Comparison of different reference values for lung function: implications of inconsistent use among centers.

BACKGROUND: For interpretation of pulmonary function tests (PFTs), reference values based on sex, age, height and ethnicity are needed. In Norway, the European Coal and Steel Community (ECSC) reference values remain widely used, in spite of recommendations to implement the more recent Global Lung Function Initiative (GLI) reference values. OBJECTIVE: To assess the effects of changing from ECSC to GLI reference values for spirometry, DLCO and static lung volumes, using a clinical cohort of adults with a broad range in age and lung function. METHODS: PFTs from 577 adults (18-85 years, 45% females) included in recent clinical studies were used to compare ECSC and GLI reference values for FVC, FEV1, DLCO, TLC and RV. Percent predicted and lower limit of normal (LLN) were calculated. Bland-Altman plots were used to assess agreement between GLI and ECSC % predicted values. RESULTS: In both sexes, GLI % predicted values were lower for FVC and FEV1, and higher for DLCO and RV, compared to ECSC. The disagreement was most pronounced in females, with mean (SD) difference 15 (5) percent points (pp) for DLCO and 17 (9) pp for RV (p < 0.001). With GLI, DLCO was below LLN in 23% of the females, with ECSC in 49% of the females. CONCLUSIONS: The observed differences between GLI and ECSC reference values are likely to entail significant consequences with respect to criteria for diagnostics and treatment, health care benefits and inclusion in clinical trials. To ensure equity of care, the same reference values should be consistently implemented across centers nationwide.

Total late effect burden in long-term lymphoma survivors after high-dose therapy with autologous stem-cell transplant and its effect on health-related quality of life.

Lymphoma survivors after high-dose therapy with autologous stem-cell transplant (HDT-ASCT) are at risk of several late effects, which might impair their health-related quality of life (HRQoL). We assessed the total late effect burden in this population, and how it affects HRQoL. All lymphoma survivors treated with HDT-ASCT as adults in Norway between 1987 and 2008 were identified, and 271 (68%) attended both a comprehensive clinical assessment and completed a questionnaire. Severity of 45 conditions in 12 organ-system categories were graded as mild, moderate, severe or life-threatening, according to a modified version of CTCAEv4.03. At a median of 8 years after HDT-ASCT, 98% of survivors had at least one moderate or more severe late effect and 56% had severe or life-threatening late effects. Fourteen percent had low, 39% medium and 47% high late effect burden, defined as having moderate or more severe late effects in 0-1, 2-3 and >3 organsystems, respectively. Female sex, increasing age, B-symptoms at diagnosis and >1 treatment line prior to HDT-ASCT were independently associated with having high late effect burden. The survivors had significantly poorer physical and mental HRQoL assessed by the Short Form-36 compared to age- and sex-matched controls. The prevalence of poor physical and mental HRQoL increased with higher late effect burden (both P<0.001), and the low burden group had better physical HRQoL than controls (P<0.001). In conclusion, lymphoma survivors after HDT-ASCT have impaired HRQoL, seemingly driven by a high late effect burden. This highlights the importance of prevention, regular assessments for early detection and treatment of late effects and modifiable risk factors.

Late-Onset, Noninfectious Pulmonary Complications following Allogeneic Hematopoietic Stem Cell Transplantation: A Nationwide Cohort Study of Long-Term Survivors.

