The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis

We have retrospectively studied 53 patients with idiopathic pulmonary fibrosis and a histologic diagnosis of usual interstitial pneumonia and evaluated the prognostic significance of four individual histologic features (fibroblastic foci [FF], interstitial mononuclear cell infiltrate, established fibrosis, and intra-alveolar macrophages) using a semiquantitative scale of 0-6. An objective count of FF was also undertaken. Using weighted kappa coefficients, interobserver agreement between pathologists was moderate to good (0.56-0.76). Subjective and objective FF scores were strongly associated (R(S) = 0.88, < 0.00005). Mortality was independently linked to a high FF score, p = 0.006, and a low percent predicted carbon monoxide diffusing capacity (DL(CO)), p = 0.01. For pulmonary function, on univariate analysis, the strongest correlations were observed between increasing interstitial mononuclear cell infiltrate or FF scores and greater declines in forced vital capacity (FVC) or DL(CO) at 6 months. Multivariate models revealed that increasing FF scores were independently associated with greater declines in FVC and DL(CO) at both 6 and 12 months. Increasing interstitial mononuclear cell infiltrate scores were also independently linked to functional decline, but only at 6 months. These data suggest a reproducible method on biopsy for predicting rate of disease progression in patients with idiopathic pulmonary fibrosis.     

Effect of anti-reflux therapy on pulmonary function in idiopathic pulmonary fibrosis: a systematic review and meta-analysis

BackgroundCurrent guideline conditionally recommends regular use of anti-reflux medication in idiopathic pulmonary fibrosis (IPF). However, the effect of anti-reflux therapy in this group remains controversial. We systematically reviewed literatures to evaluate whether anti-reflux therapy could ameliorate pulmonary function in IPF.MethodsWe performed electronic search in PubMed, Embase and CENTRAL (Cochrane Central Register of Controlled Trials) to identify original articles published in English language. We included randomized controlled trials (RCTs) and observational studies regarding anti-reflux therapy on pulmonary function in IPF. Qualitative and quantitative analyses were conducted. In quantitative analysis, the inverse-variance method with fixed-effect model was used to analyze pooled data.ResultsFifteen studies (2 RCTs and 13 observational studies) including 3,891 patients with IPF were included. Pooled analysis suggested that anti-reflux therapy did not improve forced vital capacity (FVC)% predicted [mean difference (MD) =0.88, 95% confidence interval (CI): −0.22 to 1.98, P=0.12, I² =0%, 8 studies, n=3,076], diffusing capacity of the lung for carbon monoxide (DLCO) % predicted (MD =0.75, 95% CI: −0.13 to 1.62, P=0.10, I² =0%, 8 studies, n=3,073), and FVC decline (MD =0.02, 95% CI: −0.01 to 0.04, P=0.29, I² =17%, 5 studies, n=1,586) in IPF.DiscussionAnti-reflux therapy may not ameliorate pulmonary function in IPF. However, adequately powered studies are warranted to validate the present findings.     

Validation of a method to screen for pulmonary hypertension in advanced idiopathic pulmonary fibrosis

BACKGROUND: We have developed a method to screen for pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) patients, based on a formula to predict mean pulmonary artery pressure (MPAP) from standard lung function measurements. The objective of this study was to validate this method in a separate group of IPF patients. METHODS: Cross-sectional study of 60 IPF patients from two institutions. The accuracy of the MPAP estimation was assessed by examining the correlation between the predicted and measured MPAPs and the magnitude of the estimation error. The discriminatory ability of the method for PH was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS: There was strong correlation in the expected direction between the predicted and measured MPAPs (r = 0.72; p < 0.0001). The estimated MPAP was within 5 mm Hg of the measured MPAP 72% of the time. The AUC for predicting PH was 0.85, and did not differ by institution. A formula-predicted MPAP > 21 mm Hg was associated with a sensitivity, specificity, positive predictive value, and negative predictive value of 95%, 58%, 51%, and 96%, respectively, for PH defined as MPAP from right-heart catheterization > 25 mm Hg. CONCLUSIONS: A prediction formula for MPAP using standard lung function measurements can be used to screen for PH in IPF patients.     

