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Background: Exercise-induced hypoxaemia is a hallmark of chronic fibrotic interstitial lung disease ( f -ILD). It remains unclear whether patients' severe hypoxaemia may exaggerate locomotor muscle fatigue and, if so, to what extent oxygen (O 2 ) supplementation can ameliorate these abnormalities., Methods: Fifteen patients (12 males, 9 with idiopathic pulmonary fibrosis) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) while breathing medical air. Fifteen age-matched and sex-matched controls cycled up to patients' Tlim. Patients repeated the exercise test on supplemental O 2 (42%±7%) for the same duration. Near-infrared spectroscopy assessed vastus lateralis oxyhaemoglobin concentration ((HbO 2 )). Pre-exercise to postexercise variation in twitch force (∆Tw) induced by femoral nerve magnetic stimulation quantified muscle fatigue., Results: Patients showed severe hypoxaemia (lowest O 2 saturation by pulse oximetry=80.0%±7.6%) which was associated with a blunted increase in muscle (HbO 2) during exercise vs controls (+1.3±0.3 µmol vs +4.4±0.4 µmol, respectively; p<0.001). Despite exercising at work rates ∼ one-third lower than controls (42±13 W vs 66±13 W), ∆Tw was greater in patients (∆Tw/external work performed by the leg muscles=-0.59±0.21 %/kJ vs -0.25±0.19 %/kJ; p<0.001). Reversal of exertional hypoxaemia with supplemental O 2 was associated with a significant increase in muscle (HbO 2) , leading to a reduced decrease in ∆Tw in patients (-0.33±0.19 %/kJ; p<0.001 vs air). Supplemental O 2 significantly improved leg discomfort (p=0.005)., Conclusion: O 2 supplementation during exercise improves leg muscle oxygenation and fatigue in f -ILD. Lessening peripheral muscle fatigue to enhance exercise tolerance is a neglected therapeutic target that deserves clinical attention in this patient population., Competing Interests: Competing interests: MM was funded by a European Respiratory Society’s Long Term Fellowship and the John Alexander Stuart Fellowship, Queen’s University. JAN has been funded by the New Clinician Scientist Program from the Southeastern Ontario Academic Medical Association (SEAMO), Canada. His laboratory was established owing to the Canadian Foundation for Innovation’s John R. Evans Leaders Fund, Canada., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To determine high resolution computed tomography (HRCT) patterns and pulmonary function indices which are associated with increased mortality in patients with connective tissue disease related fibrotic lung disease (CTD-FLD)., Methods: HRCTs from 168 patients with CTD-FLD were scored by 2 observers for a variety of HRCT patterns and traction bronchiectasis. A radiological diagnosis of usual interstitial pneumonia (UIP), fibrotic non-specific interstitial pneumonia (NSIP) or indeterminate was also assigned. Using Cox regression analysis, associations with mortality were identified. Honeycombing and traction bronchiectasis scores were converted to binary absence/presence scores and also tested. A subgroup analysis of patients with biopsy material (n=51) was performed by classifying patients according to radiological and histopathological diagnoses, as concordant UIP, discordant UIP and fibrotic NSIP. The prognostic separation of this classification was also evaluated., Results: Severity of traction bronchiectasis (HR 1.10, p=0.001, 95% CIs 1.04 to 1.17), increasing extent of honeycombing (HR 1.08, p=0.021, 95% CI 1.03 to 1.13) and reduction in DLco (HR 0.97, p=0.013, 95% CI 0.95 to 0.99) were independently associated with increased mortality. Interobserver agreement and prognostic strength were higher for binary traction bronchiectasis scores (weighted κ (κw)=0.69, HR 4.00, p=0.001, 95%CI 1.19 to 13.38), than binary honeycombing scores (κw=0.50, HR 2.87, p=0.022, 95% CI 1.53 to 5.43). The radiological-histopathological classification was strongly associated with increased mortality (HR 2.74, p<0.001, 95% CI 1.57 to 4.77) and patients with discordant UIP had a better prognosis than concordant UIP but worse prognosis than fibrotic NSIP., Conclusions: Severity of traction bronchiectasis, extent of honeycombing and DLco are strongly associated with mortality in CTD-FLD. Interobserver agreement for traction bronchiectasis is higher than for honeycombing. In CTD-FLD, radiological diagnosis has survival implications in biopsy proven UIP.

Background: A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population., Methods: Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis., Results: A significant association of the MUC5B promoter single nucleotide polymorphism with IPF (p=2.04 × 10(-17); OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF., Conclusions: We confirm the MUC5B variant association with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association.

Background: Pulmonary fibrosis (PF), cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often cause chronic respiratory failure (CRF)., Methods: In order to investigate if there are different patterns of adaptation of the ventilatory pump in CRF, in three groups of lung transplant candidates with PF (n=9, forced expiratory volume in 1 s (FEV(1))=37+/-3% predicted, forced vital capacity (FVC)=32+/-2% predicted), CF (n=9, FEV(1)=22+/-3% predicted, FVC=30+/-3% predicted) and COPD (n=21, FEV(1)=21+/-1% predicted, FVC=46+/-2% predicted), 10 healthy controls and 16 transplanted patients, total and compartmental chest wall volumes were measured by opto-electronic plethysmography during rest and exercise., Results: Three different breathing patterns were found during CRF in PF, CF and COPD. Patients with COPD were characterised by a reduced duty cycle at rest and maximal exercise (34+/-1%, p<0.001), while patients with PF and CF showed an increased breathing frequency (49+/-6 and 34+/-2/min, respectively) and decreased tidal volume (0.75+/-0.10 and 0.79+/-0.07 litres) (p<0.05). During exercise, end-expiratory chest wall and rib cage volumes increased significantly in patients with COPD and CF but not in those with PF. End-inspiratory volumes did not increase in CF and PF. The breathing pattern of transplanted patients was similar to that of healthy controls., Conclusions: There are three distinct patterns of CRF in patients with PF, CF and COPD adopted by the ventilatory pump to cope with the underlying lung disease that may explain why patients with PF and CF are prone to respiratory failure earlier than patients with COPD. After lung transplantation the chronic adaptations of the ventilatory pattern to advanced lung diseases are reversible and indicate that the main contributing factor is the lung itself rather than systemic effects of the disease.