BACKGROUND: Survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk for pulmonary adverse events. Data on late-onset noninfectious pulmonary complications in long-term adult survivors of allo-HSCT are limited and incomplete. OBJECTIVES: This study aimed (1) to determine occurrence and degree of pulmonary sequelae in adult survivors of allo-HSCT and (2) to identify associations between pulmonary function, high-resolution CT (HRCT), and clinical characteristics. METHOD: In a nationwide, single-center cross-sectional study, 103 survivors (aged median [range] 35 [17-58] years, 53% females) were examined 17 (6-32) years after allo-HSCT and compared with healthy controls (n = 105). Methods included pulmonary function tests and HRCT. RESULTS: Chronic graft-versus-host disease was diagnosed in 33% of survivors, including 12% with bronchiolitis obliterans syndrome (BOS). Mean lung volumes (TLC, FVC, and FEV1) and gas diffusing capacity were >80% of predicted for the survivors as a group, but significantly lower than in healthy controls. Pathological HRCT findings were detected in 48% of the survivors (71% airways disease, 35% interstitial lung disease, and 24% apical subpleural interstitial thickening). Air trapping (%) on HRCT correlated with % predicted FEV1, p < 0.001. In a multiple logistic regression model, both BOS and pathological findings on HRCT were associated with chemotherapy prior to allo-HSCT, p < 0.05. CONCLUSIONS: Long-term allo-HSCT survivors had significantly lower pulmonary function than age- and gender-matched healthy controls and nearly half had pathological findings on HRCT. Longitudinal data will determine if pulmonary sequelae will remain stable or progress. We recommend lifelong monitoring of pulmonary function in allo-HSCT survivors. HRCT provides additional information, but is not suited for surveillance.

Determinants of cardiorespiratory fitness in very long-term survivors of allogeneic hematopoietic stem cell transplantation: a national cohort study.

PURPOSE: Survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk for cardiopulmonary adverse events. Data on long-term effects on cardiorespiratory fitness are limited. To address the gap in knowledge, we aimed to determine peak oxygen uptake (V̇O2peak) and identify associations between cardiorespiratory fitness and clinical characteristics, self-reported physical activity, cardiac, and pulmonary function. METHODS: In a nationwide, single-center cross-sectional study, 90 survivors [aged median (range) 35 (17-54) years, 56% females] were examined, 17 (6-26) years after allo-HSCT. Myeloablative conditioning comprised busulfan/cyclophosphamide or cyclophosphamide only. Methods included pulmonary function tests, echocardiography, and cardiopulmonary exercise test. RESULTS: Chronic graft-versus-host disease (cGVHD) was found in 31% of the subjects, of whom 40% had bronchiolitis obliterans syndrome (BOS). Seventy-one percent of the survivors did not meet WHO recommendations for physical activity and 42% were overweight. Reduced gas diffusion (DLCO) and systolic ventricular dysfunction (LVEF) were found in 44% and 31%, respectively. For the group, mean (95% CI), V̇O2peak was 36.4 (34.7-38.0) mL/min/kg [89 (85-93)% of predicted]. V̇O2peak was low at 43%. Cardiopulmonary factors and deconditioning were equally common limitations for exercise. In a multiple linear regression model, low V̇O2peak was associated with low DLCO, low LVEF, BOS, overweight, and inactivity. CONCLUSION: Half of the survivors had reduced cardiorespiratory fitness median 17 years after allo-HSCT. Cardiopulmonary factors and deconditioning were equally common limitations to exercise. We encourage long-term cardiopulmonary monitoring of allo-HSCT survivors and targeted advice on modifiable lifestyle factors.

Risk factors for impaired pulmonary function and cardiorespiratory fitness in very long-term adult survivors of childhood acute lymphoblastic leukemia after treatment with chemotherapy only.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk of late treatment-related side-effects. Data regarding prevalence and risk factors for impairments in pulmonary function and cardiorespiratory fitness are limited, and reported findings are inconsistent and inconclusive. MATERIAL AND METHODS: In a cross-sectional study, 116 ALL survivors (median 5 years at diagnosis, 29 years at follow-up, 53% females) were examined, median 23 years after treatment with chemotherapy only. Individual cumulative doses of cytostatic agents were calculated. Methods included blood tests, echocardiography, pulmonary function tests and cardiorespiratory exercise test. RESULTS: Females had lower % predicted gas diffusing capacity (DLCO) than males (mean [SD] 84 [13] versus 97 [14], p < .001). Impairment in DLCO was found in 34% females versus 7% males, p < .001. In a multiple linear regression model, female gender, body mass index (BMI) and smoking were risk factors for reduced % predicted DLCO, with a borderline significant effect of left ventricular ejection fraction (LVEF). Impaired cardiorespiratory fitness was found in 42% of the survivors, with a borderline increased risk in females, p = .06. Smoking and BMI were risk factors for reduced % predicted VO2peak. Subjects exposed to anthracyclines had lower LVEF% and % predicted VO2peak than those not exposed, (mean [SD] 56.2 [4.3] versus 59.2 [5.2], p = .01 and 86.9 [18.4] versus 92.8 [18.4], p = .03, respectively). CONCLUSIONS: Impairments in pulmonary function and cardiorespiratory fitness are common in very long-term survivors of childhood ALL. Risk factors are female gender, BMI and smoking. In order to preserve pulmonary function and cardiorespiratory fitness, we suggest increased attention and targeted advice on modifiable lifestyle factors such as smoking, inactivity and overweight.

