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S56 Table 1Table to show measures of complement activation, inflammation and coagulation in patients with COVID-19 stratified by disease severityMildModerateSevereOverall P-ValueMild vs Mod*Mild vs Sev*Mod vs Sev*Number (%)30289----CRP (mg/L)75.5 [28.5,117.25]93.5 [72,143.5]60 [34,157.5]NSNSNSNSFerritin (ug/L)426 [290.5,847.5]728 [381.25,1071.5]857 [443,1607.5]NSNSNSNSPCT (ug/L)0.08 [0.06,0.19]0.16 [0.09,0.49]0.19 [0.12,0.8]0.019NS0.046NSLDH (U/L)708.5 [523.5,903]830 [569,1122]1037 [927.5,1086]0.008NS0.006NSPlatelets (10*9/L)220 [174.75,328.75]255 [203.5, 335]292 [209.5, 329.5]NSNSNSNSINR1.1 [1.08,1.23]1.1 [1.1, 1.2]1.1 [1.1, 1.15]NSNSNSNSAPTR0.9 [0.9,1.0]0.9 [0.9, 1.0]1.0 [0.95, 1.10]NSNSNS0.038D-dimer (ugFEU/ml)0.56 [0.38,0.95]0.74 [0.55, 1.52]0.85 [0.54, 19.2]NSNSNSNSFibrinogen (g/L)4.45 [4.05,5.22]4.7 [4.3, 6.38]4.3 [3.9, 6.0]NSNSNSNSThrombin-AT III Complex ug/L)4.75 [2.65,12.13]8.8 [5.3, 12]14.3 [6.9, 40.7]0.045NSNSNSProthrombin Fragment 1&2 (pMol/L)275 [164.5,380.5]311 [163, 492]301 [258, 709]NSNSNSNSCH50 (U Eq/ml)123.4 [101.75,174.7]113.4[88.68, 153.43]114.7 [74.6,158.9]NSNSNSNSComplement C5a (ng/ml)29 [21.5, 36]36.5[25.5, 48.75]68 [39.5,122.5]

Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE 2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE 2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE 4 and the PGD 2 metabolite 2,3-dinor-11β-PGF 2α. High concentrations of LTE 4 and PGD 2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).

BackgroundAlthough several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.ObjectiveWe sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.MethodsAn IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS–specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.ResultsActivation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the absence of systemic inflammation. The IL-6TS–high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.ConclusionsLocal lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.

Background The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

Background The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX ® Quattro Plus 1.0 ml Birch 100%) is an effective, well‐tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose. Methods The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012‐004336‐28 PQBirch203 and 2015‐000984‐15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3‐4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED 50), a measure of potency. Results Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED 50 2723 SU, just over half the current dose. Prevalence of treatment‐emergent adverse events was similar for active doses, most being short‐lived and mild. Compliance was over 85% in all groups. Conclusion Increasing the cumulative dose of PQBirch 5.5‐fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.

Background: Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous samples. Objective: We sought to identify gene profiles associated with adult-onset severe asthma. Methods: This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (

Exacerbations of chronic obstructive pulmonary disease (COPD) can be defined symptomatically or by healthcare contacts, yet the relationship between these events is unknown. Data were collected during a 1-yr study of the budesonide/formoterol combination in COPD patients, where exacerbations, defined by increases in treatment, were compared with daily records of respiratory symptoms, rescue medication use and peak expiratory flow (PEF). The relationship between changes in these variables and the medical event was examined using different modelling approaches. Data from the first exacerbation treated with oral corticosteroids and/or antibiotics and/or hospitalisation (event based) were available in 468 patients. Patients exacerbating were significantly more breathless and more likely to report cough than healthy patients, but did not differ in baseline spirometry. Exacerbations defined by changes in individual symptoms were only weakly related to event-based exacerbations; however, defined with 63% of such events being predicted from symptom changes. Changes in rescue medication use or PEF were poor predictors of event-based exacerbations. The mean peak change in symptoms was closely related to the onset of therapy. In conclusion, event-based exacerbations are a valid way of identifying acute symptom change in a chronic obstructive pulmonary disease population. However, daily symptom monitoring is too variable using the current diary cards to make individual management decisions.

Drugs have been implicated in lung injury as a result of direct pharmacological action, persistence or metabolism in the tissue, or via the production of a reactive metabolite or metabolites. The result of this apparent drug-associated injury ranges from cellular dysfunction through to cell death (apoptosis) and alteration of repair mechanisms that are essential in replacing critical tissue elements and function. There is limited knowledge on how timing of drug administration or drug interactions may interfere with the repair mechanisms or modulate the expression of pulmonary toxicity. Chemotherapeutic drugs and novel agents, such as those targeting the epidermal growth factor receptor (EGFR), appear to affect both normal and neoplastic cells. However, unlike chemotherapy, where the actions are systemic and directly as a result of biotransformation or cell injury, it has been postulated that effects of EGFR-targeting agents are more likely to be focused on epithelia via a pharmacological effect. Furthermore, risk factors for the development of adverse pulmonary reactions, as well as biological markers indicating incipient toxicity, need to be prospectively identified. Proteomics, through the identification of >/=1000 proteins or peptides in blood samples, will hopefully identify candidates for this role.