Background and Aims: Pulmonary hypertension (PH) is increasingly recognised in patients with diffuse lung disease, and is associated with increased mortality. Cardiac output (CO) is a prognostic marker in PH. Non-invasive assessment of pulmonary blood flow (PBF(INNOCOR)) with the inert gas rebreathing Innocor device has been validated against CO in PH, but not in PH associated with parenchymal lung disease. PBF(INNOCOR) may be less accurate in patients with lung disease because of intrapulmonary shunting and/or incomplete gas mixing. Our aim was to determine the variability of PBF(INNOCOR) in normal subjects, before evaluating PBF(INNOCOR) in diffuse lung disease against CO measured by the indirect Fick method (CO(FICK)) at right heart catheterisation (RHC)., Methods and Results: 23 normal subjects had lung volume measurements by a constant-volume body plethysmograph and three consecutive PBF(INNOCOR) measurements on the same day. 20 subjects returned for repeat assessment. PBF(INNOCOR) had good intrasession repeatability (coefficient of variation (CV)=6.57%) and intersession reproducibility (mean CO difference=0.13; single determinant SD=0.49; CV=9.7%). 28 consecutive patients with lung fibrosis referred for RHC had PBF(INNOCOR) measured within 24 h of RHC. There was good agreement between CO(FICK) and PBF(INNOCOR), with no evidence of systematic bias (mean CO(FICK) 4.3+/-1.0; PBF(INNOCOR) 4.0+/-1.2l/ min; p=0.07). Bland-Altman analysis revealed a mean difference of -0.32 and limits of agreement of -2.10 to +1.45., Conclusion: Non-invasive PBF measured by the inert gas rebreathing Innocor device has good intrasession repeatability and intersession reproducibility. In diffuse lung disease, CO can be accurately and non-invasively measured by the Innocor device.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterised by accumulation of activated (myo)fibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of (myo)fibroblasts may be attributed, in part, to the process of transforming growth factor beta1 (TGFbeta1)-induced epithelial-mesenchymal transition (EMT), the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II (ATII) cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in IPF., Methods: Using quantitative reverse transcription-PCR (RT-PCR), immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in TGFbeta1-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human IPF in vivo., Results: TGFbeta1 treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA (siRNA)-mediated SNAI depletion attenuated TGFbeta1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human IPF and localised to hyperplastic ATII cells in vivo., Conclusions: The results demonstrate that TGFbeta1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human IPF in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.

Background and Objective: The initial results of a survey of 588 patients with a clinical presentation of cryptogenic fibrosing alveolitis (CFA) also known as idiopathic pulmonary fibrosis, have been published. This article reports further results pertaining to response to treatment and survival., Methods: Data on the treatment given and lung function response were collected over 4-6 years. Survival data were collected over 10 years., Results: Treatment was given to 445 (76%) patients, 55% were given prednisolone alone and the remainder another immunosuppressive agent, usually with prednisolone. Treated patients had worse lung function initially. At 3 months after study entry, treated patients were more likely to have improved forced vital capacity (FVC) than the untreated patients. Patients whose FVC improved were younger (p = 0.001 analysis of variance (ANOVA)) and had lower initial FVC (p<0.001, ANOVA). Patients who responded to treatment at 3 months or at 1 year survived longer than those who remained stable, who in turn survived longer than those who deteriorated (p = 0.002). These differences were largely accounted for by patients with better lung function surviving longer. Younger age at entry, female sex and higher percentage predicted FVC and carbon monoxide transfer factor [corrected] at study entry were associated with greater chances of survival at 4 years. Overall median survival from entry was 2.43 years (95% confidence interval (CI) 2.17 to 3.18)., Conclusions: About a third of patients with CFA showed improved lung function after initiation of corticosteroid or immunosuppressive treatment, and those who improved survived longer. Poorer lung function, male sex and age are adverse prognostic features. Overall survival was poor.

Background: Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in advanced disease., Methods: A retrospective series of 22 sarcoidosis patients (16 men) of mean (SD) age 46 (13) years with PH was divided into two groups depending on the absence (stage 0: n = 2, stage II: n = 4, stage III: n = 1) or presence (n = 15) of radiographic pulmonary fibrosis at the time of PH diagnosis., Results: In both groups PH was moderate to severe and there was no response to acute vasodilator challenge. In non-fibrotic cases no other cause of PH was found, suggesting a specific sarcoidosis vasculopathy, although no histological specimens were available. In cases with fibrosis there was no correlation between haemodynamics and lung volumes or arterial oxygen tensions, suggesting other mechanisms for PH in addition to pulmonary destruction and hypoxaemia. These included extrinsic arterial compression by lymphadenopathies in three cases and histologically proven pulmonary veno-occlusive disease in the five patients who underwent lung transplantation. Ten patients received high doses of oral prednisone for PH (stage 0: n = 1, stage II: n = 4 and stage IV: n = 5); three patients without pulmonary fibrosis experienced a sustained haemodynamic response. Survival of the overall population was poor (59% at 5 years). Mortality was associated with NYHA functional class IV but not with haemodynamic parameters or with lung function., Conclusion: Two very different phenotypes of sarcoidosis combined with PH are observed depending on the presence or absence of pulmonary fibrosis. PH is a severe complication of sarcoidosis.

Background: Neutrophils are thought to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Human neutrophils contain antimicrobial and cytotoxic peptides in the azurophil granules which belong to a family of mammalian neutrophil peptides named alpha-defensins. A study was undertaken to investigate the role of alpha-defensins in the pathogenesis of IPF., Methods: The concentrations of alpha-defensins (human neutrophil peptides (HNPs) 1, 2, and 3) in plasma and bronchoalveolar lavage (BAL) fluid of 30 patients with IPF and 15 healthy subjects were measured by radioimmunoassay., Results: The concentrations of alpha-defensins in plasma, but not in BAL fluid, were significantly higher in IPF patients than in controls. BAL fluid concentrations of interleukin (IL)-8 in patients with IPF, which were significantly higher than in controls, correlated with those of alpha-defensins. An inverse relationship was seen between plasma alpha-defensin levels and the arterial oxygen tension (PaO(2)) and pulmonary function (vital capacity (%VC), forced expiratory volume in 1 second (FEV(1)), and carbon monoxide transfer factor (%TLCO)) in patients with IPF. Plasma levels of alpha-defensins also correlated with the clinical course in IPF patients with an acute exacerbation. Immunohistochemically, positive staining was observed inside and outside neutrophils in the alveolar septa, especially in dense fibrotic areas., Conclusion: These findings suggest that alpha-defensins play an important role in the pathogenesis of IPF, and that the plasma alpha-defensin level may be a useful marker of disease severity and activity.

Background: Cough is a common and troublesome symptom in cryptogenic fibrosing alveolitis (CFA) but the mechanisms responsible are not known. The cough threshold to inhaled capsaicin is increased in asthma and chronic obstructive pulmonary disease (COPD) where lung volumes are increased, but the relationship between cough response and symptom intensity has not been studied in CFA where lung volumes are reduced., Methods: Capsaicin challenge tests were performed on 15 subjects with proven CFA and 96 healthy controls. Symptoms, as assessed by daily diary card cough score and by visual analogue scale (VAS), were related to the capsaicin sensitivity (C5) and compared with lung volumes. Volume restriction was produced in a group of 12 normal healthy subjects by a plastic shell tightly strapped to the chest wall. Capsaicin challenge tests were performed in these subjects, both strapped and unstrapped, to determine whether volume restriction altered the cough reflex., Results: The median C5 response in normal subjects was more than 500 microM compared with 15.6 microM in those with CFA (p<0.001). The C5 response of the CFA patients was not related to symptoms of cough (whether measured by diary card or by VAS), nor was it related to percentage predicted total lung capacity (TLC) or forced vital capacity (FVC). Volume restriction of normal subjects with chest strapping successfully restricted lung volumes to levels similar to that of the CFA patients but did not change the sensitivity to capsaicin., Conclusions: The cough reflex measured using capsaicin is markedly increased in patients with CFA. This increase is not the result of alterations in the deposition of inhaled particles of capsaicin brought about by volume restriction. It could be related to reduced lung compliance leading to sensitisation of rapidly adapting receptors, other mechanical changes, or to destruction of pulmonary C fibres secondary to interstitial inflammation. The capsaicin test may be a useful method of objectively monitoring cough propensity in CFA.