Assessment of the pulmonary volume pulse in idiopathic pulmonary arterial hypertension by means of electrical impedance tomography

BACKGROUND: Electrical impedance tomography (EIT) is a non-invasive imaging technique which can be used to measure the blood volume changes in the pulmonary vascular bed during the cardiac cycle. STUDY OBJECTIVES: This study was performed to evaluate the differences in the EIT signal of the pulmonary vascular bed between healthy subjects and patients with idiopathic pulmonary arterial hypertension (IPAH), who are known to have a remodelled pulmonary vascular bed. PATIENTS AND METHODS: Twenty-one patients (17 females, 4 males) with IPAH and 30 healthy controls (5 females, 25 males) were measured. EIT measurements were performed in duplicate, on the same day as right heart catheterization to obtain haemodynamic data. The maximal impedance change during systole (Delta Z(sys)) was used as a measure of the pulmonary volume pulse and expressed in arbitrary units (AU). Total lung capacity, spirometric values and diffusion capacity for carbon monoxide were measured as well. RESULTS: Mean Delta Z(sys) was 215 +/- 58 x 10(-2) AU (95% CI 193 x 10(-2) to 236 x 10(-2)) in the healthy subjects and 78 +/- 27 x 10(-2) AU (95% CI 66 x 10(-2) to 91 x 10(-2)) in the IPAH patient group (p < 0.0001). No significant correlation was found between Delta Z(sys) and any of the haemodynamic or lung function data. CONCLUSION: The impedance pulsation of the pulmonary vascular bed is reduced in IPAH in comparison with controls, indicating a reduced volume pulse. This might represent the reduced cross section area, as well as the reduced compliance and number of the pulmonary vessels in these patients.     

Pulmonary function testing prior to reduced intensity conditioning allogeneic stem cell transplantation in an unselected patient cohort predicts posttransplantation pulmonary complications and outcome

Pretransplant pulmonary function tests (PFTs) have been checked mostly in myeloablative allogeneic stem cell transplantation (Allo-SCT). Their value in the setting of reduced intensity conditioning Allo-SCT (Allo-RIC) has been less explored. We retrospectively evaluated the predictive value of PFTs on posttransplant pulmonary complications (PPC) and outcomes in 195 consecutive Allo-RIC patients, based on fludarabine plus busulphan or melphalan. PFT parameters included forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, total lung capacity (TLC), residual volume, and diffusion capacity for carbon monoxide (DLCo) corrected for the hemoglobin levels. Pretransplant PFTs abnormalities were observed in 130 patients (66%). The most frequent abnormalities were abnormal DLCO (n = 83, 44%), followed by FEV1/FVC (n = 75, 38%) and FVC (n = 47, 24%). The abnormalities were severe in 25 (13%) patients, moderate in 65 (33%) and mild in 40 patients (21%). Multivariate analysis showed that TLC was significantly associated with PPC, nonrelapse mortality and overall survival (OS), (HR 4.2, 95% CI. 2-8.5; HR 3.8, 95% CI. 1.7-8.5; HR 2.3, 95% CI. 1.3-4.1, respectively, P = 0.01), while abnormal FVC had a negative impact on PPC and OS (HR 1.8, 95% CI. 0.98-3.6, P = 0.06 and HR 1.7, 95% CI. 1.1-2.6, P = 0.008). This study emphasizes the valuable role of PFTs in identifying patients at risk for PPC, NRM, and lower OS in the Allo-RIC setting.     

Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis

There is significant heterogeneity in survival time among patients with idiopathic pulmonary fibrosis. Studies of baseline clinical and physiologic variables as predictors of survival time have reported inconsistent results. We evaluated the predictive value of changes in clinical and physiologic variables over time for survival time in 81 patients with biopsy-proven idiopathic pulmonary fibrosis. Six-month changes in dyspnea score, total lung capacity, thoracic gas volume, FVC, FEV1, diffusing capacity of carbon monoxide, partial pressure of arterial oxygen, oxygen saturation, and alveolar-arterial oxygen gradient were predictive of survival time even after adjustment for baseline values. Analyses were repeated on 51 patients with 12-month change data. Twelve-month changes in dyspnea score, total lung capacity, FVC, partial pressure of arterial oxygen, oxygen saturation, and alveolar-arterial oxygen gradient were predictive of survival time after adjustment for baseline values. Evaluation of changes in clinical and physiological variables over 6 and 12 months may provide clinicians with more accurate prognostic information than baseline values alone.     

Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests

Objective

To construct a readily applicable formula for selecting patients with systemic sclerosis (SSc) for right‐sided heart catheterization (RHC) based on the results of their pulmonary function tests (PFTs).

Methods

The diagnostic value of PFT variables was quantified in 386 patients with SSc against data obtained from RHC.

Results

We derived the following formula using data from 257 patients: predicted mPAP = 136 – SpO ₂ – 0.25 × DLCO % predicted, where mPAP is the mean pulmonary artery pressure, SpO ₂ is the oxygen saturation as measured by pulse oximetry, and DLCO is the diffusing capacity for carbon monoxide. We validated the formula in the remaining 129 SSc patients. The area under the curve was 0.75 (95% confidence interval [95% CI] 0.67, 0.84). Using a predicted threshold of 25 mm Hg, the sensitivity was 90.1% (95% CI 82, 96) and the specificity was 29.2% (95% CI 17, 44). When used as a screening procedure in a typical scleroderma patient population, it is projected that those with an mPAP below 25 mm Hg are unlikely to have pulmonary hypertension (PH; prevalence 4.4%), those with a predicted mPAP of 25–35 mm Hg are at average risk of having PH (prevalence of 11.3%), and those with a formula‐predicted mPAP above 35 mm Hg are likely to have PH (prevalence of 62.9%), thus justifying RHC. In patients with equivocal findings on echocardiography, a high formula‐predicted mPAP is strongly associated with the presence of PH.

Conclusion

We derived and validated an easily applied formula for determining pulmonary function in patients with SSc that identifies subgroups with a low, average, or high prevalence of PH. It provides information that is complementary to echocardiography and that should improve the selection of patients for RHC.

     

Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography

In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.     

Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis

STUDY OBJECTIVES: The development of pulmonary arterial hypertension (PAH) can complicate many interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). We sought to characterize the prevalence of PAH and its impact on survival in patients with advanced IPF. DESIGN: Retrospective analysis of consecutive IPF patients undergoing pretransplantation right heart catheterization. SETTING: Lung transplant and IPF referral center. METHODS: PAH was defined as a mean pulmonary artery pressure (mPAP) of > 25 mm Hg. We compared demographic, spirometric, 6-min walk test (6MWT) results, and survival outcomes between those with PAH and those without PAH. MEASUREMENTS AND RESULTS: Seventy-nine patients were included in the study. PAH was present in 31.6% of patients (mean [+/- SD] mPAP, 29.5 +/- 3.3 vs 19.1 +/- 3.7 mm Hg, respectively). Those patients with PAH had a lower mean diffusing capacity of the lung for carbon monoxide (Dlco) (37.6 +/- 11.3% vs 31.1 +/- 10.1%, respectively; p = 0.04) and were more likely to require supplemental oxygen (66.7% vs 17.6%, respectively; p < 0.0001). Mean distance walked (143.5 +/- 65.5 vs 365.9 +/- 81.8 m, respectively; p < 0.001) and mean pulse oximetric saturation nadir (80.1 +/- 3.7% vs 88.0 +/- 3.5%, respectively; p < 0.001) during the 6MWT were also lower among those with PAH. PAH was associated with a greater risk of death during the study period (mortality rate, 60.0% vs 29.9%, respectively; odds ratio, 2.6; 95% confidence interval [CI], 2.3 to 3.1; p = 0.001). One-year mortality rates were higher in those with PAH (28.0% vs 5.5%, respectively; p = 0.002). As a predictor of mortality, PAH had a sensitivity, specificity, and accuracy of 57.1%, 79.3%, and 73.4%, respectively. There was a linear correlation between mPAP and outcomes with higher pressures associated with a greater risk of mortality (hazard ratio, 1.09; 95% CI, 1.02 to 1.16). FVC and Dlco did not predict outcomes. CONCLUSIONS: PAH is common in advanced cases of IPF and significantly impacts survival. A reduced Dlco, supplemental oxygen requirement, or poor 6-min walk performance should raise suspicion of the presence of underlying PAH. Identifying PAH might be an important adjunct in monitoring disease progression, triaging for transplantation, and guiding therapy.     