Global Lung Function Initiative 2012 reference equations for spirometry in the Norwegian population.

We studied the fit of the Global Lung Function Initiative (GLI) all-age reference values to Norwegians, compared them with currently used references (European Community for Steel and Coal (ECSC) and Zapletal) and estimated the prevalence of obstructive lung disease.Spirometry data collected in 30 239 subjects (51.7% females) aged 12-90 years in three population-based studies were converted to z-scores.We studied healthy non-smokers comprising 2438 adults (57.4% females) aged 20-90 years and 8725 (47.7% female) adolescents aged 12-19 years. The GLI-2012 prediction equations fitted the Norwegian data satisfactorily. Median±sd z-scores were respectively 0.02±1.03, 0.01±1.04 and -0.04±0.91 for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in males, and -0.01±1.02, 0.07±0.97 and -0.21±0.82 in females. The ECSC and Zapletal references significantly underestimated FEV1 and FVC. Stricter criteria of obstruction (FEV1/FVC GLI-2012 LLN. Corresponding comparison regarding myocardial infarction showed a four-fold higher risk for women.The GLI-2012 reference values fit the Norwegian data satisfactorily and are recommended for use in Norway. Correspondingly, the FEV1/FVC GLI-2012 LLN identifies higher risk of obstructive characteristics than FEV1/FVC <0.7.

Impaired exercise capacity and left ventricular function in long-term adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for late cardiotoxic effects of cancer treatment, but conflicting evidence exists on the effects of anthracyclines on left ventricular (LV) diastolic function and exercise capacity. PROCEDURE: We performed a cross-sectional study with comprehensive echocardiography in 138 adult survivors of childhood ALL, median 23.4 years after diagnosis. Pulsed tissue Doppler measurements of early diastolic mitral annular velocities (e') were used for the assessment of diastolic function, and compared to 138 matched controls. Of the survivors, 133 also performed ergospirometry measuring peak oxygen uptake (VO2 max). Associations between cancer treatment, LV function, and VO2 max were analyzed. RESULTS: The survivor group had lower e' values than controls (e' septal 11.0 vs. 12.6 cm/s, P < 0.001), but the difference was confined to the subgroup of anthracycline treated survivors (median cumulative dose 120 mg/m(2) ). Anthracycline exposure was inversely correlated with e' (regression coefficient -1.581, P=0.009). Reduced VO2 max/kg occurred in 47% of the survivors, but more often in anthracycline treated survivors (56%) than anthracycline naïve survivors (17%, P<0.001). Anthracycline exposure was inversely correlated with VO2 max/kg (regression coefficient -3.084, P = 0.05 in multivariate analysis). Furthermore, associations were observed between measures of LV function and VO2 max/kg, and e' was the best predictor of VO2 max/kg (standardized coefficient 0.355, P < 0.001 in multivariate analysis). CONCLUSIONS: Adult survivors of childhood ALL have increased risk for impaired LV diastolic function and impaired exercise capacity, both associated with previous anthracycline exposure. Furthermore, there is an association between LV diastolic function and exercise capacity.

A role for the terminal C5-C9 complement pathway in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by damage to the alveolar epithelium, leading to fibrosis and excessive accumulation of extracellular matrix in the interstitium of the lung. In the present study we performed high-resolution proteomic profiling of bronchoalveolar lavage (BAL) from IPF patients and controls, and found that the complement pathway was highly upregulated in IPF. The proteins C5, C6, C7, C8, and C9, all of which are part of the complement end product, TCC, were all upregulated. We also found that TCC levels were increased in plasma among IPF patients compared to controls, after adjustment for age, sex and BMI [mean (SD) 0.62 (0.24) vs. 0.33 (0.10), p = 0.031]. These findings suggest a role for the complement system in the pathogenesis of IPF.