Background: The reasons why cryptogenic fibrosing alveolitis has emerged as a new clinical entity during the second half of the 20th century are unclear. Some environmental exposures have been identified as potential risk factors including occupational dust, cigarette smoking and antidepressants, but there have been no studies of the role of early life exposures. Since adult height reflects, in part, early life experience, we have examined the relation between adult height and the risk of cryptogenic fibrosing alveolitis., Methods: A case-control study of 569 cases and 3669 age, sex, and community matched controls drawn from the UK General Practice Research Database was undertaken., Results: Evidence was found of an inverse association between quintile of height and cryptogenic fibrosing alveolitis (odds ratio (OR) per increase in height quintile 0.93, 95% CI 0.86 to 0.99). This association was not diminished by adjustment for smoking status (OR 0.93, 95% CI 0.87 to 1.00), but some minor attenuation did occur after adjustment for oral corticosteroid use (OR 0.94, 95% CI 0.88 to 1.02). There was a significant interaction with sex such that the effect of height was strong in women (OR 0.85, 95% CI 0.75 to 0.97) and absent in men (OR 1.00, 95% CI 0.91 to 1.09)., Conclusions: These findings raise the possibility that early life exposures may be important in determining the lifetime risk of developing cryptogenic fibrosing alveolitis.

Background: Idiopathic pulmonary fibrosis is an inflammatory disease which leads to chronic ventilatory insufficiency and is characterised by a reduction in pulmonary static and dynamic volumes. It has been suggested that lung elastance may also be abnormally increased, particularly in end stage disease, but this has not been systematically tested. The aim of this study was to assess the respiratory mechanics during mechanical ventilation in patients affected by end stage disease., Methods: Respiratory mechanics were monitored in seven patients with idiopathic pulmonary fibrosis being ventilated for acute respiratory failure (PaO2/FiO2 5.8 (0.3); pH 7. 28 (0.02); PaCO2 8.44 (0.82) kPa; tidal volume 3.4 (0.2) ml/kg; respiratory rate 35.1 (8.8) breaths/min) using an oesophageal balloon and airway occlusion during constant flow inflation. The total respiratory system mechanics (rs) was partitioned into lung (L) and chest wall (w) mechanics to measure static intrinsic positive end expiratory pressure (PEEPi), static (Est) and dynamic (Edyn) elastances, total respiratory resistance (Rrs), interrupter respiratory resistance (Rint,rs), and additional respiratory resistance (DeltaRrs)., Results: PEEPi was negligible in all patients. Edyn,rs and Est,rs were markedly increased (60.9 (7.3) and 51.9 (8. 0) cm H2O/l, respectively), and this was due to abnormal lung elastance (dynamic 53.9 (8.0) cm H2O/l, static 46.1 (8.1) cm H2O/l) while chest wall elastance was only slightly increased. Rrs and Rint, rs were also increased above the normal range (16.7 (4.5) and 13.7 (3.5) cm H2O/l/s, respectively). RL and Rint,L contributed 88% and 89%, on average, to the total. Edyn,rs, Est,rs, Rrs and Rint,rs were significantly correlated with the degree of hypercapnia (r = 0.64 (p<0.01), r = 0.54 (p<0.05), r = 0.84 (p<0.001), and r = 0.72 (p<0. 001), respectively)., Conclusions: The elastances and resistances of the respiratory system are significantly altered in ventilated patients with end stage idiopathic pulmonary fibrosis. These features are almost totally due to abnormalities in lung mechanics. These profound alterations in elastic and resistive mechanical properties at this stage of the disease may be responsible for the onset of hypercapnia.

Background: Single lung transplantation (SLT) is now a treatment option for patients with both pulmonary fibrosis and advanced chronic airway obstruction. Lung function after transplantation might be expected to be different in these two groups of patients because of the effect of the remaining native lung, but the implications of these differences have not been fully explored., Methods: The functional results of a stable population of 20 patients (13 chronic airway obstruction, seven pulmonary fibrosis) after SLT with no evidence of obliterative bronchiolitis were analysed. The differences between the two populations in the interrelations between and determinants of total lung capacity (TLC), subdivisions of lung volume, airway function (spirometry, maximum expiratory flow volume curves, and moments analysis of the spirogram) respiratory mechanics (PV curves and maximal respiratory pressures), CO transfer factor (TLCO) and the distribution of perfusion, ventilation and volume of the transplanted and native lungs were compared., Results: Total lung capacity after SLT (TLCpost) was normal in the patients with pulmonary fibrosis (mean (SE) 103.9 (6.9)% predicted) but remained significantly elevated in patients with airway obstruction (126.4 (4.4)%. Forced expiratory volume in one second (FEV1) and vital capacity (VC) improved to similar values after SLT in both groups with a final VC of 76.8 (5.9)% and 66.7 (3.9)% in patients with fibrosis and airway obstruction, respectively. Maximum expiratory flows were generally lower and moments analysis of the spirogram showed slower lung emptying with significantly greater second and third moments (alpha 2 and alpha 3) in patients with airway obstruction. Relative ventilation and perfusion of the transplanted lung were both greater in both populations but relative ventilation of the transplanted lung was significantly greater in patients treated for airway disease than in those with pulmonary fibrosis. TLCO was also significantly higher in patients who had received a transplant for chronic airway obstruction., Conclusions: These results suggest that differences in the functional results of SLT for airway disease and pulmonary fibrosis are relatively minor. In this series the native hyperinflated lung in chronic airway disease was not more disadvantageous to overall function than the native lung in pulmonary fibrosis. However, tests of lung function based on the terminal portion of the forced spirogram are likely to be less sensitive for the detection of obliterative bronchiolitis in patients who have received a transplant for advanced airway obstruction than in those with pulmonary fibrosis.

Background: Clinical and epidemiological studies have given discordant results on the usefulness of the level of circulating elastin peptide (EP), a potential marker of both elastin destruction (a key phenomenon in pulmonary emphysema) and neosynthesis, for assessing structural changes in the lung extracellular matrix. The aim of the present study was to explore the relationship between levels of EP and forced expiratory volume in one second (FEV1) and single breath transfer factor for carbon monoxide (TLCO and KCO) in coal miners., Methods: The study population comprised 227 working coal miners aged 34-50 years consisting of 75 miners heavily exposed to underground coal dust with pulmonary radiographs classified as 0/1 or 1/0 by the International Labour Office classification, 75 exposed miners with radiographs classified as normal (0/0), and 77 miners slightly exposed to coal dust with normal radiographs. The subjects answered a standardised questionnaire and performed spirometric tests and a carbon monoxide (CO) transfer test., Results: No association was observed between EP levels and % predicted FEV1 (or FEV1/FVC). The level of EP increased significantly with decreased % predicted TLCO (r = -0.20). Miners in the lowest % predicted KCO quintile had higher EP levels than the rest (3.28 (1.37) vs 2.47 (1.16)). A significantly lower EP level was observed in miners with radiographs classified as 1/0 or 0/1, especially in those with round opacities, compared with miners with a normal radiograph, and in current smokers compared with the rest., Conclusions: The results of this study suggest that the level of EP may reflect some remodelling activity in emphysema and lung fibrosis.