Following the experience of asthma, characterised by the presence of bronchial hyper-responsiveness, the notion has been accepted that the chronic cough of disease occurs as a result of altered sensitivity of the afferent limb of the cough reflex. Methods for testing for the 'threshold' for eliciting the cough reflex have also been borrowed from asthma care. In the main aerosols are inhaled that contain the relevant stimulus.A number of factors influence the cough response to inhaled aerosols. The distribution of the inhaled aerosol is important as certain chemically sensitive receptors are distributed in different regions of the lungs. The larynx and central airways are important but so too are the peripheral airways. The degree of bronchodilatation is also important as airway narrowing can, itself, induce coughing in man.Asthma, oesophageal reflux and rhinitis patients experience increased coughing, that is associated with increased sensitivity to inhaled capsaicin. In syndromes of chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) increased sensitivity to coughing with capsaicin is common. This appears a specific effect of the pathogenic process of the disease. Modification of the disease process can lessen coughing and the sensitivity to capsaicin.

Background Nitric oxide has been detected by chemiluminescence in the lumen of nasal airway, which is increased in nasal breathing in patients with seasonal rhinitis during a chronic exposure. The purpose of this study was to determinate the effect of a NO-synthase inhibitor NGL-arginine methyl ester (L-NAME) on nasal airway resistance (NAR) in patients with seasonal allergic rhinitis after an acute challenge to the allergen. Methods Nitric oxide levels in the nose were measured by the chemiluminescence method in nine non-atopic volunteers and in seven patients with seasonal rhinitis at rest and after an acute challenge with the allergen. NAR were measured by active anterior rhinomanometry. Results Basal nasal NO concentration in allergic rhinitis was 496·5 ± 151·4 parts per billion (ppb). (n = 7) and it was not significantly different from levels found in the control group: 458·4 ± 105·9 ppb (n = 9). The topical administration of L-NAME in allergic rhinitis reduced the NO concentration (338·6 ± 99·3 ppb, P

Objective: Although unlicensed, inhaled nitric oxide (NO) therapy is now widely used in the United Kingdom. Our aim was to produce guidelines for the clinical application of inhaled NO in adult intensive care practice, based upon the current level of published information.

1. The effects of exercise on the production rate of nitric oxide (NO) in exhaled air (VNO) and the effects of inhaled NO (80 p.p.m.) on cardiovascular and respiratory parameters were investigated in five Throughbred horses. 2. The concentration of NO ([NO]) in exhaled air collected from within the nasal opening was lower when collected at a high flow rate of 80 l min-1 than at a low flow rate of 20 l min-1: when trotting at 3.7 m s-1 the values were 0.78 +/- 0.15 and 1.23 +/- 9.14 p.p.b., respectively, and when cantering at 9 m s-1 the values were 1.69 +/- 0.31 and 2.25 +/- 0.32 p.p.b., respectively. 3. Nebulized methoxamine (40 mg ml-1 for 60 s), an alpha 1-adrenergic agonist, further reduced [NO] during the 9 m s-1 canter to 1.05 +/- 0.14 and 1.99 +/- 0.41 p.p.b. when collected at 80 and 20 l min-1, respectively, and induced cyclical changes in the breathing pattern. 4. Exercise induced a linear increase in VNO with work intensity to a maximum (428.1 +/- 31.6 pmol min-1 kg-1) which coincided with the maximal oxygen uptake for the horses (138.3 +/- 11.7 ml min-1 kg-1), although a further increase in VNO (779.3 +/- 38.4 pmol min-1 kg-1) occurred immediately after exercise. The changes in VNO correlated well with the tidal volume (r = 0.968; P < 0.01) and the haematocrit (r = 0.855; P < 0.01). 5. In the first 2 min of high intensity exercise, inhaled NO (80 p.p.m.) significantly (P < 0.05) reduced the pulmonary artery pressure: during the first minute, pulmonary artery pressure was 83.1 +/- 7.6 mmHg compared with a control value of 94.4 +/- 6.3 mmHg, and during the second minute, 84.2 +/- 7.1 mmHg compared with a control value of 98.4 +/- 4.7 mmHg. There were no other significant changes in cardiovascular or respiratory indices, including cardiac output, measured during exercise between control and inhaled NO tests. 6. The results show that exhaled NO is released from the airways of the horse and may contribute to the regulation of pulmonary vascular tone during exercise.

Background Recently in France, primary pulmonary hypertension developed in a cluster of patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension. Methods In a case–control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age. Results The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used for a total of more than three m...

