proceedings of the british thoracic societyproceedings ofthe british thoracic society...

Thorax 1983;38:700-719

Proceedings of the British Thoracic SocietyThe 1983 Summer Meeting of the British Thoracic Society was held on 27-29 June in the University ofCambridge

BTS smoking withdrawal study: fators assodated withgiving up smoking

IA CAMPBELL for BTS Research Committee In the BritishThoracic Society's smoking withdrawal study 9-7% of1550 patients successfully gave up smoking. Reasons forwanting to stop smoking, apart from improvement inhealth, were expense (30%), dislike of addiction (20%)and "dirty habit" (18%). Concern about weight gain wasexpressed by 41% of men and 59% of women. Men weremore successful than women and success in both sexesincreased with age. Men with ischaemic heart disease didbest (21% success). Married or single men were morelikely to give up smoking than divorced or separated men.Patients whose "most important other person" was a non-smoker did better than if such a person smoked. Womenwho thought they were addicted were less likely to suc-ceed. Confidence in ability to stop smoking for a year wasrelated to successful outcome in men. Mean weight gain inthose who were successful was 5-9 kg. Socideconomicgroup, cigarette consumption, concern about weight gainand health concern were not related to outcome. Of thesuccesses, 50% rated will power as important, and 15%mentioned illness, 13% their families and 7% their doctor.Only 1% mentioned expense. Failure was most commonlyattributed to lack of will power (28%), relief of tension bycigarettes (24%), and addiction (16%). Other smokers inthe family and pressure at home were more important inwomen than men.

Pulmonary sarcoidosis: a personal survey over 20 years

RN JOHNSTON Three hundred and thirty-eight patientswith pulmonary sarcoidosis under the care of one physicianhave been reviewed. Seventy-six were diagnosed between1956 and 1963 or earlier and a minimum follow-up of 20years is reported (average 22*5 years). All except six (8%)have been traced (92% follow-up). Fifty-five patients haveno respiratory disability after at least 20 years but 10 havex-ray evidence of minimal pulmonary fibrosis and three ofmore extensive fibrosis. Respiratory function tests at theend of the survey in 42 patients show that only 12 (29%)had a transfer factor less than 80% of predicted. Fourteenpatients received prednisolone for progressive or relapsingdisease. None of these patients died from sarcoidosis but16 died from other causes and eight (10%) developed var-ious forms of malignant disease. Among 263 patients seensubsequent to 1963 this good prognosis continues, withpulmonary fibrosis in a further four patients. Two patientshave died from progressive sarcoidosis and postmortemfindings are available in a further two patients, and in these

four there was continuing "active" disease at the time ofdeath. The average follow-up in this supplementary seriesis six years and to date there has been only one simpletumour (neurilemmoma).

Treatment of pneumothorax by simple aspiration

AAD HAMILTON, GJ ARCHER All the patients admitted toStepping Hill Hospital with an uncomplicatedpneumothorax requiring treatment during the 12 monthsup to January 1983 were admitted to the study. Thesepatients, numbering 10, were treated by simple aspirationof air using a plastic cannula used for intravenous insertion.In seven patients the procedure was successful. Of these,there has so far been only one recurrence, in a patient whohad had four previous pneumothoraces. One other elderlypatient developed a small ipsilateral pleural effusion whichhas been assumed to be neoplastic. None of the otherpneumothoraces has so far recurred. Of the patients whohad unsuccessful aspiration, all had severe coexisting lungdisease and only one had successful re-expansion afterinsertion of an intercostal tube. In this small series therewere only two patients with so-called benign spontaneouspneumothorax; all the others had presumed causative fac-tors. It is concluded that simple aspiration by means of anintravenous cannula warrants further investigation.

Tuberculous lymphadenitis: results of nine-month andeighteen-month regimens after eighteen months

CR McGAVIN for the Research Committee of the BTS Thismulticentre study compares nine versus 18 months'chemotherapy for lymph node tuberculosis. The drugregimens comprise rifampicin and isoniazid supplementedinitially by ethambutol for eight weeks. One hundred andfifty-two patients had entered the study by June 1982.Thirty-two were withdrawn, mostly because of drug errorsand non-attendance. One hundred and twenty patients,equally divided between long-course and short-coursechemotherapy, have now been observed for 18 months.Seventy-four per cent were Asian (mean age 33 years) and22% were European (mean age 50 years). In the first ninemonths after the start of therapy fresh nodes appeared in12%, existing nodes enlarged in 11%, and 8% requiredfurther surgical procedures. In the second nine monthsafter the start of therapy existing nodes enlarged in 6% andfresh nodes appeared in 3% of the short-course group, butthere were no such events in the long-course group. Nomicrobiological relapse has been recorded to date, butfollow-up continues.

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Proceedings of the British Thoracic Society

Controlled trial of six months' chemotherapy in pulmonarytuberculosis

JH ANGEL, AR SOMNER, KM CITRON for the BTS ResearchCommittee Two six-month regimens of isoniazid andrifampicin, supplemented for the first two months by strep-tomycin and pyrazinamide (SHRZ6) or by ethambutol andpyrazinamide (EHRZ6), were compared with a nine-month regimen of isoniazid and rifampicin, supplementedfor the first two months by ethambutol (EHR9). All 444patients who completed chemotherapy had negativesputum cultures by the end of treatment, but the rate ofsputum conversion was significantly more rapid with thetwo pyrazinamide-containing regimens. Adverse reactionswere not a serious problem. Hepatitis occurred in 4% ofthe, patients who received pyrazinamide (SHRZ6 andEHRZ6) and in 4% of patients in the regimen withoutpyrazinamide (EHR9). Three hundred and seventy-sixpatients have been followed up for three years from theend of chemotherapy. Relapses have occurred in one of121 SHRZ6 patients, three of 126 EHRZ6 patients, andtwo of 129 EHR9 patients. These observations reinforceour earlier conclusion that six months' chemotherapy withthese pyrazinamide-containing regimens is as effective asthe currently recommended nine months' regimen and hasthe advantage of being shorter and cheaper while beingequally well tolerated.