Background: Cryptogenic fibrosing alveolitis (CFA) is an uncommon disorder of unknown aetiology characterised by interstitial fibrosis which typically shows a restrictive pattern on pulmonary function testing. Some patients with CFA and relative preservation of lung volumes have been described and it has been suggested that their volume preservation may be due to concomitant emphysema. In a retrospective study the relative frequency of preserved lung volumes in CFA, its relationship to emphysema determined by CT scanning, its clinical features, and its subsequent natural history were investigated., Methods: Using predefined characteristics 48 patients with CFA were identified from pulmonary function records over a three year period. Volume preservation was defined as a forced vital capacity (FVC) of > 80% predicted at presentation. Patients with relative volume preservation were compared with those with more typical pulmonary restriction and clinical data at presentation, and details of their subsequent prognosis, treatment and loss of lung function with time were obtained. Where available, computed tomographic (CT) scans for the two groups were compared in a blinded fashion to score the extent of fibrosis and the presence of concomitant emphysema., Results: Twenty one (44%) of the patients with CFA had a FVC of > 80% predicted. They were more likely to be male (76% versus 48%) and to be current smokers (57% versus 22%) with a heavier life time cigarette consumption than the restricted patients (mean (SE) 38 (4.6) versus 25 (4.5) pack years). There were no significant differences in prognosis and subsequent treatment between the groups. Comparable HRCT scans were available in 23 subjects (seven preserved, 16 restricted). They showed no difference in extent of the pulmonary fibrosis but patients with volume preservation were more likely to show concomitant emphysema (86% versus 19%). Patients with emphysema on HRCT scans were heavier smokers (41(10) versus 21(17) pack years) than those without emphysema but there was no difference in the extent of CFA score between the two groups., Conclusions: In this area of high smoking prevalence a significant number of patients with CFA presented with relative preservation of lung volumes and FEV1/FVC ratio. In many of these subjects this appears to reflect coincidental emphysema. This may make interpretation of gas transfer factor used to monitor progression in CFA difficult. However, there was no evidence that lung volumes at presentation were of prognostic significance.

Background: Mortality due to cryptogenic fibrosing alveolitis (CFA) is increasing, particularly in the elderly. Optimum management remains uncertain and previous studies of the disease have largely been from specialist centres. A national study was carried out of the presentation and initial management of CFA in the UK., Methods: All respiratory physicians in England, Scotland and Wales were invited to enter patients with newly diagnosed CFA over a two year period. CFA was diagnosed on histological grounds or according to clinical criteria which included the absence of a defined connective tissue disorder or pneumoconiosis. Participating physicians (n = 150) completed a questionnaire at patient entry and at all subsequent follow up visits and death., Results: A total of 588 patients (373 men, 63%) were studied of whom 441 (75%) were referrals from primary care. Their mean (SD) age was 67.4 (10.0) years and median duration of symptoms at presentation was 9.0 months. Clubbing was more common in men (203/373; 54%) than in women (86/ 215; 40%); 209 patients (36%) were graded as severely breathless at presentation. A history of dust exposure (organic or inorganic) was present in 274 patients (47%) of whom 87 had had some exposure to asbestos. Subjects exposed to dust were more likely to have smoked and had slightly higher mean lung volumes, but were otherwise indistinguishable from those not exposed in terms of clinical presentation, management, and outcome. Transbronchial biopsy specimens were taken in 164 patients (28%) and open lung biopsy specimens in 73 (12%), but 60% had no histological diagnostic procedure. Biopsy procedures were more likely to be performed in younger patients, those with better lung function, and those with a history of asbestos exposure. At presentation a decision not to initiate specific treatment was made in 284 cases (48%). The decision to initiate treatment was made predominantly on symptomatic grounds. Two years after the close of entry to the study 266 patients (45%) had died., Conclusions: CFA is predominantly a disease of elderly patients and has a poor prognosis. Physicians generally considered CFA to be a clinical diagnosis and did not initiate treatment in up to half of patients at presentation.

Background: Inhaled morphine has previously been shown to increase exercise endurance in patients with chronic lung disease. A similar study was performed to determine whether inhaled morphine reduces the sensation of breathlessness in this group of patients., Methods: A randomised double blind study on the effect of nebulised morphine on both exercise induced breathlessness and maximum achievable power output using isotonic saline as a control was performed in 10 patients with stable chronic lung disease. Each subject performed a progressive exercise test (Jones' stage I) on an electrically braked cycle ergometer. The work load was increased by 10 watts per minute and subjects exercised to exhaustion. At the end of each minute of exercise patients were asked to rate their degree of breathlessness according to a modified Borg scale. All subjects were randomised to receive either inhaled morphine sulphate 1 mg/ml (5 ml) or isotonic saline (5 ml) by wet nebulisation. The effect of morphine and saline on the achieved exercise capacity and the development of breathlessness during exercise was tested on separate days., Results: The mean dose of morphine inhaled was 1.24 mg. There was no difference in maximum power output achieved, minute ventilation at maximum power output, nor the degree of breathlessness at maximum power output between the groups treated with morphine and placebo. The degree of breathlessness was related to the power output achieved during exercise by a power function relationship (mean r: morphine = 0.86, saline = 0.87). However, there was a wide variation in the sensation for any given power output in both groups. There was no difference in the group mean slopes (morphine = 1.15, saline = 1.00) or intercepts (morphine = 0.07, saline = 0.15) in this relationship between the morphine and saline treatment groups., Conclusions: In patients with severe chronic lung disease inhaled morphine in the doses used in this study does not relieve exercise induced breathlessness nor does it increase maximum power output achieved during progressive exercise.

Background: The migration and proliferation of fibroblasts may be important in the pathogenesis of pulmonary fibrosis. Considerable data are available on the proliferation of fibroblasts, but very few on their migration., Methods: The migratory activity of fibroblasts obtained from lung biopsy specimens from 11 patients with idiopathic pulmonary fibrosis (IPF) was studied using a 96-well chemotaxis chamber. Fibroblasts from eight normal controls, seven patients with interstitial fibrosis associated with a collagen vascular disease (IP-CVD), and 13 patients with sarcoidosis were also examined. Migratory activity was tested in a serum-free medium in the presence and absence of platelet derived growth factor (PDGF), 30 ng/ml, as a chemoattractant., Results: Migration of fibroblasts from patients with IPF was enhanced in serum-free maintenance medium alone (mean (SD) controls v IPF: 183 (86) v 689 (491) cells/field), and was also enhanced when cells were stimulated by PDGF (controls v IPF: 829 (222) v 1928 (600) cells/field). Fibroblasts from tissues with dense fibrosis had a greater capacity for migration than those from an earlier stage of fibrosis. No correlation was found between migratory activity and proliferative capacity of the individual cells., Conclusions: The fact that fibroblasts from fibrotic lungs migrate faster than those from controls suggests that migration is related to the initiation of the pulmonary fibrotic process. These in vitro studies suggest that fibroblasts derived from the lungs of patients with pulmonary fibrosis have a migratory phenotype. Such a change in fibroblast phenotype, if it occurred in vivo, may be important in the context of the pathogenesis of pulmonary fibrosis.