Considering the important surface in pulmonary circulation where blood can interact with the endothelium, the maintenance of blood fluidity through the lung, by antithrombotic pathways and products of the endothelium, is essential. This function appears to be ineffective in primary pulmonary hypertension and in severe secondary pulmonary hypertension. Thrombotic lesions are frequently found in pulmonary arteries in these diseases. Thrombin activity appears to be increased in severe pulmonary hypertension. Antithrombotic pathway disorders may account for this abnormality, particularly in chronic thromboembolic pulmonary hypertension and primary pulmonary hypertension. Injured endothelium, a constant feature in severe pulmonary hypertension, either primary or secondary, enhances thrombus formation in pulmonary vessels. This is probably related to thrombomodulin and tissue factor imbalance, impairment of prostacyclin and nitric oxide release, as well as inefficiency of fibrinolysis. Moreover, platelets appear to be activated in the pulmonary circulation of these patients. They release several mediators acting on vascular tone and as mitogenic agents, and may also contribute to thrombin and clot generation. Long-term oral anticoagulant and continuous infusion of prostacyclin, treatments which impede thrombosis, are known to improve the survival rate in patients with primary pulmonary hypertension. These are the strongest arguments, so far, in favour of the role of thrombosis in severe pulmonary hypertension. However, we do not know whether these abnormalities result from a previous vascular injury or represent the primary disturbance.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. In the European Union, COPD and asthma, together with pneumonia, are the third most common cause of death. In North America, COPD is the fourth leading cause of death, and mortality rates and prevalence are increasing. The major characteristic of COPD is the presence of chronic airflow limitation that progresses slowly over a period of years and is, by definition, largely irreversible. Most patients with COPD are, or were, cigarette smokers. Prevention by reducing the prevalence of smoking remains a priority. Although much of the damage is irreversible at the time of clinical presentation, treatments are available to improve the quality of life, the life expectancy, and perhaps the functional ability of patients with COPD. Several national and international consensus statements on optimal assessment and management of asthma have been published in recent years. These consensus statements have led to international standardization of diagnosis and management and to better care. They also form a basis for clinical audits and suggest areas of future research. However, there have been few attempts to develop consensus guidelines on management of COPD [1, 2]. The European Respiratory Society (ERS) has taken the initiative of producing a consensus statement on COPD. A Task Force of scientists and clinicians was invited to provide this European consensus. The guidelines are intended for use by physicians involved in the care of patients with COPD, and their main goals are to inform health professionals and to reverse a widespread nihilistic approach to the management of these patients. This Task Force firmly believes that treatment can significantly improve the quality and length of life of patients suffering from this chronic, progressive condition. Subcommittees of the Task Force focused on the five main sections of this project: Pathology/Pathophysiology, Epidemiology, Assessment, Treatment, and Management. Experts produced papers within each section, and these papers were brought together by the subcommittee heads. At a plenary meeting held in Wiesbaden, Germany on November 11–13, 1993, all contributions were extensively discussed, and additional working group meetings were arranged. Flowcharts for management in common clinical situations were produced. However, at all stages, members of the Task Force found themselves confronted by unresolved questions and regional differences in management across Europe. A practical approach was adopted, combining established scientific evidence and a consensus view when current data were inadequate. This approach identified more clearly those areas where further research is needed. Comments on drafts of the consensus statement were invited from participants of the original meeting, which included colleagues from North America. The edited document was sent to independent experts for external review. All members had an opportunity to comment on the document at the ERS meeting in Nice on October 2, 1994. As chairmen of the Task Force, we hope that the final document will promote better management of COPD in Europe. We would like to thank all who contributed to it. On behalf of the ERS, we also gratefully acknowledge a generous educational grant from Boehringer Ingelheim and the organizational assistance provided by M.T. Lopez-Vidriero.

1. Oxitropium bromide (Oxivent), an anticholinergic bronchodilator, inhibits coughing induced by hypotonic aerosols in both asthmatic and non-asthmatic individuals. We have now extended this work to investigate whether this antitussive activity is reproducible in cough associated with viral infection. 2. The effect of oxitropium bromide (200 micrograms three times daily) on cough and pulmonary function has been studied in 56 non-asthmatic volunteers with upper respiratory tract infections (URTI) in a double-blind, randomised, parallel group, placebo controlled study over 10 days. 3. Lung function, symptom questionnaire and cough response to ultrasonically nebulised distilled water (UNDW) inhalation were initially recorded within 72 h of development of cough and again after the 10 day treatment period. By use of a diary card at home, frequency and severity of cough, nocturnal symptoms and general malaise were assessed daily throughout the treatment period using 5 cm visual analogue scales (VAS). Peak expiratory flow rate (PEFR) was recorded thrice daily before treatment over this 10 day period. 4. VAS scores of symptoms and UNDW-induced cough frequency all decreased over the 10 days of observation whether oxitropium bromide or placebo was administered. The mean PEFR showed a statistically significant fall in morning values during the early stages of infection which lessened with recovery but no effect of treatment with oxitropium bromide was observed (P > 0.05). 5. Oxitropium bromide, which inhibits the cough response to UNDW, does not offer an effective therapy for cough associated with an upper respiratory tract viral infection.