Postoperative pulmonary function in laparoscopic versus open cholecystectomy: prospective, comparative study.

BACKGROUND: Pulmonary complications remain a leading cause of morbidity after major abdominal operations. OBJECTIVE: To compare pulmonary function and the frequency of pulmonary complications after laparoscopic cholecystectomy (LC) and open cholecystectomy (OC). METHODS: Fifty-five patients with symptomatic gallstone disease undergoing elective cholecystectomy (LC 40, OC 15) under general anesthesia were evaluated using pulmonary function tests (forced vital capacity [FVC], forced expiratory volume at 1 second [FEV1], and forced expiratory flow at 25% to 75% [FEF25% -75%], chest X-ray and pulse oximetry before and after surgery. RESULTS: FVC, FEV1 and FEF25% -75% decreased by 21.5%, 21.2% and 30.3%, respectively, on postoperative day 1 following LC, and by 44.3%, 46.2% and 58.3%, respectively, after OC. Chest X-ray showed atelectasis in 15% of patients undergoing LC and 45% of those with OC. CONCLUSION: Impairment in pulmonary function after LC was less marked than after OC.     

Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test

RATIONALE AND HYPOTHESIS: Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide. METHODS: One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation < or = 88% during a baseline 6MWT. For patients with a baseline saturation < or = 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation > 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients. CONCLUSION: These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables.     

Decline in forced vital capacity as a surrogate for mortality in patients with pulmonary fibrosis

Background and Objective

Surrogate endpoints enable determination of meaningful treatment effects more efficiently than applying the endpoint of ultimate interest. We used data from trials of nintedanib in subjects with pulmonary fibrosis to assess decline in forced vital capacity (FVC) as a surrogate for mortality.

Methods

Data from the nintedanib and placebo groups of trials in subjects with idiopathic pulmonary fibrosis, other forms of progressive pulmonary fibrosis, and pulmonary fibrosis due to systemic sclerosis (NCT00514683, NCT01335464, NCT01335477, NCT01979952, NCT02999178, NCT02597933) were pooled. Using joint models for longitudinal and time-to-event data, we assessed the association between decline in FVC % predicted and time to death over 52 weeks. The rate of change in FVC % predicted and the current value of FVC % predicted were modelled longitudinally and estimates applied as predictors in time-to-event models.

Results

Among 2583 subjects with pulmonary fibrosis, both a greater rate of decline in FVC % predicted and a lower current value of FVC % predicted were associated with an increased risk of death over 52 weeks (HR 1.79 [95% CI: 1.57, 2.03] and HR 1.24 [1.17, 1.32] per 5-percentage point decrease, respectively). Associations between the rate of change in FVC % predicted and the risk of death were consistent between patients with IPF and other ILDs.

Conclusion

Data from clinical trials in subjects with pulmonary fibrosis of diverse aetiology demonstrate a strong association between decline in FVC % predicted and mortality over 52 weeks, supporting FVC decline as a surrogate for mortality in these patients.     

Pulmonary arterial hypertension and severe pulmonary fibrosis in systemic sclerosis patients with a nucleolar antibody

OBJECTIVE: Pulmonary arterial hypertension (PAH) and severe pulmonary fibrosis (SPF) are the most common causes of death in scleroderma. Our study focuses on lung disease in patients with a nucleolar antibody in comparison to other scleroderma-specific autoantibodies. METHODS: Patients initially seen between 1972 and 1995 (and followed through 2004) with [systolic pulmonary artery pressure (sPAH) (PASP > 50 mm Hg] or SPF [forced vital capacity (FVC%) < 55% predicted) were grouped by the presence of anticentromere antibody (ACA), an isolated antinucleolar antibody (ANoA), or an antitopoisomerase antibody-I (TOPO). RESULTS: Twenty percent of ACA, 23% of TOPO, and 32% of ANoA patients had severe lung disease (p < 0.005). In ANoA patients with PAH without severe fibrosis, the FVC was lower (71% predicted) than in ACA patients, suggesting they had some interstitial fibrosis. However, they had a higher FVC%/diffusing capacity for carbon monoxide (DLCO)% ratio than the ACA patients (2.4 vs 1.8). pulmonary hypertension in TOPO patients was associated with a lower FVC%/DLCO% ratio and lower levels of PAP than either the PAH in ACA or ANoA patients. CONCLUSION: Scleroderma-specific autoantibodies are associated with characteristic subgroups of lung disease. The ANoA patients have a unique mixture of PAH and SPF subgroups of lung disease. Scleroderma-specific autoantibodies and the FVC%/DLCO% ratio are helpful in determining whether a patient has PAH alone, PAH along with pulmonary fibrosis, or secondary PAH from chronic hypoxia with SPF.     

Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis

BACKGROUND: Lung inflammation (alveolitis) may cause lung fibrosis in scleroderma. OBJECTIVE: To determine whether cyclophosphamide treatment is associated with retention of lung function and improved survival in scleroderma patients with alveolitis. DESIGN: Retrospective cohort study. SETTING: Johns Hopkins and University of Maryland Scleroderma Center. PATIENTS: 103 patients with scleroderma who had bronchoalveolar lavage or lung biopsy. INTERVENTION: Cyclophosphamide therapy. MEASUREMENTS: 1) Serial measurement of forced vital capacity (FVC) and carbon monoxide diffusing capacity and 2) survival. RESULTS: During a median follow-up of 13 months after bronchoalveolar lavage or biopsy, patients with alveolitis who did not receive cyclophosphamide therapy experienced a decrease in FVC (mean difference, -0.28 L [95% Cl, -0.41 to -0.16 L] and -7.1% of the predicted value [Cl, -10.9% to -4.0%]). Carbon monoxide diffusing capacity also decreased in these patients (mean difference, -3.3 x mmol min(-1) x kPa(-1) [Cl, -4.6 to -2.1 mmol x min(-1) x kPa(-1)] and -9.6% of the predicted value [Cl, -16.7% to -2.4%]). During a median follow-up of 16 months, patients with alveolitis who received cyclophosphamide were more likely to have a good outcome (stabilization or improvement) in FVC (relative risk, 2.5 [Cl, 1.5 to 4.1]) and diffusing capacity (relative risk, 1.5 [Cl, 1.0 to 2.2]). These patients also had improved survival; the median survival rate was 89% (25th, 75th percentiles, 84%, 94%) compared with 71% (25th, 75th percentiles, 55%, 86%) in untreated patients (P = 0.01, log-rank test). CONCLUSIONS: The presence of lung inflammation identifies patients with scleroderma who are more likely to have worsening lung function. Lung function outcomes and survival are improved in patients with alveolitis who receive cyclophosphamide.     

Clinical characteristics of idiopathic pulmonary fibrosis patients with gender,age, and physiology staging at Okinawa Chubu Hospital

Background

Gender, age, and physiology (GAP) staging was recently advocated for idiopathic pulmonary fibrosis (IPF). However, clinical findings of GAP staging for IPF are limited. We aimed to investigate the clinical characteristics of IPF patients according to GAP staging in our hospital.

Methods

We retrospectively reviewed patient medical records and chest high-resolution computed tomography (HRCT) images from June 1, 2002, to December 31, 2012.

Results

We identified 54 IPF patients with [36 men; mean age: 71 years (range, 53-85 years)]. Mean fibrosis and ground glass opacity (GGO) scores were 1.9 (0-4) and 1.6 (1-3.3), respectively. Mean percent predicted forced vital capacity (% FVC), percent predicted diffusing capacity of the lung for carbon monoxide (% DLco) were 70.6 (6.4-114.3), 49.2 (15-105.9), respectively. Cox proportional hazards model showed that gender, percent predicted diffusing capacity of the lung for carbon monoxide (% DLco), and composite physiologic index (CPI) were strong predictors of mortality. Stage III patients had more pulmonary hypertension (50% vs. 23%, 0%) and progressive modified Medical Research Council (mMRC) changes at 1 year (1.3 vs. 0.6, 1.1; P=0.07) compared with other stages.