Background: Some of the prominent features of silicosis are hyperplasia and hypertrophy of epithelial type II cells, which in experimental animals are often accompanied by accumulation of phospholipids in the lung., Methods: The total phospholipid content of lung lavage fluid and its composition in 28 granite stone cutters with long term exposure to silica dust (23 with radiological silicosis) was compared with that of lavage fluid in 15 normal volunteers, 15 patients with untreated idiopathic pulmonary fibrosis, and 19 patients with untreated stage 2 or 3 sarcoidosis. All lavage fluid was obtained at the time of first pulmonary investigation, which also included lung function tests., Results: In the normal subjects total phospholipid content was 1.13 (0.16) micrograms phosphorus/ml of lung lavage, in the patients with idiopathic pulmonary fibrosis 0.52 (0.07) microgram/ml (p < 0.05), and in the patients with sarcoidosis 1.02 (0.20) microgram/ml composition being in the range reported in humans. In the patients with silicosis total phospholipid content was significantly decreased to an average of 0.46 (0.08) microgram/ml compared with the findings in normal subjects and patients with sarcoidosis. Within the group exposed to silica changes in total phospholipid content did not correlate with the severity of the radiographic disease, changes in lung function, the cellularity of lung lavage fluid, or hyaluronate concentrations. The secretory capacity of rat epithelial type II cells was not significantly different when cultured with bronchoalveolar lavage fluid from all four groups of subjects., Conclusions: Total phospholipid content in lung lavage fluid was significantly reduced in granite workers with radiological evidence of lung disease, but showed no correlation with radiological or functional markers of disease severity.

Background: In fibrosing alveolitis activation of lung fibroblasts is the decisive event in the pathogenetic sequence leading to pulmonary fibrosis. Fibroblast stimulating activity was measured in bronchoalveolar lavage (BAL) fluid to assess its relationship to the activity of fibrosing alveolitis., Methods: Nine control subjects and 40 patients with fibrosing alveolitis caused by idiopathic pulmonary fibrosis (n = 22) or pulmonary involvement in systemic sclerosis (n = 18) were studied. All patients were followed up by lung function testing for a minimum of six months (mean (SE) 13.3 (1.4) months). Twenty five patients received immunosuppressive therapy and 15 refused. At the beginning of follow up BAL was performed and, as a possible indicator of fibroblast stimulating mediators within the lungs, chemotactic migration of cultured human fibroblasts elicited by native BAL fluid was measured in Boyden-type chambers and expressed as a percentage of the chemoattractant effect of 25 ng/ml platelet derived growth factor. The procollagen III peptide level in BAL fluid served as a marker for collagen synthesis., Results: Chemoattractant activity was elevated in the patients with idiopathic pulmonary fibrosis and systemic sclerosis compared with the control group, (mean (SE) 56.4% (8.5%)) and 72.3% (16.3%) v 12.6% (4.0%). Chemoattractant activity was inversely correlated with total lung capacity (TLC) (r = -0.45) and with vital capacity (VC) (r = -0.33). Procollagen III peptide concentrations in BAL fluid and chemoattractant activity were not significantly correlated. For further evaluation chemoattractant activity of 36% (mean value of controls +2 SD) was used to separate normal (< 36%) from elevated (> or = 36%) activity. At the end of follow up, untreated patients with high chemoattractant activity (> or = 36%) showed a significant reduction of VC, TLC, and exercise arterial oxygen tension (PaO2) and a small decrease in carbon monoxide transfer factor (TLCO), whereas a significant improvement in VC, TLC, and TLCO and a small increase of exercise PaO2 occurred in treated patients with high chemoattractant activity. Patients with low chemoattractant activity (< 36%) showed no consistent change in lung function measurements, irrespective of treatment. In contrast, lung function results and differential cell counts in BAL fluid failed to identify progressive disease., Conclusions: In patients with fibrosing alveolitis the chemoattractant activity of BAL fluid seems to be an independent indicator of lung fibroblast stimulating activity providing relevant information about disease activity, and may help to improve the clinical management of these patients.

Background: A report has recently been published concerning a patient with a cryptogenic fibrosing alveolitis who showed a striking improvement after being treated with the antiviral drug ribavirin (tribavirin, Virazid). The objective of this study was to further evaluate, in an open trial, the efficacy of rivabirin in cryptogenic fibrosing alveolitis., Methods: Ten patients (eight women) with advanced cryptogenic fibrosing alveolitis received aerosolised ribavirin (6 g/day for 15 days). Chest radiographs, lung function, and severity of dyspnoea were evaluated before and after two weeks of rivabirin treatment and also at three and 12 months., Results: No differences in radiographs, lung function impairment, or severity of dyspnoea were found after treatment. No side effects were detected., Conclusions: Administration of high doses of aerosolised ribavirin has no beneficial effects in patients with advanced cryptogenic fibrosing alveolitis.

Background: Interstitial pulmonary fibrosis is a disease with a highly variable clinical course. To ascertain if an inadequate selection of patients might explain part of this variability, two different groups of patients with interstitial pulmonary fibrosis, those with the "lone" form of the disease (LIPF) and those with associated collagen vascular disorders (AIPF), were studied separately., Methods: Twenty consecutive patients (nine with LIPF and 11 with AIPF) were included. Their clinical and radiographic findings and results of pulmonary function tests, gallium-67 lung scanning, and cellular analysis of bronchoalveolar lavage fluid were compared at diagnosis. Moreover, the evolution of LIPF and AIPF was contrasted after a follow up of two years, both groups having received a similar treatment regimen of corticosteroids., Results: At enrollment, patients with LIPF and AIPF were of similar age, and had similar symptoms and derangement of lung function, but patients with LIPF presented with finger clubbing, more obvious radiographic abnormalities, and a greater percentage of eosinophils in bronchoalveolar lavage fluid. Two years later, patients with LIPF had significantly decreased FVC, FEV1, TLC, TLCO, and PaO2. By contrast, lung function remained unaltered in patients with AIPF. Similarly, when the percentage change from entry to the study was compared, patients with LIPF showed a significant decrease in FVC, FEV1, and PaO2., Conclusions: Unlike the patients with AIPF, those with LIPF showed a deterioration in lung function and developed further restrictive impairment and poorer gas exchange. This has implications in their clinical management.

Background: Low dose methotrexate has become established in the treatment of refractory rheumatoid arthritis. Until recently it has been considered that the use of a low dose regimen (< 20 mg/week) would avoid the pulmonary toxicity associated with the higher doses prescribed in malignant disease. Although initial experience with low dose methotrexate was encouraging, an increasing number of cases of an acute, life threatening pneumonitis are being reported in patients with refractory rheumatoid arthritis., Patients: Since 1984 43 patients with refractory rheumatoid arthritis have been established on low dose methotrexate in the Oxford Health District. Five of these patients have subsequently developed acute methotrexate induced pneumonitis. The clinical and radiological features of these cases are described and previous reports reviewed., Results: Five patients having low dose methotrexate treatment developed acute pneumonitis. Presentation was subacute and dominated by constitutional features. Respiratory symptoms developed insidiously but progressed rapidly with increasing dyspnoea associated with severe hypoxia. Chest radiographs were non-specific, showing diffuse interstitial infiltration and alveolar shadowing. Microbiological investigation gave negative results. In all cases methotrexate was discontinued and high dose corticosteroids started, with rapid clinical and radiological improvement. After withdrawal of steroid both clinical and radiological resolution was maintained at follow up., Conclusion: Acute pneumonitis is an uncommon but serious adverse effect of low dose methotrexate treatment for refractory rheumatoid arthritis. The initial presentation is non-specific and a high index of suspicion is required as respiratory failure may develop rapidly. Management depends on exclusion of infection, withdrawal of methotrexate, and high dose corticosteroid treatment. Full supportive treatment is indicated as the prognosis in such patients is good.