A total of 104 asthmatic patients with symptoms of asthma and/or a ‘morning dip’ in the peak expiratory flow rate (PEFR) who were receiving multiple therapies, including inhaled or oral steroids, were treated in addition once nightly with controlled-release theophylline in an 8-week double-blind, placebo-controlled crossover study. Theophylline produced an improvement in symptoms of cough, wheeze, sleep disturbance and PEFR in the 73 completing patients compared to run-in and placebo treatment. Theophylline also produced an improvement in the forced expiratory volume in 1 s and forced vital capacity relative to baseline, and in the difference between actual and predicted PEFR values. Nausea was the most frequent side-effect but both patients' and investigators' global impressions of the effect of study medication were in favour of theophylline.

The introduction of cyclosporine as a highly effective immunosuppressive agent and the development of new techniques for heart-lung and lung transplantation have led to a new treatment for a wide range of fatal cardiopulmonary diseases. Indications for surgery are now becoming clear, together with major contra-indications. Suppurative lung disease, such as cystic fibrosis, can be effectively treated by heart-lung transplant (HLT). A whole new field of pulmonary medicine is emerging to provide the physiological monitoring and diagnostic techniques for major complications such as opportunistic lung infection and pulmonary rejection. Obliterative bronchiolitis, a consequence of frequent and severe rejection, still provides a major challenge to the immunological scientist and respiratory physician. Lung transplantation, by disrupting the vascular supply and innervation of the lung, is raising major questions about the generally accepted beliefs of regulation of breathing and pulmonary mechanics. Finally, as the survival rate improves beyond the current 50% at 3 yrs, lung transplantation will perhaps present further challenges to our understanding of the pathogenesis of various diseases such as asthma and cystic fibrosis.

Patients restored to a normal healthy life after heart-lung transplantation have grossly abnormal physiology. Review of recent pathophysiological observations in this group of patients has led to new ideas on the mechanism of bronchoconstriction and control of ventilation during exercise and question the role of vagal reflexes in regulation of breathing at rest.

Circulating mediators, including thromboxane A2, the vasoconstrictor, platelet aggregant, and smooth muscle mitogen, may contribute to the progression of vascular narrowing in primary pulmonary hypertension (PPH).To further understand the contribution of thromboxane and to provide novel therapy for PPH, we administered the potent orally active thromboxane synthetase inhibitor and thromboxane receptor antagonist terbogrel for 12 weeks to patients with New York Heart Association functional classification II and III PPH. The study had a multicenter randomized placebo-controlled design. The primary endpoint was a change in the distance walked during 6 minutes. The pharmacologic effects of terbogrel on thromboxane and prostacyclin metabolism also were studied.Although the planned enrollment was 135 patients, the study was halted after only 71 patients had been randomized because of the unforeseen side effect of leg pain, which occurred almost exclusively in patients with terbogrel treatment. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. The leg pain confounded the primary endpoint of walking distance. On an intention-to-treat analysis, no improvements in 6-minute walk distance or in hemodynamics in patients with terbogrel treatment were seen. However, terbogrel was effective from a pharmacologic standpoint, reducing thromboxane metabolites by as much as 98% (P.0001), with a modest but statistically insignificant (39%) rise in prostacyclin metabolites.Inhibition of thromboxane with an orally active agent is feasible in PPH, but the incidence of severe leg pain with terbogrel precludes its use in this disorder. Similar therapeutic efforts, with other thromboxane inhibitors, should be considered.

Uncontrolled studies suggested that aerosolized iloprost, a stable analogue of prostacyclin, causes selective pulmonary vasodilatation and improves hemodynamics and exercise capacity in patients with pulmonary hypertension.We compared repeated daily inhalations of 2.5 or 5.0 microg of iloprost (six or nine times per day; median inhaled dose, 30 microg per day) with inhalation of placebo. A total of 203 patients with selected forms of severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (New York Heart Association [NYHA] functional class III or IV) were included. The primary end point was met if, after week 12, the NYHA class and distance walked in six minutes were improved by at least one class and at least 10 percent, respectively, in the absence of clinical deterioration according to predefined criteria and death.The combined clinical end point was met by 16.8 percent of the patients receiving iloprost, as compared with 4.9 percent of the patients receiving placebo (P=0.007). There were increases in the distance walked in six minutes of 36.4 m in the iloprost group as a whole (P=0.004) and of 58.8 m in the subgroup of patients with primary pulmonary hypertension. Overall, 4.0 percent of patients in the iloprost group (including one who died) and 13.7 percent of those in the placebo group (including four who died) did not complete the study (P=0.024); the most common reason for withdrawal was clinical deterioration. As compared with base-line values, hemodynamic values were significantly improved at 12 weeks when measured after iloprost inhalation (P0.001), were largely unchanged when measured before iloprost inhalation, and were significantly worse in the placebo group. Further significant beneficial effects of iloprost treatment included an improvement in the NYHA class (P=0.03), dyspnea (P=0.015), and quality of life (P=0.026). Syncope occurred with similar frequency in the two groups but was more frequently rated as serious in the iloprost group, although this adverse effect was not associated with clinical deterioration.Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension.