Controlled trial of short-course and standard-durationchemotherapy for pulmonary tuberculosis in the AlgerianSahara: Algerian worldng group and Medical ResearchCouncil collaborative study

JANET J DARBYSHIRE (presenter) A six-month daily oralregimen of isoniazid and rifampicin supplemented bypyrazinamide and ethambutol for the first two months hasbeen compared with a 12-month daily oral regimen ofisoniazid and ethambutol, supplemented by streptomycinfor the first month, in an area of the Algerian Sahara wherea substantial proportion of the population is nomadic. Thestudy was conducted under conditions approaching thoseachievable in the routine treatment services and, in particu-lar, the nomads were allowed to continue their nomadicway of life. A total of 601 patients all with a positivesputum smear in the local laboratory were admitted to thestudy, 28% being nomads. Confirmation of the diagnosisby culture in the reference laboratory in Algiers was poss-ible in 70%; a further 25% had confirmation either from apositive smear in the reference laboratory or from aradiographic lesion at independent assessment. In all, 95patients were excluded, the majority because of default.For the patients known to have fully sensitive strainsbefore treatment the 12-month regimen had an overallfailure rate of 17% in 154 patients assessed at two years,significantly higher (p < 0-001) than the 3% of 131patients on the six-month regimen. If we consider allpatients assessed at two years, the overall failure rates were3% of 59 nomads and 4% of 170 settled residents on thesix-month regimen, compared with 14% of 58 nomads and17% of 173 settled residents on the 12-month regimen.

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Thus the six-month regimen was superior to the 12-monthregimen and for both regimens the results were as good fornomads as for the settled residents.

Anfthistamines in seasonal aflergic rhinitis: a double-blindstudy of demastine and ketotifen

AD BLAINEY, S OLLUER, C GOULD, RJ DAVIES Antihistaminesare widely used in the treatment of allergic rhinitis and areconsidered effective. It has recently been shown thatketotifen is a powerful antihistamine (Phillips et al. Br JClin Pharmacol 1983, in press), though it is claimed that itmay also have additional "antiallergic" properties. Wehave conducted a double-blind placebo-controlled com-parison of ketotifen with clemastine, an established antihis-tamine, in adults with seasonal allergic rhinitis to deter-mine whether ketotifen provides any advantage overclemastine. Forty-eight patients with seasonal allergicrhinitis due to grass pollen entered the study; 16 receivedketotifen and 16 clemastine (both at a dose of 1 mg twicedaily). Sixteen received identical placebo tablets. Symp-toms of rhinorrhoea, sneezing, and nasal blockage wererecorded on visual-analogue scales and diary cards atthree-weekly intervals throughout the summer, and dose-response curves for the increase in nasal resistance inresponse to increasing doses of histamine were producedon each occasion. Symptom scores and the nasal responseto histamine initially increased in all three groups but aftermore than six weeks of therapy both symptoms and thenasal response to histamine were significantly reduced inthe ketotifen-treated group in comparison with placebo.The clemastine-treated patients showed a significantreduction in the nasal response to histamine but noimprovement in symptoms. We conclude that ketotifen iseffective in the treatment of seasonal allergic rhinitis inadults. This may be the result of its potent antihistaminicactivity or the drug may have additional properties.

Isosorbide dinstrate and isoxsuprine in exercise-inducedasthma

WM TULLETT, KR PATEL The effects of saline, isosorbide,isoxsuprine, salbutamol, and sodium cromoglycate (SCG)were compared in seven patients with exercise-inducedasthma (EIA). The protective effect of isoxsuprine andisosorbide as measured by FEV, after eight minutes oftreadmill exercise was significant, being comparable to thatof SCG but not as effective as salbutamol. It appears thatirrespective of the mechanism of action in EIA a smooth-muscle relaxant compound which does not act via the cal-cium channels can afford significant protection. The factthat there was no statistical difference between isoxsup-rine, isosorbide, and SCG may lend fuel to the argumentthat SCG's main effect in EIA is via bronchial smoothmuscle and not via mast cells. Apart from beta-blockers, itis beginning to appear that all antianginal preparationshave an action in EIA and we would suggest that isosor-bide dinitrate would be a safe and indeed effective prep-aration in patients with both chronic obstructive airwaysdisease and ischaemic heart disease.

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Incidence of cardiac dysrhythmias in asthmatic patientstaking sustained-release oral f82-adrenergic agonists

AH AL-HILLAWI, R HAYWARD, N McI JOHNSON We havelooked at the incidence of cardiac dysrhythmias in 16stable asthmatics (mean age 39 years, range 19-60 years)with early morning dipping who were prescribedsustained-release f82-adrenergic agonists. In a single-blindcrossover study patients were randomly allocated to sal-butamol spandet (8 mg at night) for one week or ter-butaline SA tablet (7-5 mg twice daily) for one week withthe appropriate metered-dose inhaler. Twelve-hour ECGtapes were worn overnight on the day before the trial, atthe end of the first week of medication, and at the end ofthe second week of medication. Although no significantchange in maximum heart rate was recorded with eitherpreparation, five patients developed arrhythmias duringthe study. Three patients had abnormal ECG tapes beforetreatment: two had atrial ectopics and subsequentlydeveloped paroxysmal atrial tachycardia during the weekon salbutamol spandet; and one had single ventricularectopics progressing to paired ectopics on terbutaline SA.Two patients with normal baseline recordings developedventricular ectopics on both salbutamol spandet and ter-butaline SA. Eleven of the trial patients also recorded theirPEFR recordings before going to bed and on awakening.These patients showed no significant improvement eitherin actual values or in the morning dips with either prepara-tion over baseline recordings.