Background: Lung function often deteriorates after bone marrow transplantation for haematological malignancies. Whether pulmonary function measurements are useful for monitoring patients' progress after transplantation and for alerting clinicians to the development of pneumonitis is uncertain., Methods: Serial pulmonary function measurements were made in 39 patients with a haematological malignancy, and the values from 18 recipients of T cell depleted allogeneic (n = 17) or autologous (n = 1) bone marrow transplants who developed interstitial pneumonitis were compared retrospectively with values from 21 recipients of allogeneic (n = 17) or autologous (n = 4) transplants who did not develop pneumonitis. Lung function was measured at the onset of a further 18 episodes of pneumonitis., Results: Measurements made before transplantation showed no difference in forced expiratory volume in one second (FEV1), transfer factor for carbon monoxide (TLCO), or total lung capacity between the two groups, but the forced vital capacity (FVC) was slightly higher in those who developed pneumonitis (mean (SD)% predicted 104 (12)) than in those who did not (93 (17%)). Six weeks and three months after transplantation all pulmonary function measurements had fallen slightly in both groups but TLCO had fallen considerably more in those who later developed pneumonitis, being 71% (SD 11%) and 77% (7%) of pretransplant values in patients who later developed pneumonitis compared with 109% (38%) and 96% (26%) in those who did not. All lung function measurements were significantly lower at the onset of pneumonitis than three months after transplantation, even in patients with no abnormal signs and a normal chest radiograph., Conclusions: Serial measurements of gas transfer before and after bone marrow transplantation may be useful for predicting which patients will be at risk of developing pneumonitis and may help to diagnose pneumonitis in breathless patients with no abnormal signs.

Background: The aim of this study was to determine the relation between the severity of abnormalities in ventilatory function tests and tidal breathing pattern and gas exchange indices in interstitial lung disease., Methods: Pulmonary function, ventilation, carbon dioxide production, oxygen consumption, arterial blood gas tensions, and pH were measured during resting steady state conditions in 60 patients with proved interstitial lung disease. Patients were categorised by forced vital capacity (FVC) (percentage of predicted values) as having a mild, moderate, or severe restrictive defect with means (SD) of 71% (4%), 57% (4%), and 41% (7%) of predicted values, respectively., Results: FVC varied from 29% to 79% of predicted values and from 0.99 l to 4.32 l. The two measurements of FVC correlated strongly with most static lung volumes and with transfer factor for carbon monoxide. Mean respiratory rates (per minute) and tidal volumes (ml) were 17 (4) and 484 (131), 20 (4) and 460 (139), and 23 (5) and 377 (109) in mild, moderate, and severe restrictive defects, respectively. FVC correlated negatively with respiratory rate and positively with tidal volume. Arterial carbon dioxide tension ranged from 30 to 49 mm Hg; only two patients were hypercapnic. Mean arterial oxygen tensions were not significantly different among the three groups, and there were no significant correlations between forced expiratory volume in one second or FVC and arterial carbon dioxide tension or carbon dioxide production., Conclusion: Low values of FVC were associated with increased respiratory rate and decreased tidal volume; this pattern of breathing mimics external elastic loading, suggesting that mechanoreceptors may contribute to the rapid and shallow pattern of breathing in interstitial lung disease. Hypercapnia seems to be rare in interstitial lung disease even when functional impairment is severe and tidal volume is small. The increased respiratory rate is important in maintaining adequate ventilation. In the face of a severe restrictive defect carbon dioxide production did not increase, which also contributed to the maintenance of eucapnia.

To investigate the relation between lung function and inflammation and fibrosis in patients with diffuse lung fibrosis, a study was made of untreated patients without appreciable airway obstruction (14 patients with cryptogenic fibrosing alveolitis and seven with pneumoconiosis). Quantitative assessment of inflammatory infiltration and fibrosis was carried out on open lung biopsy specimens and compared with lung volumes, carbon monoxide transfer factor (TLCO), TLCO corrected for alveolar volume (TLCO/VA), and arterial blood gases at rest and during exercise. The degree of fibrosis and the degree of cellular infiltration were positively correlated. Lung volumes and TLCO were correlated with the grades of fibrosis and cellular infiltration of alveoli; arterial blood gases during exercise tended to correlate with both fibrosis and infiltration (p less than 0.06). In contrast, morphological data were not correlated with gas exchange at rest or with TLCO/VA. It is concluded that, in untreated patients with diffuse lung fibrosis, lung volumes, TLCO, and arterial blood gases during exercise reflect the lung lesions, and that the pulmonary function tests used cannot discriminate between fibrosis and infiltration of the lung by inflammatory cells.

Ventilation and gas exchange during overnight sleep was studied in a group of seven patients with severe interstitial lung disease (mean vital capacity 50%, mean diffusing capacity 46% predicted), to see whether clinically significant oxygen desaturation occurred. Patients with a history of loud snoring or clinically significant airflow obstruction were excluded. Sleep was fragmented in these patients, but all achieved rapid eye movement (REM) sleep. All patients showed episodes of oxygen desaturation during sleep--mean (SEM) awake arterial oxygen saturation (SaO2) was 92.9% (0.3%) compared with a mean minimum SaO2 during sleep of 83.2% (2.1%) (p less than 0.01). These episodes were, however, transient, and mean SaO2 showed only a slight fall between wakefulness and sleep (non-REM 91.5%, REM 90.4%; NS). Furthermore, SaO2 during non-REM sleep correlated well (p less than 0.001) with SaO2 during wakefulness. Respiratory frequency showed a significant fall between wakefulness and sleep--21.1 (1.8) versus 17.3 (1.5) breaths per minute (p less than 0.02). Our data suggest that nocturnal oxygen treatment need not be considered in patients with interstitial lung disease unless the level of oxygenation while they are awake indicates the need for such treatment.