Nitric oxide has been detected by chemiluminescence in the lumen of nasal airway, which is increased in nasal breathing in patients with seasonal rhinitis during a chronic exposure. The purpose of this study was to determinate the effect of a NO-synthase inhibitor NGL-arginine methyl ester (L-NAME) on nasal airway resistance (NAR) in patients with seasonal allergic rhinitis after an acute challenge to the allergen.Nitric oxide levels in the nose were measured by the chemiluminescence method in nine non-atopic volunteers and in seven patients with seasonal rhinitis at rest and after an acute challenge with the allergen. NAR were measured by active anterior rhinomanometry.Basal nasal NO concentration in allergic rhinitis was 496.5 +/- 151.4 parts per billion (ppb). (n = 7) and it was not significantly different from levels found in the control group: 458.4 +/- 105.9 ppb (n = 9). The topical administration of L-NAME in allergic rhinitis reduced the NO concentration (338.6 +/- 99.3 ppb, P0.001; n = 7). In the rhinitic patients the challenge with the allergen did not modify the nasal NO levels (504.5 +/- 138.5 ppb). The application of the allergen after the pretreatment with placebo caused a significant increase in NAR (from 0.32 +/- 0.11 Pa s cm-3 to 1.01 +/- 0.12 Pa s cm-3, P0.001; n = 7). Pre-treatment with L-NAME did not prevent the increase in NAR induced by allergen challenge (from 0.36 +/- 0.15 Pa s cm-3 to 1.06 +/- 0.26 Pa s cm-3).The results indicate that nasal administration of a NOS inhibitor L-NAME, at doses capable of decreasing nasal NO levels, has no effect on NAR and it does not prevent the NAR increase induced by an acute challenge with allergen in subjects with seasonal rhinitis.

Objective—To investigate the relation between the severity of pulmonary hypertension and the outcome of medical treatment. Methods—98 patients with primary pulmonary hypertension—nine (6%) with systemic disease and pulmonary hypertension and 39 (27%) with thromboembolic pulmonary hypertension—received medical treatment and were followed between 1982 and 1995. They were given long term intravenous prostaglandin treatment (either epoprostenol (n = 61) or iloprost (n = 13)) or conventional treatment with oral anticoagulants (n = 24) with or without calcium channel blockers. Event-free survival was measured to death or transplant surgery, or pulmonary thromboendarterectomy. Results—Prognosis (hazard ratio) was affected by: New York Heart Association grade, 1.52 (95% confidence interval 1.11 to 2.09); mixed venous oxygen saturation (SvO2%), 0.97 (0.95 to 0.98); cardiac index, 0.72 (0.49 to 1.06); mean right atrial pressure, 1.04 (1.01 to 1.07); and pulmonary vascular resistance, 1.02 (1.00 to 1.04). The median event-free survival time of patients with SvO2

Although unlicensed, inhaled nitric oxide (NO) therapy is now widely used in the United Kingdom. Our aim was to produce guidelines for the clinical application of inhaled NO in adult intensive care practice, based upon the current level of published information.The published data regarding the use of inhaled NO in the acute respiratory distress syndrome and right-sided cardiac failure was presented, analysed and discussed. Recommendations based on these data as well as on current experience in the United Kingdom were formulated.An expert group comprising intensive care specialists from within the United Kingdom, representatives from the European Society of Intensive Care Medicine and the Society of Critical Care Medicine and individuals from the Departments of Health and Industry related to the field was assembled.United Kingdom guidelines for the indications, contraindications, dose, delivery, monitoring and scavenging of inhaled NO therapy were produced.The need for additional quality research to establish evidence of efficacy and safety was emphasized. The guidelines are designed to act within the context of current practice and knowledge and should be revised as further data emerge.

The focus of interest on pulmonary hypertension (PH) has come through recent therapeutic advances which prolong and improve quality of life. From this interest, recent observations from family studies indicate that a gene located on chromosome 2 is associated with PH. Environmental factors, the use of an anorectic agent, dexfenfluramine, has been associated with a risk of developing primary PH. A link with hypoxic induced PH has emerged in that a strain of rat, the fawn-hooded rat (FHR) which has a susceptibility to developing PH with mild hypoxia has an inherited storage defect to serotonin. Dexfenfluramine, by inhibiting the serotonin transporter, produces a similar pattern of disturbance of biogenic amine metabolism. This observation provides some insight into potential mechanisms for this complex disorder.

Recently, a cluster of patients was observed in France in whom primary pulmonary hypertension developed in patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension.In a case-control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age.The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used to a total of more than three months, the odds ratio was 23.1 (95 percent confidence interval, 6.9 to 77.7). We also confirmed an association with several previously identified risk factors: a family history of pulmonary hypertension, infection with the human immunodeficiency virus, cirrhosis, and use of cocaine or intravenous drugs.The use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future.