Conclusions

In our cohort, GAP staging was useful for evaluating IPF severity. Stage III patients might had more pulmonary hypertension and progressive dyspnea. Multicenter analyses are warranted to confirm these findings.

Keywords

Idiopathic pulmonary fibrosis (IPF); modified Medical Research Council (mMRC); mortality; pulmonary hypertension; staging     

Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.

The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper zones and diffuse parenchymal lung disease with fibrosis of the lower zones of the lungs on chest computed tomography. Patients (all smokers) included 60 males and one female, with a mean age of 65 yrs. Dyspnoea on exertion was present in all patients. Basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests were as follows (mean+/-sd): total lung capacity 88%+/-17, forced vital capacity (FVC) 88%+/-18, forced expiratory volume in one second (FEV1) 80%+/-21 (% predicted), FEV1/FVC 69%+/-13, carbon monoxide diffusion capacity of the lung 37%+/-16 (% predicted), carbon monoxide transfer coefficient 46%+/-19. Pulmonary hypertension was present in 47% of patients at diagnosis, and 55% during follow-up. Patients were followed for a mean of 2.1+/-2.8 yrs from diagnosis. Survival was 87.5% at 2 yrs and 54.6% at 5 yrs, with a median of 6.1 yrs. The presence of pulmonary hypertension at diagnosis was a critical determinant of prognosis. The authors hereby individualise the computer tomography-defined syndrome of combined pulmonary fibrosis and emphysema characterised by subnormal spirometry, severe impairment of gas exchange, high prevalence of pulmonary hypertension, and poor survival.     

The relationship between serum immunoglobulin levels and pulmonary involvement in systemic sclerosis

OBJECTIVE: To examine the relationship between serum immunoglobulin (Ig) levels and pulmonary function in patients with systemic sclerosis (SSc). METHODS: Twenty-four patients with SSc who had at least 2 sets of pulmonary function tests (PFT) at intervals of more than one year were eligible. Multiple linear regression models were constructed for prediction of the annualized rates of change of forced vital capacity (FVC), carbon monoxide diffusing capacity (DL(CO)), and DL(CO) per unit alveolar volume (K(CO)). RESULTS: The rates of change of FVC and K(CO) correlated with the annualized rate of change of IgG (p < 0.001 and p = 0.005, respectively), and the rate of change of DL(CO) correlated with the serum IgM level at the first PFT (p = 0.020) and with the annualized rate of change of IgG (p = 0.007). CONCLUSION: The rates of change of serum Ig levels are associated with those of pulmonary function in SSc. Use of this model may assist investigation of pulmonary involvement.     

Predictability of oxygen desaturation during sleep in patients with cystic fibrosis : clinical, spirometric, and exercise parameters

BACKGROUND: The purpose of this study was to determine how common sleep-related desaturation with preserved awake resting pulse oximetric saturation (SpO(2)) was in a large cohort of adult cystic fibrosis (CF) patients with variable degrees of pulmonary disease. We then determined whether nocturnal desaturation could reliably be predicted from standard clinical and exercise parameters. METHODS: Seventy CF patients participated in the study (mean [SD] age, 27.3 [8.7] years; women, 54%; percent predicted FEV(1) [%predFEV(1)], 55.7% [23.9%]). Nocturnal, resting, and exercise SpO(2) were measured. Nocturnal oximetry was measured in the patient's home. Maximal oxygen capacity (Vo(2)max) was determined from a graded exercise test on a stationary bicycle ergometer. The Shwachman-Kulczycki (S-K) illness severity score was calculated incorporating categories of functional capacity, physical examination, nutrition, and chest radiograph. RESULTS: Multivariate analysis reported significant differences (p < 0.0001) between pulmonary disease severity and overall distribution of nocturnal SpO(2), with the main difference being for patients with severe pulmonary disease (%predFEV(1) of < 50%) compared to patients with mild or moderate disease in the SpO(2) intervals of 100 to 96% (p < 0.0001) and 90 to 86% (p = 0.0001). Pulmonary function, S-K clinical scores, f1.gif" BORDER="0">O(2)max, and resting and maximal SpO(2) correlated significantly (p < 0.05) with nocturnal SpO(2) levels. Stepwise discriminant analysis identified %predFEV(1) (or S-K scores) and resting SpO(2) as the parameters that could best discriminate patients not likely to experience nocturnal desaturation. Specifically, our equation could predict 91% of cases less likely to nocturnally desaturate, but could only modestly predict those more likely to desaturate (i.e., 26% of cases). CONCLUSIONS: Spirometric parameters and measurements of awake resting oxygenation are of limited utility in predicting nocturnal desaturation. Nocturnal oximetry should be considered in patients with moderate to severe lung disease even with preserved awake resting SpO(2).     