Sympathoadrenal responses in asthma

PW IND, M1 BROWN, PJ BARNES The physiological impor-tance of circulating catecholamines, in particularadrenaline, in asthma is suggested by the actions ofI32adrenoceptor agonists and antagonists on airway calibre,in the absence of a functional pulmonary sympatheticnerve supply. We previously reported a surprising impair-ment of plasma catecholamine in asthmatics developingexercise-induced asthma (EIA) compared with controlsperforming matched exercise (PJ Barnes et al. Thorax1981; 36:435-40). We have now extended these observa-tions. In view of conflicting reports of catecholamineresponse to exercise in asthmatics, we performed treadmillexercise tests (6 min at 6 kph, slope 8-10') in five malesubjects (mean age 28 ± 2-9 (SEM) years). Maximum fallin FEV, was 35% + 6-6% (SEM) of baseline but plasmaadrenaline was unchanged and plasma noradrenaline roseby 311% ± 52% from baseline five minutes after exercise,confirming our previous finding that the sympathoadrenalresponse to exercise is blunted in asthmatics comparedwith normal subjects. The catecholamine response tohypoglycaemia was investigated in five asthmatic childrenwith EIA and five non-asthmatic controls by a standardinsulin tolerance test. There was no significant differencebetween the groups in plasma glucose, noradrenaline, oradrenaline before or after insulin. Plasma noradrenalinerose 140% in both groups; adrenaline rose 32-fold in theasthmatics and 28-fold in the controls. Incremental his-tamine infusion was also studied as a less profoundstimulus to adrenaline secretion. In six normal male sub-


jects (aged 30 + 1*8 years) plasma adrenaline rose 1-2-foldwhile noradrenaline was unchanged after a 15-minuteinfusion of histamine at 128 ng/kg/min. The same infusionin five atopic asthmatics (24 + 3-2 years) increased plasmaadrenaline 3*1-fold, while noradrenaline rose 1-4-fold andpeak expiratory flow fell by 16% + 8-2% from baseline.We conclude that the sympathoadrenal response to exer-cise is impaired in asthmatic subjects while the response tohypoglycaemia and histamine is normal. The mechanismfor this selective defect is uncertain.

Hyperreactivity of the nasal airways: fact or fiction?

OJ CORRADO, CAL GOULD, RJ DAVIES Increased reactivityof the airways is considered by some to be a cardinal fea-ture of asthma, although the underlying mechanisms havestill to be explained. The increased responsiveness of thebronchi of asthmatics to non-specific stimuli may simply bea reflection of their decreased calibre; alternatively it maybe the result of true differences in behaviour of the airway,due perhaps to alteration in the function of bronchialepithelium, nerve endings, or smooth muscle. Even thoughit is a readily accessible organ, there have been few studieson the response of the nasal airways to non-specific stimuli.Further, apart from the vasculature, the nose is devoid ofsmooth muscle. We have studied the response to histaminein 20 patients with perennial rhinitis and 16 non-rhiniticcontrol subjects. Nasal airways resistance (NAR) wasmeasured in both nostrils by anterior rhinomanometry andrepeat measurements were made two and five minutesafter 100 ,ul of phenol saline and increasing concentrationsof histamine (1, 2 5, 5, 10, and 25 mg/ml) had beensprayed into the nostril with the lowest resistance. Therewas no significant difference in NAR before provocationtesting or after application of phenol saline in the patientswith rhinitis compared with controls. There was asignificantly greater increase in NAR following provoca-tion with histamine (2.5 mg/ml) in the patients with peren-nial rhinitis compared with non-rhinitic control subjects (p< 0.05), suggesting that nasal reactivity does indeed occur.

Bronchoalveolar lavage in asthma: the effect of sodiumcromoglycate on leucocyte counts, immunoglobulins, andcomplement

PATRICIA DIAZ, FR GALLEGUILLOS, M CRISTINA GONZALEZ, ABKAY In a double-blind placebo-controlled study wemeasured the effect of sodium cromoglycate (DSCG) onleucocyte counts, total IgE, IgG, IgA, IgM, house-dust-mite(HDM)-specific IgE, C3, and C4 in bronchoalveolarlavage (BAL) fluid and peripheral blood in 36 atopic,perennial asthmatic subjects (SCG 19; placebo 17). Diffe-rential cell counts on bronchial mucus were also per-formed. The percentage of eosinophils in bronchial mucusand BAL fluid were significantly decreased following SCG.There was also a significant decrease in the concentrationof total IgA (expressed as an IgA:albumin ratio) in BALfluid following 28 days treatment with SCG. When the

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SCG-treated patients were divided into responders andnon-responders on the basis of average daily symptomscores, the responders had a significant decrease in bron-chial mucus eosinophils, BAL eosinophils, and HDM-specific IgE (but not IgA) following SCG. No significantdifferences in any of the measurements were observed inthe non-responders. These results suggest that the efficacyof SCG in bronchial asthma might be related to its abilityto suppress the local accumulation of eosinophils andspecific IgE antibodies.