The presence of a systemic disease has traditionally been considered a contraindication to lung transplantation.We present a retrospective review of 19 patients undergoing lung transplantation for end-stage pulmonary disease associated with a systemic illness since 1984. There were 11 male and 8 female patients, aged from 23 to 59 years (median 43 years) with end-stage pulmonary involvement by sarcoidosis (11 patients), Langerhan's cell histiocytosis (three patients), systemic vasculitis (four patients: three with systemic lupus erythrematosis, one with Churg-Strauss), and common variable immunodeficiency (one patient). Ten patients received a heart-lung transplant, and eight patients received a single lung transplant. One patient underwent single lung transplantation after an earlier heart-lung transplant.The 30-day mortality was 5.3%. Nine patients died overall. Two of these had systemic lupus erythrematosis with anticardiolipin antibodies and died from complications of their underlying vasculitis. The mean 1- and 2-year actuarial survivals for all patients were 71% (standard error +/- 10.8%) and 64% (standard error +/- 11.9%), respectively. All patients surviving longer than 3 months achieved an improvement in functional status to New York Heart Association class I or II, and a significant increase occurred in mean forced expiratory volume in 1 second and forced vital capacity. Disease recurrence without clinical significance occurred in two patients with sarcoidosis. Of the nine patients who died, seven had autopsies and none showed evidence of disease recurrence in the lungs.Patients with systemic diseases can be considered for lung transplantation and each case should be judged on its individual merits. However, patients with systemic lupus erythrematosis (particularly when associated with anticardiolipin antibodies) should probably not be offered lung transplantation because they are likely to develop further complications of their underlying vasculitis.

With the increasing number of successfully performed lung transplants and a longer follow up of patients, there is an interest in the analysis of long-term complications and their impact on patient survival. Heart-lung transplantation was performed in 157 patients with 126 patients surviving at least 6 months. Early death was mainly caused by bacterial and viral infection. Long-term patient survival was decisively influenced by obliterative bronchiolitis. With the new international definition of bronchiolitis obliterans syndrome (BOS) based on an irreversible decline of FEV1 from baseline values, it became possible to analyse the incidence of BOS and the impact on patient mortality in long-term survivors. FEV1 reached a peak value of 102% predicted at a median of 219 days. In 106 of 126 patients (84%), FEV1 showed no decline within the first year. A total of 60 patients (47.6%) developed BOS grade 1 with progression to BOS grade 2 in 85% of these patients. The incidence of BOS was 12.6% at 1 year increasing to more than 50% 5 years after transplantation. Patient mortality due to obliterative bronchiolitis increased from 1% at 1 year to 18% more than 5 years after transplantation. Almost all deaths (86%; 32/37) more than 1 year after HLT were associated with bronchiolitis obliterans. In summary, bronchiolitis obliterans decisively contributes to long-term patient morbidity and mortality after heart-lung transplantation. Clinical and research efforts should be directed towards avoiding this important complication.

The mixed expired nitric oxide (NO) production of the lungs of patients with primary pulmonary hypertension (PPH) and normal subjects was measured to determine the relationship between NO production and the diffusion capacity of the lung (KCO). Expired air was collected from eight patients with PPH and 20 healthy volunteers for analysis by a chemiluminescent analyser. Mean pulmonary artery pressure in the PPH patients was 59.5 +/- 6.45 mmHg and their mean cardiac output was 2.95 +/- 0.35 l/min. All patients and subjects underwent measurements of FEV1, VC and KCO. The rate of production of NO in mixed exhaled air was lower in the PPH group compared to the controls (2.85 +/- 0.7 vs. 4.69 +/- 0.35 nM/min; p0.05). There was a good correlation of expired NO with the KCO (r = 0.7; n = 30; p0.001). When corrected, KCO differences in exhaled NO were not significant (p = 0.09). We conclude that the low exhaled NO observed in PPH patients is a reflection of the reduced blood capillary volume in these patients rather than a decreased basal production of NO.

Between August 1982 and December 1992, 260 patients were accepted for heart and lung transplantation, of whom 139 patients underwent transplant surgery. One hundred twenty-one patients have not received transplants, of whom 80 have died, four were transferred to other lists, and 37 were still waiting for suitable organs at the close of the study. Median waiting time for those patients who underwent heart and lung transplantation was 7 months, whereas patients who died waiting spent a median of 5 months on the list. Recipients are matched to donor organs according to blood type, size (total lung capacity), and cytomegalovirus antibody status. These factors, along with age, gender, underlying diagnosis, and Toxoplasma antibody status, were studied to assess their influence on survival after acceptance and time to transplantation. The only characteristic that significantly influenced survival after acceptance was the underlying disease, with patients with Eisenmenger's syndrome having significantly longer survival than the other groups (relative risk = 0.21; p0.001). Patients with Eisenmenger's syndrome underwent transplantation at a slower rate than did other patients (relative risk = 0.51; p = 0.012). Patients who had a total lung capacity of more than 6 L underwent transplantation significantly more quickly than did smaller patients (relative risk = 1.98; p = 0.005). Male patients underwent heart and lung transplantation at a quicker rate than did female patients (relative risk = 1.86; p0.001), although this was related to size. Patients who had cytomegalovirus-positive antibodies underwent transplantation at almost twice the rate of patients who had cytomegalovirus-negative antibodies (relative risk = 1.92; p0.001). Age at acceptance, blood type, and Toxoplasma status did not significantly influence time to heart and lung transplantation. In summary, cytomegalovirus antibody status, patient size, and gender significantly affect the waiting time to heart and lung transplantation. Patients with Eisenmenger's syndrome wait longer than other patients as a result of the natural history of their disease.