Melatonin administration acutely decreases the diffusing capacity of carbon monoxide in human lungs

BACKGROUND: Most physiological measurements of the pulmonary diffusing capacity use carbon monoxide (CO) as a tracer gas. Similar to CO, melatonin binds the hemoglobin in the blood. OBJECTIVE: The present study was designed to assess the effect of exogenous melatonin administration on pulmonary functions including diffusing capacity for carbon monoxide (DL(CO)) in healthy subjects. METHODS: The study was performed in a randomized, double-blind, placebo-controlled manner. DL(CO) was measured in 22 healthy male volunteers (age 18-25 years) who were randomized to melatonin (n = 11) and placebo administration (n = 11). At baseline, DL(CO), alveolar volume (V(A)) and other spirometric parameters such as forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), peak expiratory flow (PEF) and maximal voluntary ventilation (MVV) were measured. DL(CO) was then corrected for the hemoglobin concentration. Measurements were repeated in a double-blind fashion 60 min after the administration of melatonin (1 mg) or placebo. RESULTS: DL(CO) was significantly decreased (39.31 +/- 4.75 vs. 34.82 +/- 6.18 ml/min/mm Hg) 60 min after the melatonin administration (p = 0.01), while FEV(1), FVC, FEV(1)/FVC, PEF and MVV values did not demonstrate significant differences. Placebo administration did not result in significant alteration in any of these parameters. CONCLUSIONS: In healthy subjects, oral administration of melatonin acutely influences the DL(CO) without affecting other pulmonary function test results. We conclude that melatonin may have a reducing effect on the DL(CO) in the lungs.     

Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids

STUDY OBJECTIVES: To prospectively examine the role of cyclophosphamide in patients with idiopathic pulmonary fibrosis that is unresponsive to or intolerant of high-dose steroid treatment. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Nineteen patients with biopsy specimen-proven usual interstitial pneumonia who failed to respond (n = 16) or experienced adverse effects (n = 3) from corticosteroid treatment (1 mg/kg/d for 3 months). INTERVENTION: Steroid therapy was tapered quickly, and oral cyclophosphamide, 2 mg/kg/d, was prescribed (mean duration of treatment, 6.0 +/- 0.9 months). MEASUREMENTS AND RESULTS: In 10 patients, response to therapy was determined by pretreatment and posttreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function, including exercise saturation) scores (CRP). Response was defined as a > 10-point drop in CRP; stable as +/- 10-point change in CRP; and nonresponders as > 10-point rise in CRP. In nine patients, physiologic criteria were used to assess response; significant changes in pulmonary function were defined as follows: total lung capacity, +/- 10% of baseline value; FVC, +/- 10% of baseline value, diffusion capacity of the lung for carbon monoxide, +/- 20% of baseline value; and resting pulse oximetry, +/- 4% of baseline value. Patients who died while receiving or shortly after discontinuing cyclophosphamide were classified as nonresponders (n = 2). Among 19 patients treated with cyclophosphamide, only 1 patient demonstrated sustained response; 7 patients remained stable and 11 deteriorated while receiving the drug. Toxicity associated with cyclophosphamide was substantial; more than two thirds of the patients developed drug-related adverse effects, and almost half discontinued the drug prematurely due to side effects. In the remaining patients, cyclophosphamide therapy was discontinued due to lack of improvement or progressive deterioration. CONCLUSIONS: Cyclophosphamide therapy is of limited efficacy in patients with idiopathic pulmonary fibrosis who fail to respond or who experience adverse effects from corticosteroid treatment, and adverse effects often complicate its use.