Inununoglobulin G2 defidency in chronic and recurrentrespiratory infections

Pi STANLEY, Pi COLE Immunoglobulin (Tg) G subclasses1-4 have different biological properties. In particular, cer-tain antibodies are subclass specific, for example, anticar-bohydrate antibodies are of IgG2 subclass (Yount et al, JExp Med 1968; 127:633). Sixty-six percent of serum IgGis IgG, (IgG2 - 23%, IgG3 - 7%, IgG4- 4%) and defi-ciency of a subclass can occur with normal total IgG.Oxelius (Clin Exp Immunol 1974;17:19) reported IgG2and G4 deficiency in a family suffering from chronic infec-tions, mostly due to Haemophilus influenzae, with absenceof serum antibodies to H infiuenzae polysaccharide.Oxelius et al (New Engl J Med 1981;304:1476) reportedIgG2 deficiency in seven of 48 patients with selective IgAdeficiency. We measured serum IgA, total IgG, and IgG14in 80 patients (40 with bronchiectasis, 40 with recurrentrespiratory infections) using radial immunodiffusion. Allpatients had normal or raised total IgG but 14 had lowserum IgA. Deficiency of IgG2 was found in seven patients(five with recurrent infection, two with bronchiectasis).Five of these seven had concomitant IgA deficiency. Inview of the reported beneficial response to gammaglobulinreplacement in IgG subclass deficiency, the latter may bean important condition to recognise. It will not be detectedif only total IgG is estimated.

Radiographic chanes in psfttacosis infection

II COUTrS, S MACKENZIE, RI wHITE The incidence of psit-tacosis has increased in recent years. Forty-four cases,serologically confirmed by the Public Health LaboratoryService, occurred in Bristol in 1980 and 1981. Eleven weremanaged entirely by their general practitioners. Thirty-three attended hospital and 11 were admitted. The meanage of the patients was 41-7 years (range 8-76). The initialchest film was normal in 11 of the 33 hospital attenders,including three inpatients. The most common radiographicabnormality was patchy consolidation (64%). This wasbilateral in three cases. Eleven had purely segmental con-solidation. Lobar consolidation was present in five and in afurther two cases more than one lobe of the lung wasaffected. Pleural effusion occurred twice, one being associ-ated with consolidation. The radiograph subsequentlydeteriorated in only one patient. No abnormality wasobserved to develop in those who presented with a normalfilm. The consolidation showed no predeliction for any par-ticular lobe or segment. Twelve radiographs returned tonormal after a mean of 7-25 weeks (range 3-20) and a

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further eight had improved at final attendance after a meanof 4-4 weeks (range 1-10). There were no radiographicfeatures that appeared to be characteristic of psittacosisinfection but segmental consolidation was the commonestabnormality seen.

Branhamefs lower respiratory tract infection in patientswith chronic lung disease

J POWER, DF AHMAD, DT McLEOD, MA CALDER Branhamellacatarrhalis is widely regarded as a commensal of theoropharynx and is therefore not commonly reported whenseen on sputum examination. A few cases of B catarrhalisas a pulmonary pathogen capable of producing,B-lactamase in a minority of isolates have, however, beenreported (Ninane et al. Br Med J 1978;i:276-8). We reporta striking increase in the incidence of B catarrhalis in thesputum of patients with longstanding pulmonary diseasewho presented with symptoms of an infective exacerbationin November and December 1982 and January 1983. Inour laboratory B catarrhalis is routinely reported, thecriteria for pathogenicity being: numerous pus cells in theGram stain with intracellular and extracellular Gram-negative diplococci, a moderate-to-profuse growth of Bcatarrhalis, and absence of any other known respiratorypathogens. Such isolates are normally very few. Trans-tracheal aspiration of sputum is unnecessary (Thornley etal. Br Med J 1982;285:1537-8). Of 48 cases documented,eight were in outpatients. Although one-quarter of thecases were admitted with B catarrhalis, three-quartersacquired their infection in hospital. One such patientrequired assisted ventilation. Over 60% were,3-lactamase-producing strains. We conclude that B catar-rhalis is a pathogen which should be looked for andreported in exacerbations of chronic chest disease as infec-tion with a 83-lactamase-producing strain may be treatedwith an inappropriate antibiotic.

Abnormanities of the lungs and thoradc cage in theEhlers-Danlos syndrome

JG AYRES, FM POPE, JF REIDY, TJH CLARK Case reports ofbullae, pneumothorax, and haemoptysis have all beenreported in the Ehlers-Danlos syndrome (EDS) but theincidence of these complications in EDS is unknown. Westudied 20 patients with fully documented EDS (10 type I,6 type II, and 4 type IV) by measuring lung volumes,flow-volume curves, and gas transfer and by using a ques-tionnaire. A chest radiograph was also obtained. Twopatients had bullous lung disease, one having had threepneumothoraces followed by a pleurodesis. Five patientshad had at least one minor haemoptysis and in two theepisodes had been recurrent. One patient had tracheomeg-aly (the Mounier-Kahn abnormality). Gas transfer (Kco)was greater than 120% of predicted in seven patients, poss-ibly owing to an increased intrapulmonary vascular vol-ume. Compliance was measured in two patients; onepatient showed a shift of the pressure-volume curveupwards, suggesting loss of elastic recoil, but with no clini-cal evidence of asthma or emphysema. The straight back

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syndrome or other thoracic skeletal abnormalities werenoted in 11 patients. Type IV patients appear to be espe-cially likely to have lung or chest wall abnormalities. In anypatient with haemoptysis, bullae, or pneumothorax with noobvious cause, a diagnosis of EDS should be considered.