Between October 1985 and July 1992 we performed heart-lung transplantation in 42 patients with end-stage respiratory disease caused by cystic fibrosis. Twenty-eight of these patients are alive at 3 months to 7 years after heart-lung transplantation. Actuarial survival at 1 year and 3 years after transplantation was 78% and 65%, respectively, in this group, which compares favorably with 77% and 60%, respectively, in patients without cystic fibrosis undergoing heart-lung transplantation. Similarly no significant difference was found in the incidence of postoperative infections between patients with cystic fibrosis and patients without cystic fibrosis undergoing heart-lung transplantation. Quality of life indexes analyzed by the Nottingham Health Profile reveal significant improvements for patients surviving longer than 3 months from surgery. Long-term survival is determined by the development of obliterative bronchiolitis, which has occurred in 11 patients, six of whom have died. Early postoperative survival appears to be compromised by poor preoperative nutritional status. The study provides evidence that patients with end-stage respiratory disease caused by cystic fibrosis gain a survival advantage and improvement in quality of life after heart-lung transplantation when compared with patients who do not receive this form of therapy.

A clinically applicable, standardized method for assessing functional results after lung transplantation is required to evaluate factors that may affect long-term outcome, to permit comparison of results from different centers, and to evaluate results of clinical trials. An ad hoc working group was established under the auspices of the International Society for Heart and Lung Transplantation for the purpose of developing such a clinically applicable system. Chronic allograft dysfunction is often associated with pathologic findings of obliterative bronchiolitis, the cause of which has not been defined. Physiologically, such dysfunction is associated with obstructive airways disease. The group concluded that the forced expiratory volume in 1 second was the most reliable and consistent indicator of graft dysfunction, excluding other identifiable causes. The term bronchiolitis obliterans syndrome was adopted to describe such dysfunction, recognizing that there may or may not be pathologic evidence of bronchiolitis obliterans present. Four stages of bronchiolitis obliterans syndrome were defined, each with two subcategories to indicate whether pathologic evidence of obliterative bronchiolitis had been identified. This working formulation will require reappraisal in the future to reassess its practical application and to make such adjustments as may seem appropriate.

The development of secondary pulmonary hypertension (PH) as a result of pulmonary disease, both in adults and children, considerably worsens prognosis. Chronic hypoxia appears to be the cause, as long-term oxygen therapy (LTOT) reverses or at least impedes the progressive development of PH. There is now clear evidence that acute hypoxia causes smooth muscle contraction in pulmonary arteries through a direct effect on intracellular calcium levels. Subsequent relaxation depends upon activation of ion transport mechanisms which can be modified by circulating hormones such as the naturally occurring ouabain. Sustained hypoxia can cause adaptation of pulmonary endothelium. One change is a reduction in nitric oxide (NO) production, possibly through reduced activity of the formative enzyme nitric oxide synthase. Basal production of NO appears important in many species including man in determining the low pulmonary vascular resistance. Impaired endothelial NO production as a result of sustained hypoxia may well enhance the development of secondary PH. Much attention is now focused on the regulation of nitric oxide synthase, both the constitutive form in endothelium as well as the inducible form of inflammatory cells. It is possible that either gene transcription or translation are modified when endothelial cells are exposed to chronic hypoxia. This allows the opportunity for therapeutic intervention. More needs to be learnt about the cellular and molecular adaptation to hypoxia in man but novel approaches to treatment may soon arrive for patients with chronic obstructive lung disease and secondary pulmonary hypertension.