Measurements of the lowest mouth pressures developed during maximum static inspiratory efforts are related to the recoil force of the lung and occasionally are influenced by glottic closure. The measurement of minimal pleural pressures (P pl min) over the entire range of inspiratory capacity eliminates both problems and, in addition, provides a good estimate of the subject's cooperation. Using this technique, we have investigated the inspiratory muscle force in 120 healthy adults (60 men, 60 women) aged 21 to 76 years, and 15 healthy children (eight boys, seven girls) aged 7 to 13 years. Twelve patients with interstitial lung disease were studied for comparison. In the healthy adults, at any fixed (fractional) lung volume, P pl min increased, that is, became less negative with advancing age, both in males and females (all r greater than 0.56, p less than 0.001). This pattern was not modified after correction of the data for the static recoil pressure of the chest wall, indicating that the inspiratory muscle force actually decreases with age. In any age group, and after correction of lung volume for the difference in stature, the P pl min values in women were between 80 and 90% of the values found in men; moreover the children generated pressures that were as low as those developed by the younger adults. This is probably because women and children have a smaller thorax than men and are therefore able to generate low pressures, despite weaker muscles. When the reduction in lung volume was taken into account, the relationship between lung volume and P pl min was normal in the patients with interstitial lung disease. These patients showed a close relationship between the degree of lung volume restriction and the increase of the static recoil pressure of the lung at full inflation, suggesting that their thorax is normally compliant. It appears therefore that these patients have normal inspiratory muscle force, at least when they are not in an advanced stage of the disease.

Fifty patients with fibrosing alveolitis studied on 104 occasions exhibited significant direct correlations between vital capacity (VC), maximum mid-expiratory flow rate (MMFR), and transfer factor for carbon monoxide (TLCO). Forced expired volume in the first second (FEV1)/VC ratio bore a weak negative correlation with VC. Peak expiratory flow, MMFR, and maximum flow rates at 50% and 25% of VC were often reduced in patients with severe grades of pulmonary dysfunction. It appears that as the severity of the fibrotic process increases, the lung volumes shrink and the transfer factor for CO decreases. The total lung capacity decreases predominantly on account of reduction in VC. With a decrease in lung volume the MMFR also falls. Decrease in flow rates at low lung volumes is greater as compared to the fall in peak flow. The expiratory flow rates however were normal or even increased when related to absolute lung volume. Some patients exhibit disproportionate expiratory slowing as evidenced by a decrease in MMFR which is out of proportion to the reduction in VC. These patients also have a reduced FEV1/VC ratio. These changes are probably the consequence of associated peripheral airway narrowing.

The responses to exercise were studied in 41 patients with pulmonary fibrosis, in whom vital capacity (VC) was reduced to 62% of predicted normal values. Maximum power output (POmax) was 53% predicted; there was a significant relationship between POmax and VC (r = 0.564). The maximum ventilation achieved during exercise was also related to VC (r = 0.614). Although arterial oxygen saturation (SaO2) fell by more than 5% in 13 of 31 patients, there was no relationship between either SaO2 at POmax or the exercise related fall in SaO2 and POmax. Heart rate responses were higher than normal predicted values in seven patients, all of whom showed a low POmax (36% predicted); this finding was due only in part to a fall in SaO2. The ventilatory response to exercise was within normal limits for the patients as a whole; those subjects with the lowest POmax showed relatively higher ventilatory responses to exercise but the difference was not significant. The pattern and timing of breathing was studied in 32 patients and compared with control subjects matched by sex, age, and size. Tidal volume (VT) was low in the patients; maximum VT was related to VC (r = 0.761), but at low values of VC VTmax was higher than in healthy subjects with comparable VC. The total breathing cycle time (Ttot) fell with progressive exercise in patients and controls; Ttot for a given ventilation was shorter in the patients. Inspiratory time (Ti) was shorter in patients than controls, as was Ti/Ttot. In most patients with diffuse pulmonary fibrosis exercise is limited by a reduced ventilatory capacity, despite the adoption of a short Ti and high inspiratory flow rate, both of which serve to optimise tidal volume and breathing frequency and presumably reduce both the force developed by inspiratory muscles and the sensation of breathlessness.

The relations between mean and maximum fall in arterial oxygen saturation (SaO2) during sleep, hypoxaemia during moderate and maximum exercise, and lung mechanics were studied in 16 patients with interstitial lung disease. Mean and minimum SaO2 during sleep were significantly related to each other and to daytime oxygenation but not to lung mechanics. Although the maximum fall in SaO2 during sleep was similar to the fall during maximum exercise (a level seldom achieved during normal daily activities), profound hypoxaemic episodes during sleep were rare and brief and therefore contributed little to the mean SaO2. The fall in mean SaO2 during sleep was not significant and was considerably less than during moderate exercise (average 0.5 v an estimated 4.5%, p less than 0.05). It is therefore concluded that in patients with interstitial lung disease oxygen desaturation during sleep is mild and less severe than hypoxaemia during exercise.

The pathological features in the lung in asbestosis and cryptogenic fibrosing alveolitis are similar. Patients with asbestosis, however, appear to have less severe impairment of transfer factor (TLCO) than those with fibrosing alveolitis for a given level of radiographic abnormality when assessed on the basis of the International Labour Organisation (ILO) profusion score. The impairment of lung function in the two disorders has been compared in more detail in 29 patients with asbestosis and 25 with fibrosing alveolitis, arterial oxygen desaturation during exercise being used to define the severity of the disorders. Arterial oxygen saturation (ear oximeter) and oxygen uptake were measured during incremental exercise on a cycle ergometer. TLCO (single breath technique) and total lung capacity (TLC, plethysmograph) were measured. Chest radiographs were graded for profusion according to the ILO international classification. Patients with asbestosis had significantly higher mean values for TLCO and TLC and lower mean profusion scores than those with fibrosing alveolitis. When stratified for the degree of arterial oxygen desaturation, however, no significant differences were found in TLCO, TLC, or profusion score between the two disorders. To the extent that arterial oxygen desaturation with exercise reflects the morphological severity of the disease, these results suggest that, for a given degree of interstitial lung disease, asbestosis and cryptogenic fibrosing alveolitis are functionally and radiologically similar.

Cardiovascular complications are common in fibrosing alveolitis, but there have been few physiological studies of the pulmonary circulation in this condition, and those that have been carried out have usually depended on right heart catheterisation. This paper reports non-invasive measurements of effective pulmonary blood flow, oxygen uptake, pulmonary arteriovenous oxygen content differences, and estimates of mixed venous oxygen saturation in 20 patients with histologically proved cryptogenic fibrosing alveolitis at rest and while exercising on a motorized treadmill. Results were compared with those of 20 age and sex matched normal subjects, at rest and at an arbitrarily chosen oxygen uptake of 0.75 l/min. The latter results were obtained by linear interpolation. Effective pulmonary blood flow was normal at rest, but oxygen dispatch to the tissues (blood flow x blood oxygen content) was significantly reduced at rest (mean reduction 190 (SD 68) ml/l/min; p less than 0.01) and at an oxygen uptake of 0.75 l/min (mean reduction 128 (50) ml/l/min; p less than 0.02), reflecting the presence of systemic arterial hypoxaemia. Pulmonary arteriovenous oxygen content differences were similar in patients and normal subjects, but mixed venous saturation was lower in the patients at rest (mean % reduction 6.8 (2.6); p less than 0.02) and at an oxygen uptake of 0.75 l/min (mean % reduction 9.6 (2.9); p less than 0.002). It is concluded that the supply of oxygen potentially available to the tissues is reduced at rest and during exercise in patients with fibrosing alveolitis and hence, by analogy with normal people exercising under hypoxic conditions, that pulmonary blood flow is inappropriately low in this condition. The low mixed venous oxygen saturation may contribute to the development of pulmonary hypertension in some patients. The rebreathing technique used in this study may be of use in monitoring treatment; it could be applied many times to the same patient, and might be a suitable way of following the response to pulmonary vasodilators.