Pulmonary embofism in children

DJ MAT-tIEW, M LEVINE Pulmonary embolism in childhoocis a rare but underdiagnosed Condition. A recent reviem(JR Buck, RH Connors, WW Coon, et al. J Pediat Surg1981;16:385) of 25 years of paediatric necropsy experience in Miechigan reported an incidence of 3-7%, of whicdless than 10% had been suspected in life. While the vasimajority of pulmonary emboli in adults originate in thedeep veins of the pelvis and legs, these are reported to berare sites of origin in children, the heart and vena cavaebeing the most common. We report the four children agec5-13 recognised to have pulmonary emboli in our unit oveithe last two years. Their primary diagnoses were:craniopharyngioma, asthma, chronic subacute jejunal obs-truction, and Reye's Syndrome. In three the diagnoseswere supported by multiple or massive perfusion defectson technetium microaggregate lung perfusion scans. Thefourth and only child to die was diagnosed at necropsy.Three of the children had markedly elevated plasmaosmolality, one as a consequence of his diabetes insipidusand two as a result of hyperosmolar therapy for cerebraloedema. All were treated with heparin. The child who diedwas found to have a femoral vein thrombosis but the sitesof origin of emboli in the other children were not defined.

Prediction of loading and maintenance doses of warfarin inpatients with thromboembolic disease

A FENNERTY, J DOLBEN, P THOMAS, P BENTLEY, IA CAMPBELL,PA ROUTLEDGE The chest physician has to deal frequentlywith thromboembolic disease and its treatment with anti-coagulants. With the recommended loading dose of warfa-rin (10 mg on three consecutive days) up to one-third ofpatients will be above the therapeutic blood concentrationrange (BCR) by day 4. (PA Routledge et al. Predictingpatients' warfarin requirement. Lancet 1977; i 854-5).From previous work, nomograms were constructed basedon BCRs measured while the patients were on a heparininfusion. On the basis of these nomograms a flexible load-ing dose regimen was used, foilowing a single 10 mg load-ing dose of warfarin, and a prediction of the maintenancewarfarin dose was made. In 33 consecutive patients only6% were over-anticoagulated by day 4 (70% were withinthe therapeutic BCR 2-4). These two patients wereidentified after the second loading dose, which enabled usto prevent the steeper rise in BCR that would have occur-red after a conventional loading scheme. The actualmaintenance dose, defined as that giving therapeutic BCRson three consecutive occasions, each separated by at least24 hours, correlated well with the predicted dose (r =0-898, n = 33, p < 0-001), the mean BCR being 2-45 ±0-27. In 31 of the subjects the actual maintenance dose was


within 1 mg of the predicted value. We believe that the useof these nomograms will improve the management ofpatients being anticoagulated for thromboembolic disease.

Total and free plasma theophylline concentrations inobstructive airways disease

P EBDEN, D LEOPOLD, D BUSS, AP SMITH, PA ROUTLEDGEThere is marked variability in clinical response betweenindividuals at any given total plasma theophylline concent-ration. A recent study showed that the fraction oftheophylline free in plasma could vary more than four-foldin obstructive airways disease, which might be responsiblefor much of the variability in response (Lesko et al. ClinPharmacol Ther 1981;29:776-81). We therefore meas-ured the plasma protein binding of theophylline in plasmafrom 39 outpatients with obstructive airways diseasereceiving chronic oral theophylline therapy. The proteinbinding was measured at 37°C and pH 7-4 by equilibriumdialysis. Total plasma theophylline concentration wasmeasured by high-performance liquid chromatography andthe free concentration calculated by multiplying total con-centration by the free (unbound) fraction.The total plasma theophylline concentration varied from

0-7 to 22-0,Ag/ml (mean 10-6 + 5-3 (SD) ,uG/ml SD). Thefree fraction of theophylline varied only between 0-575and 0-688 (mean 0-626 ± 0-024 ,ug/ml) and was notrelated to the total concentration (r = -0-225; n = 39; p >0.05). There was therefore a very close relationship be-tween free and total plasma concentrations (r = 0-996; n =39; p < 0.001). We conclude that there is little variabilityin plasma protein binding of theophylline in obstructiveairways disease. Other factors appear to be responsible forvariability in the response to a given total plasma theophyl-line concentration.

Receptor patterns on lymphocytes and their modulation bydrugs

WR WILLIAMS, BH DAVIES The distribution of /8- anda-receptors on peripheral blood cells has usually beeninvestigated by isolated membrane techniques..These haveconsiderable technical difficulties and are not physiologi-cal. A technique of whole viable lymphocyte binding to thetritiated a,- and 82-antagonists prazosin and dihydroal-prenolol has been developed and the modulation of recep-tor binding by physiological mediators of asthmaticresponses and commonly used anti-asthmatic drugs inves-tigated. Results expressed as % change in specific antagon-ist binding with each agent indicate that theophylline,sodium cromoglycate, salbutamol, and histamine (100,umol/1-10 nmol/l), PGF2c, PGE2 and adrenalin substan-tially inhibit prazosin binding but had little or no consistenteffect on dihydroalprenolol binding. Verapamil, clemas-tine, and ketotifen competed with both antagonists athigher concentrations (1 umol/l) while cimetidine inhibitedprazosin binding with less affinity for the /3-receptor site.Prednisolone (0- 1-1 umol/l) moderately inhibited prazosinbinding (37%). PGE2 and prednisolone both decreasedagonist inhibition of prazosin binding. All agents investi-gated showed some binding to a-receptors. Verapamil,

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clemastine, ketotifen, and to a lesser extent cimetidine,also bind to the (3-receptor site. Studies to compare iso-lated peripheral lymphocytes and pulnmonary wash lym-phocytes are now in progress to indicate the meaning ofthese results.

