-ILD. METHODS: Subjects were enrolled from the Autoimmune Lung Database (ALD) at National Jewish Health. Chronbach's alpha was used to assess the internal consistency reliability of the two dyspnea questionnaires. We used the Multi-Dimensional Health Assessment Questionnaire [MDHAQ] as a measure of health status and examined associations between health status and dyspnea by using Pearson product-moment correlation and linear regression. RESULTS: The internal consistency reliability of each of the two dyspnea questionnaires was excellent (alpha=0.9 for each). There were significant correlations between either of the two dyspnea measures and MDHAQ components. While controlling for ILD severity, dyspnea as assessed by the UCSD, was a significant predictor of physical function (p=0.04), psychological well-being (p=0.005), and fatigue (p=0.02); dyspnea as assessed the D-12, was a significant predictor of psychological well-being (p=0.01) and global status (p=0.03). CONCLUSION: Dyspnea significantly affects day-to-day functioning and global well-being in patients with CTD-ILD. The UCSD and D-12 yield meaningful information about these patients that measures of pulmonary physiology cannot. Future studies should examine other performance characteristics of these self-report measures in patients with CTD-ILD.

Heart rate recovery after 6-min walk test predicts survival in patients with idiopathic pulmonary fibrosis.

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF), our objectives were to identify predictors of abnormal heart rate recovery (HRR) at 1 min after completion of a 6-min walk test (6MWT) [HRR1] and 2 min after completion of a 6MWT (HRR2), and to determine whether abnormal HRR predicts mortality. METHODS: From 2003 to 2008, we identified IPF patients who had been evaluated at our center (n = 76) with a pulmonary physiologic examination and the 6MWT. We used logistic regression to identify predictors of abnormal HRR, the product-limit method to compare survival in the sample stratified on HRR, and Cox proportional hazards analysis to estimate the prognostic capability of abnormal HRR. RESULTS: Cutoff values were 13 beats for abnormal HRR1 and 22 beats for HRR2. In a multivariable model, predictors of abnormal HRR1 were diffusing capacity of the lung for carbon monoxide (odds ratio [OR], 0.4 per 10% predicted; 95% confidence interval [CI], 0.2 to 0.7; p = 0.003), change in heart rate from baseline to maximum (OR, 0.9; 95% CI, 0.8 to 0.97; p = 0.01), and having a right ventricular systolic pressure > 35 mm Hg as determined by transthoracic echocardiogram (OR, 12.7; 95% CI, 2.0 to 79.7; p = 0.01). Subjects with an abnormal HRR had significantly worse survival than subjects with a normal HRR (for HRR1, p = 0.0007 [log-rank test]; for HRR2, p = 0.03 [log-rank test]); these results held for the subgroup of 30 subjects without resting pulmonary hypertension (HRR1, p = 0.04 [log-rank test]). Among several candidate variables, abnormal HRR1 appeared to be the most potent predictor of mortality (hazard ratio, 5.2; 95% CI, 1.8 to 15.2; p = 0.004). CONCLUSION: Abnormal HRR after 6MWT predicts mortality in IPF patients. Research is needed to confirm these findings prospectively and to examine the mechanisms of HRR in IPF patients.