Thoracoabdominal motion and intrathoracic (oesophageal), intra-abdominal (gastric), and transdiaphragmatic pressures were measured during tidal breathing in 20 erect subjects--six normal, seven, with emphysema, and seven with fibrosing alveolitis. In normal subjects all diameters increased synchronously during inspiration and were accompanied by rises in abdominal and transdiaphragmatic pressures. Five patients with fibrosing alveolitis showed a reduction in upper ribcage motion, but normal lower ribcage and abdominal motion; stiff fibrotic lungs may sometimes impair the ability of the diaphragm to expand the upper ribcage and result in proportionally more expansion of the bases. Four emphysematous patients showed increased anteroposterior motion of the ribcage and four showed paradoxical inward motion of the lower ribcage during inspiration. These changes apparently result from increased activity of intercostal and accessory muscles and altered configuration of the diaphragm. The muscles of patients with large, overinflated lungs are at a greater disadvantage than those with small fibrosed lungs.

The value of non-invasive procedures for predicting pulmonary arterial pressure was investigated in 370 patients with chronic obstructive lung diseases and in 73 with fibrosing alveolitis in a combined study at nine centres in six European countries. Measurements included forced expiratory volume in one second, arterial blood gas tensions, standard electrocardiogram, radiographic dimensions of pulmonary artery, right ventricle dimensions by M mode echocardiography, and myocardial scintigraphy with thallium-201; and certain clinical signs were also used. No single variable was correlated closely enough to allow accurate prediction of pulmonary arterial pressure. Four methods were used to incorporate several variables into mathematical functions for predicting pulmonary arterial pressure. In patients with chronic obstructive lung disease multiple stepwise regression explained 49% of the variance in pulmonary arterial pressure but was not useful for prediction. Discriminant analysis allowed patients to be allocated to bands of pulmonary arterial pressure, as did two non-parametric procedures, in which decision trees were established using either the Kolmogoroff-Smirnoff statistic or Fisher's exact test. Patients with a pulmonary arterial pressure of 30 mm Hg or more were identified with a sensitivity of 83% and a specificity of 91%. The non-parametric tests gave better results than discriminant function. A further 54 patients were studied to validate the functions. Of these, 90% with a pulmonary arterial pressure above 20 mm Hg were correctly identified, and 80% of those with a pulmonary arterial pressure above 29 mm Hg. Similar results were obtained in subjects with fibrosing alveolitis. These mathematical functions allow the use of combinations of non-invasive procedures to select from populations at risk of pulmonary hypertension those in whom direct measurement is required. The mathematical functions are capable of further development by incorporation of variables from newer non-invasive procedures.

The relation between pulmonary distensibility, lung volume, and elastic recoil pressure was examined in 45 patients (38 men) with cryptogenic fibrosing alveolitis (mean age 61 (SD 14) years). Exponential analysis of static pressure-volume data obtained during deflation of the lungs gave the exponent K, an index of the distensibility of the remaining inflatable lung tissue. Total lung capacity (TLC) was measured in a body plethysmograph or by nitrogen washout. The results were compared with values obtained in 147 healthy subjects (95 men), of mean age 39 (SD 16) years. Fibrosing alveolitis decreased K by 0.62 (SEM 0.04) kPa-1. This decrease was approximately equal to 2 SD of the regression of log K on age in healthy subjects. TLC was decreased to a mean of 70% (SD 14%) predicted in the patients with fibrosing alveolitis. Lung recoil pressure at maximum inspiration was about twice the expected value and regression analysis showed that most of this increase was related to the decreased K rather than to the decreased TLC. In the men with fibrosing alveolitis the regression of height standardised TLC (TLC/Ht3) on K was significant (p less than 0.02); the regression slope was similar to that for 95 healthy men, but was displaced to a smaller lung volume. The dependence of TLC/Ht3 on K is consistent with the close relation between K and peripheral airspace size found in normal lungs. In fibrosing alveolitis decreased pulmonary distensibility probably reflects a decrease in airspace size, whereas most of the decrease in lung volume reflects the loss of inflatable tissue in the fibrotic process.

Twelve patients with chronic airflow limitation and 12 patients with a histological diagnosis of fibrosing alveolitis were studied. The calculated mean (SD) tissue volume of a single lung at total lung capacity was 467 (91) ml in the patients with alveolitis, which was 43% (14%) more than predicted for healthy people of the same age, sex, and height. The tissue volume of a single lung at total lung capacity was 436 (82) ml in the patients with chronic airflow limitation, which was 26% (21%) more than predicted. At residual volumes the tissue contents of the fibrotic and the obstructed lungs changed very little (to 407 (84) ml and 433 (84) ml respectively). This allowed tissue volume to be used as a marker of position within the lung, to match inspiratory and expiratory slices and to calculate regional ventilation. In both groups local ventilation was diminished and more variable than in healthy lungs--that is, in the mid 70% of lung volume the local residual volume to total gas volume ratios (RV/TGV) were 32% (10%) in the fibrotic group and 66% (14%) in the group with chronic airflow limitation, compared with 23% (5%) in healthy subjects. As expected, the fibrotic lungs were much denser (0.246 (0.036) g/ml) and the lungs with chronic airflow obstruction were less dense (0.114 (0.026) g/ml) than were healthy lungs (0.126 (0.017) g/ml).

Low dose nebulised morphine may relieve dyspnoea through a direct effect on lung afferent nerves. To study this further 11 adult patients with advanced chronic lung disease (FEV1 range 0.4-1.41), whose exercise endurance was limited by dyspnoea, were entered into a double blind, randomised, crossover study in which low dose morphine or a placebo was inhaled. The effects were assessed by an endurance exercise test at 80% of maximum work load. One hour after a control endurance test patients inhaled 5 ml of morphine 1 mg/ml or isotonic saline for 12 minutes from a jet nebuliser. An endurance exercise test was repeated 15 minutes later and change in endurance time recorded. The two endurance tests were repeated on a separate day, before and after inhalation of the alternative solution. In all tests 100% oxygen was inhaled from a demand valve. The mean (SD) increase in endurance time was significantly greater after the subjects had inhaled morphine (64.6 (115) s, 35%) than after placebo (8.9 (55) s, 0.8%; p less than 0.01). The mean dose of morphine nebulised was 1.7 (0.66) mg, giving a mean inhaled dose of about 0.6 mg, on the assumption of 30% retention of the nebulised dose by each patient. No side effects were reported. Possibly small amounts of morphine delivered to the lungs act directly on lung afferent nerves to reduce dyspnoea.

Regional lung density (g lung/ml thoracic volume) and fractional pulmonary blood volume (ml blood/ml thoracic volume) have been measured by positron tomography in 10 patients with interstitial disease. From the measurements regional extravascular lung density (g tissue and interstitial water/ml thoracic volume) was derived, providing a non-invasive measurement of the interstitial reaction. Extravascular lung density was increased and large regional variations were observed. Fractional blood volume was reduced in patients with pulmonary fibrosis. In two patients with sarcoidosis, a reduction in extravascular lung density occurred after treatment with oral prednisone. Abnormalities in extravascular lung density and fractional blood volume correlated with abnormalities shown by tests of overall pulmonary function.