Adenouine-induced bronchoconstriction in asthma:specificity and relationship to airway reactivity

HI CUSHLEY, ST HOLGATE Adenosine, a purine nucleoside,is released from lung tissue with antigen challenge andhypoxaemia, two conditions which occur during an asthmaattack. We have previously shown that adenosine is abronchoconstrictor in asthma (Cushley et al. Br J ClinPharm 1983;15:161-5) whose effect may be competitivelyantagonised by low concentrations of theophylline. Todefine further the bronchoconstrictor effect of adenosine,29 allergic asthmatic patients were challenged with increas-ing concentrations of nebulised adenosine and, on a sepa-rate occasion, histamine to assess airway reactivity. Airwayresponses were measured as specific conductafice (sGaw).Both adenosine and histamine caused bronchoconstriction,concentrations producing a 40% fall in sGaw (PC40) being0-86 ± 0-18 (mean ± 1 SEM) and 0-24 ± 0-07 mg/mlrespectively. Airway reactivity (PC40) to adenosine corre-lated closely with that to histamine (r = 0-59, p < 0.001).The specificity of adenosine's response was investigated ineight asthmatic subjects, who were challenged with increas-ing concentrations of adenosine, its parent nucleotide 5'adenosine monophosphate (AMP), and its principlebreakdown product, inosine. Adenosine and AMP causedsimilar bronchoconstriction (PC40, 1-46 ± 0-51, 2-99 ±1-15 mg/ml, p > 0-005), whereas inosine was withouteffect. Thus adenosine and AMP (which can be metabol-ised to adenosine) are potent bronchoconstrictors whoseeffects are mediated by factors related to airway reactivity.

Influence of airway reactivity on circulating histamine andneutrophil chemotactic activity

PH HOWARTH, GJ-K PAO, SR DURHAM, TH LEE, AB KAY, HOL-GATE ST Controversy exists over the detection of plasmahistamine change following allergen-induced bronchocon-striction in asthma. To investigate this histamine and neut-rophil chemotatic activity (NCA) were measured inperipheral blood following antigen challenge in two groupsof six asthmatics, one with hyperreactive airways and onewith less reactive airways. Following challenge a 38-5 +

5.3% fall in FEVI in the group with hyperreactive airwayswas accompanied over the same time course by a 78-8 +

Severity of asthma, airways reactivity, and sensitivity toantigen (mean values ± SEM) in asthmatics with hyper-reactive (HA) and less reactive airways

Subjects FEVI(% Methacholine Antigen Antigenpredicted) PC20 (mg/ml) skin weal dilution

(mm) inhaledHA 97-3±5-1 0-09 (0-023-0-25) 12-6+1-54 1-92x10 2LRA 113-2±3-7 1-89 (1-20-2-85) 17-8+3-15 2-92x10-3

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15-4% increase in NCA, but no significant change inplasma histamine from a mean baseline of 3.75 + 0.59nmol/l. In contrast, a 29.4 ± 4-3% fall in FEV, in thegroup with less reactive airways was associated with nosignificant change in NCA despite an increase in plasmahistamine from a mean baseline of 1.66 ± 0.36 nmol/l to4-44 ± 0.09 nmolI five minutes after challenge. Thesefindings support the idea that with antigen challenge lessintrapulmonary mediator release is required to produceequivalent bronchoconstriction in patients with hyperreac-tive airways than in those with less reactive airways. Theabsence of NCA change in those with less reactive airways,in contrast with those with hyperreactive airways implies aseparate source of NCA from histamine. This studyemphasises the importance of subjects' antigen sensitivityand airway reactivity as separate factors influencing theperipheral detection of mediators following antigen chal-lenge.

Effect of corticosteroids on lung /3-adrenergic receptor siteconcentrtion and affinity

PDJ HANDSLIP, JPT WARD, IR CAMERON Corticosteroidshave been shown to potentiate the bronchodilatorresponse and to restore (3-agonist sensitivity in asthmatics.We have investigated the effect of hydrocortisone on thedensity and affinity of (3-adrenergic receptors in a rat lungmembrane preparation. Male CSE rats (200-270 g)received intraperitoneal injections of hydrocortisone.Group 1 received 50 mg/kg/day and group 2 4 mg/kg/dayfor 14 days, and group 3 received 10 mg/kg/day for sevendays. The respective control groups received 0-2 ml sterilewater daily. A lung membrane suspension was preparedand f-adrenergic receptor site concentration (Bmax) andaffinity (KD) was determined with specific 3H-dihydroalprenolol binding and liquid scintillation counting.Results were calculated with a weighted least-squarescurve-fitting algorithm ("Ligand," a modified form ofScatchard plot). In group 1 Bmax increased from 391 + 22(SEM) fmol/mg in the controls to 492 ± 22 fmol/mg in thetreated group (p < 0-005; n = 20). In group 2 Bmaxincreased from 325 + 22 fmbl/mg to 620 ± 69 fmol/mg (p< 0.001; n = 20). In group 3 Bmax increased from 592 ±36 fmol/mg to 789 ± 70 fmol/mg (p < 0*005; n = 17).Affinity (KD) was not significantly different between con-trols and treated in any group. We have clearly shown anincrease in lung 8-adrenergic receptor site concentrationwith hydrocortisone treatment at three different doselevels and after one and two weeks duration of treatment.We suggest that this is a possible mechanism of action ofcorticosteroids in asthma.

Relationship between in vivo airway responsiveness and invitro smooth muscle sensitivity to methacholine in man

JA ROBERTS, D RAEBURN, IW RODGER, NC THOMSON Airwayresponsiveness to methacholine varies between normalsubjects and is increased in certain respiratory disorders.The importance of airway smooth muscle sensitivity indetermining in vivo responsiveness is unknown. We have

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examined this by comparing in vivo airway responsivenesswith in vitro airway smooth muscle sensitivity tomethacholine in 10 patients (age range 43-69 years)undergoing thoracic surgery. In vivo responsiveness wasdetermined by administration of inhalations of doublingconcentrations of methacholine with a modification of themethod of Cockcroft et al (Clin Allergy 1977;7:235-43).Results were expressed as the provocation concentrationcausing a decrease in forced expiratory volume in one secof 20% (PC20-FEV,) and in specific conductance of 35%(PC35ssGaw). In vitro airway smooth muscle sensitivity wasdetermined on specimens obtained at thoracotomy. Logdose-response curves for methacholine were constructedand the concentration causing a 50% maximum contrac-tion (ED5O) was derived. PC20-FEV, ranged from 0-9 to61.3 mg/ml and PC3-sGaW from 0.9 to 16.5 mg/ml. Therewas no significant correlation between PC2,_FEV, and ED50(r = -0.35) or between PC35-sGaw and ED50 (r = -0.03).These results suggest that other factors, rather than smoothmuscle sensitivity alone, must influence in vivo airwayresponsiveness to methacholine.