Effect of high-intensity training on peak oxygen uptake and muscular strength after lung transplantation: A randomized controlled trial.

BACKGROUND: Peak oxygen uptake (VO2peak) remains low after lung transplantation (LTx). We evaluated the effect of high-intensity interval training (HIIT) on VO2peak, muscular strength, health-related quality of life (HRQOL), pulmonary function, and physical function after LTx. METHODS: In this randomized controlled trial, 54 participants were enrolled from 6 to 60 months after LTx. The HIIT group (n = 25) followed a supervised HIIT program, consisting of endurance and strength trainings 3 times a week for 20 weeks. The control group (n = 29) received usual care. The primary outcome was a change in VO2peak measured by cardiopulmonary exercise testing. The secondary outcomes were changes in 1-repetition maximum (1RM) for arm press and leg press, HRQOL (36-Item Short-Form Health Survey [SF-36]), pulmonary function (forced expiratory volume in 1 sec, diffusing capacity of the lungs for carbon monoxide), and physical function (1RM in handgrip, 15-sec stair run, and 30-sec chair stand). RESULTS: A total of 46 participants completed the study, including 23 of 25 in the intervention group. For the primary outcome, the intention-to-treat analysis revealed a non-significant between-group difference for change in VO2peak of 0.7 ml/(kg.min) (95% CI = ‒0.3, 1.8) (p = 0.17). The between-group differences for 1RM arm press and leg press and mental aspect of SF-36 were 4.9 kg (95% CI = ‒0.1, 9.9) (p = 0.05), 11.6 kg (95% CI = 0.1, 23.0) (p < 0.05), and 5.7 kg (95% CI = 0.9, 10.4) (p = 0.02), respectively. There were no between-group differences in pulmonary function or physical function. When excluding participants with an attendance of <70% (n = 16), the between-group difference for VO2peak was 1.2 ml/(kg.min) (95% CI = 0.1, 2.4) (p = 0.032). CONCLUSIONS: HIIT improved muscular strength and HRQOL but did not improve VO2peak more than usual care after LTx. However, with acceptable adherence, HIIT appears to have beneficial effects on VO2peak.

Association Between Nailfold Capillary Density and Pulmonary and Cardiac Involvement in Medium to Longstanding Juvenile Dermatomyositis.

OBJECTIVE: To explore the associations between microvascular abnormalities as assessed by nailfold capillaroscopy (NFC) and pulmonary and cardiac involvement in patients with juvenile dermatomyositis (DM) who are assessed after medium- to long-term follow-up. METHODS: Fifty-eight patients with juvenile DM were examined a mean ± SD of 17.0 ± 10.6 years after symptom onset. Nailfold capillary density (NCD) and a neovascular pattern (defined as an active or late scleroderma pattern) were analyzed, with blinding to clinical data. Pulmonary involvement was assessed by pulmonary function tests including spirometry, diffusing capacity for carbon monoxide (DLco), and body plethysmography. High-resolution computed tomography (HRCT) was also performed. Cardiac involvement was assessed by electrocardiography, Holter monitoring (heart rate variability), and echocardiography. RESULTS: Patients with low NCD (<6 capillaries/mm) (n = 21), compared to patients with normal NCD (≥6 capillaries/mm) (n = 37) had lower forced vital capacity (89.7% versus 98.5% predicted), total lung capacity (87.8% versus 94.5% predicted), and more often had low DLco values (15 [71%] of 21 patients versus 14 [38%] of 37 controls) (all P < 0.05). Use of HRCT to assess airway disease was more frequent in the group with low NCD (6 [30%] of 20 patients versus 3 [8%] of 36 patients in the normal NCD group; P = 0.034). No associations between NCD and cardiac parameters or between neovascular pattern and pulmonary or cardiac parameters were observed. CONCLUSION: In patients with juvenile DM, low NCD was associated with lung involvement, which was mostly subclinical. No significant associations with cardiac involvement were observed. These results shed light on possible mechanisms underlying organ involvement, but further and preferably larger studies are needed to identify NCD as a potential biomarker for lung and cardiac involvement in juvenile DM.