Heart-lung transplantation is a successful treatment for patients with cystic fibrosis and chronic respiratory failure. Patients are assessed for surgery when life expectancy is deemed short. This study assesses the ability of measurements of pulmonary function, blood gas levels, and nutritional status to predict survival of patients awaiting heart-lung transplantation and to assess the effect of heart-lung transplantation on survival. Sixty-seven patients with cystic fibrosis were accepted for heart-lung transplantation from 1985 through 1990. Each patient underwent tests of pulmonary function, exercise tolerance, blood-gas levels, and nutritional status. Cox regression was used to analyze the prognostic value of these data. Of the 67 patients accepted for heart-lung transplantation, organs became available for 30; 24 patients died waiting, and 13 patients were on the list December 31, 1990. Eight patients died after transplantation. Patients with above-average forced expiratory volume in 1 second (FEV1) (median, 17% predicted) at assessment were half as likely to die waiting (relative risk, 0.47; 95% confidence interval, 0.23 to 0.97) as patients with below-average FEV1. The relative risk of death for patients on the waiting list was 1.44 (95% confidence interval, 1.17 to 1.77) for each increment in PCO2 of 1 kPa. No effect of nutritional status on waiting list death was found, but seven of eight patients who died after heart-lung transplantation were below 80% predicted weight for height. Using a time-dependent analysis, heart-lung transplantation almost halved the risk of death (relative risk, 0.57; 95% confidence interval, 0.22 to 1.48). Postoperative actuarial survival was 79% (95% confidence interval, 63% to 95%).(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary hypertension in its many different forms 1 was considered untreatable until the 1990s. With the exception of pulmonary hypertension associated with hypoxic lung disease, where long-term oxygen therapy (LTOT) improves survival in those patients with respiratory failure 2, the various forms of the disease often progress rapidly and lead to premature death. Work carried out in the early 1980s suggested that long-term, continuous intravenous prostacyclin might increase survival in severe primary pulmonary hypertension (PPH) 3, 4. However, these papers reported unrandomized studies. This was also true of a report that showed that long-term anticoagulation improved survival in PPH and chronic thrombo-embolic pulmonary hypertension 5. …

A prospective study of 219 bronchoscopies in 54 heart-lung and in 2 single lung transplant recipients was undertaken over a 12-month period by a single operator. For histologic study, an average of 17.3 transbronchial biopsy specimens (range, 6 to 56) were taken from three lobes (or from two lobes and lingula of one lung). A further two specimens were taken for culture. The average procedure time was 14.4 minutes (SE 0.31). An estimate of the probability of rejection being missed, depending on the number of specimens taken and based on the method of Gilman and Wang, suggests 18 biopsy specimens are required to have 95% confidence of diagnosing rejection. Sensitivity for diagnosing rejection by histologic study of transbronchial biopsy specimens was 94%, and specificity was 90%. The simple grading of severity of rejection that was used was related both to the number of specimens demonstrating rejection and to the severity of graft airway mucosal inflammation seen at bronchoscopy. The major complication encountered, on 27 occasions, was bleeding of more than 100 ml. On no occasion did bleeding result in any long-term complication. Extensive transbronchial biopsy is a simple, relatively safe, and quick procedure, with a high sensitivity and specificity for diagnosing rejection and lung infection.

From among 112 patients with cystic fibrosis who were assessed for heart-lung transplantation, 83 were accepted. Twenty-six died while awaiting heart-lung transplantation and 32 had the operation. The management and the outcome of these 32 patients is reported. Survival, infection, and rejection rates among these patients were compared with those of 61 patients without cystic fibrosis who underwent heart-lung transplantation between 1984 and 1990. The cumulative survival rate was 72.29% +/- 94.91% at 1 year and 55.59% +/- 7.50% at 3 years. The mortality rate was slightly higher in the group with cystic fibrosis during the first year after the operation but it was lower at 3 years. The difference, however, could have been due to chance alone (p = 0.308). The same was true for the prevalence of rejection (up to 6 months: chi 2 = 1.8141, p = 0.17), and infection (up to 6 months: chi 2 = 2.20, p = 0.14), between the two groups. It is concluded that cystic fibrosis does not constitute an additional risk in terms of survival and morbidity after heart-lung transplantation.

The development of research into the mechanisms and so of treatment of asthma has reached a crossroads. Research into the physiology of 'mature' inflammatory cells and their mediators have not provided treatments as effective as steroids. Whilst it is tempting to pursue this systematic approach, new ideas are emerging which beckon the scientist along a separate path. From molecular biology and modern genetics emerges the idea that a regulatory dysfunction of a lymphocyte is the fundamental abnormality of asthma. Bone marrow transplantation and transfer of 'asthma' from one individual to another supports this view. From lung transplantation has emerged the idea that the distribution of the infiltrate of inflammatory cells may be important in airway hyperresponsiveness. Transplantation also points to the possibility of correlating pathology with physiology by use of small lung biopsies. Perhaps completely new treatments may result from such a novel and 'human' based approach.

Sixty patients underwent heart-lung transplantation at our institution between April 1984 and March 1989. The first five donor organs were removed in an adjacent operating room. Subsequently, organs were removed from distant centers. The method of preservation consisted of cold crystalloid cardioplegic arrest of the heart followed by a cold colloid pulmonary artery flush of a perfusate developed at Papworth Hospital. The lung perfusate is preceded by an infusion of prostacyclin into the pulmonary artery, during preliminary dissection of the donor organs. The total ischemic time ranged from 48 to 51 minutes (mean, 49.6 minutes) for the near-procurement group and from 70 to 249 minutes (mean, 157.6 minutes) for the distant-procurement group. Function of the lungs was assessed by gas exchange, pulmonary function tests, extubation, and survival data. Serial x-ray films were used to monitor graft performance in the postoperative period. We record our clinical experience of early graft function after heart-lung transplantation.