Pulmonary platelet accumulation in antigen-inducedbronchoconstriction

PJ THOMPSON, CP PAGE, W PAUL, J MORLEY IgE-mediatedactivation of basophils or alveolar macrophages fromexperimental animals or man causes release of the phos-pholipid PAF-acether. Both PAF-acether and plateletsappear to play a part in antigen-induced anaphylaxis inrabbits and intravenous PAF-acether produces platelet-dependent bronchoconstriction in the guinea pig. Continu-ous monitoring techniques have been used to measuresimultaneously bronchoconstriction and platelet accumula-tion in the lungs of sensitised guinea pigs challenged withantigen. Platelet accumulation in the lungs was detectedusing "'In-labelled platelets as described elsewhere (Pageet al. Thromb Haemostas 1982;47:210) and bronchocon-striction was measured as resistance to lung inflation inanaesthetised, artificially ventilated animals. The guineapigs were immunised with albumin in Freund's completeadjuvant four to five weeks before the experiments. In thesensitised animals intravenous challenge with ovalbumin 1mg/kg consistently produced both bronchoconstriction andplatelet accumulation in the lungs. Lower doses of antigen(10-100 ug/kg), however, frequently induced plateletaccumulation in the absence of significant bronchospasm.Thus antigen-induced bronchoconstriction in sensitisedguinea pigs appears not to be triggered by platelet accumu-lation per se and may, like PAF-acether induced bron-chospasm, be dependent on a platelet release reaction.

Inuhibition of bronchoconstriction sdimulated by respiratoryheat los: comparison of cromoglycate powder andpressurized aerosol

KM LATIMER, RS ROBERTS, MM MORRIS, FE HARGREAVE Themagnitude of protective effect of sodium cromoglycate(SCG) delivered as a pressurised aerosol against bron-

Proceedings of the British Thoracic Societychoconstriction stimulated by respiratory heat loss (RHL)has not been examined. We compared the effect of threedoses of SCG given as pressurised aerosol (2, 10, 20 mg)with SCG powder (20 mg) and placebo (two tests) in 10adult asthmatics. The test medications were inhaled in ran-dom order, double blind, 20 minutes before eucapnichyperventilation of subfreezing dry air (- 15°C, 0% humid-ity) in two-fold doubling volumes as described by O'Bymeet al (Am Rev Respir Dis 1982;125:281-5). Results wereexpressed as the provocative dose of respiratory heat lossto cause a decrease in FEV, of 15% (PD,5). Two wayanalysis of variance was applied to the group mean values.Baseline FEV, exceeded 85% predicted normal and didnot differ between tests (p > 0-05). Premedication causeda small decrease in FEV,, which was greater after placebothan SCG (p < 0.001) but was not different after any doseof SCG. After placebo the intraclass correlation for PD,5was 94%. All doses of SCG shifted the respiratory heatloss dose-response curve to the right. The mean ± SD ofPD,5 (kcal/min) were 1*64 ± 0-37, and 1-59 ± 0*42 afterplacebo; 2*00 ± 0-62, 1*99 ± 0*52, and 2*01 ± 0*58 after2, 10, and 20 mg of SCG aerosol; and 194 ± 0*47 afterSCG powder. The effect of each dose of SCG was greaterthan placebo (p < 0-0001) but was not different betweenany dose of SCG. We conclude that the magnitude of effectof 2 mg SCG aerosol is as great as that of 20 mg aerosol orpowder.

Effect of route of administration on the guinea pigpulmonary mechancal responses to LTC4 and themodification of these responses by indomethadn

AG LEITCH, EJ COREY, KF AUSTEN JM DRAZEN Leukotriene(LT) C4 is one of the components of slow-reacting sub-stance of anaphylaxis, which may be implicated in asthma.Intravenous administration of LTC4 (1 ,ug/kg) to fouranaesthetised, mechanically ventilated guinea pigs causeddecrements in lung dynamic compliance (Cdyn) and con-ductance (GL), which were maximal 30 seconds after injec-tion and persisted for 20-30 minutes. In another four ani-mals pretreatment with indomethacin (30 mg/kgintraperitoneally) abolished the early (< 1 minute) fall inCdyn and GL, maximal decrements now occurring at fiveminutes; significantly attenuated the fall in Cdyn at all timepoints; and significantly potentiated the fall in GL fromthree to five minutes after the infusion. Administration of30 tidal volumes of aerosolised LTC4 (nebuliser concentra-tion 1 ,ug/ml) to four guinea pigs caused decrements inCdyn and GL that were maximal five minutes afteradministration, persisted for 20-30 minutes, and weresignificantly potentiated by indomethacin pretreatment.These findings suggest that LTC4 has a primary bron-choconstrictor action on the guinea pig lung, which is mod-ulated by the generation and release of cyclo-oxygenaseproducts that cause an early (< 1 minute) and short-livedbronchoconstriction and a later (3-5 minutes) bron-chodilatation when LTC4 is given intravenously. With localadministration by aerosol only the bronchodilator cyclo-oxygenase component is found, an observation which mayhave importance for the phenomenon of analgesic-inducedasthma.

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Use of prophylactic drugs for wheeze in genenl practice

AG WARDMAN, NJ COOKE Good control of asthma oftendepends on appropriate prophylaxis, but there are fewcommunity-based data concerning its use. From 1982 to1983 we interviewed 312 patients (aged 16-80) from fivegroup practices in three cities, all on regular treatment forwheeze to assess prophylactic drug use. One hundred andfifty-seven (50%) patients used prophylaxis. Ninety-eightof the 157 (62%) used inhaled corticosteroids (aerosol 86,dry powder 12), 54 (34%) sodium cromoglycate (com-pound 30, plain 20, aerosol four), 33 (21%) systemiccorticosteroids, and three (2%) ketotifen. Fifty-six (39%of prophylactic inhaler users) missed one or more treat-ments per day, usually the lunch-time dose of a four-times-daily regimen. Fifteen (11%) used their inhalersentirely on demand, and 19 (21% using aerosolprophylaxis) had an inefficient inhaler technique. Seven-teen compliant patients (12% of inhaler users) were pre-scribed below-standard doses (<400 ,ug inhaled cortico-steroid or <4 caps sodium cromoglycate per day) and 28(20%) standard doses even though both groups had symp-tom scores suggesting that higher doses or additionaltherapy may have been beneficial. Fourteen of 33 (42%)patients on systemic corticosteroids were receiving noinhaled corticosteroids. Prophylactic drugs are prescribedcommonly in general practice. This study shows that themain problems in their use are poor compliance andinhaler technique, the use of prophylactic drugs ondemand, and under-prescription by the doctor.

Effect of oral amnnophyfline on asthmatics maximallybronchodilated with nebulised salbutamol

NC BARNES, JR WEBB The increase in bronchodilatationachieved by oral theophylline over maximal bronchodilata-tion achieved with nebulised salbutamol was studied innine patients with stable asthma (seven men, two women),average age 54 years (range 36-66 years), in a double-blind, placebo-controlled, randomised, crossover trial.None of the patients was taking theophyllines and allrefrained from taking ,82-agonists for 12 hours before thestudy. Two sets of baseline measurements of FEV,, VC,and SGAW were made half an hour apart. The patients werethen given enough slow-release aminophylline tablets togive a therapeutic level of theophylline or matched placebotablets. After one and a half hours FEV., VC, and sGawwere measured. The patients were given salbutamol 2 mgvia a nebuliser four times in the next two and a half hoursin an attempt to achieve maximal bronchodilatation. Afterthe last dose of salbutamol FEV,, VC, and sGaw weremeasured and blood was taken for measurement oftheophylline level. The mean theophylline level was 11-5(range 8-5-15.1) mg/l. The increase in FEV,, VC, andsGaw was higher after aminophylline and salbutamol thanit was after salbutamol alone. The mean increases for sal-butamol alone were: FEV, 0-75 + 0-31 1; VC 0-85 + 0-431; and sGaw 0-50 + 0-39 s-' kPa-'. The mean increases forsalbutamol and aminophylline were: FEV, 0-83 + 0-371;VC 1.00 + 0-57 1; and sGaw 1-23 + 1-3 s-'. These differ-

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ences were not statistically significant. We conclude thatthe additional therapeutic action of oral theophylline overmaximal bronchodilatation with nebulised salbutamol inpatients with chronic stable asthma is small.

Acute and domiciliary study of terbutaline inhalation via aconical spacer in severe and chronic asthma

JOHN F O'REILLY, GRAHAM GOULD, G LASZLO We havecompared the bronchodilator response to terbutaline inha-lation given by pressurised aerosol (PA), pressurisedaerosol fitted with a conical spacer (CS), and Acorn nebul-izer (AN) in 10 patients with severe chronic asthma (meanage 52 years; range 24-72 years. Mean FEVi 1.26; range0-7-2.2 litres. Mean FVC 2.6 litres; range 1i9-3-7 litres).Patients were given cumulative doubling doses of ter-butaline (0-5 + 1.0 + 4*0 mgs) in random order, using eachtechnique, on three days within one week. FEV, and FVCwere measured before terbutaline administration and 20minutes after each dose. Nine patients completed adomiciliary trial of terbutaline 1-0 mg thrice daily, adminis-tered by PA and CS in random order, each for two weeks,They made thrice daily assessments of PEFR and severityof symptoms. In the acute dose response study there was asignificantly greater mean percentage rise in FEV, at adose of 0-5 mg for both CS (21-2%) and AN (18.2%)compared with PA (5.6%) (p < 0.05). There was asignificantly greater rise in FVC at a dosage of 0-5 mg afterAN (14-6%) compared with PA (3.7%), (p < 0.01). Therewere no significant differences between the responses ofFVC to CS (9.7%), PA, and AN. The domiciliary studyshowed significant differences in mean daily PEFR bet-ween PA (325 litres/min) and CS (275 litres/min) and insymptoms of asthma.

Effect of salbutamol delivered by metered-dose inhalerand jet and ultrasonic nebuliser on FEV, and heart rate inpatients with chronic asthma

JN STAINFORTH, PJ STURGISS, AE TATFERSFIELD Inhalationof fl agonists can be achieved by metered-dose inhaler(MDI) or nebuliser, the nebulised droplets being gener-ated by air jet or ultrasonic disruption. We compared thebronchodilatation and change in heart rate after inhaledsalbutamol delivered by jet nebuliser (Inspiron Mini-Neb),ultrasonic nebuliser (Pulmasonic), and MDI in patientswith chronic asthma. Seven patients (two men, fivewomen) with chronic, stable asthma were studied on threeseparate occasions. The mean age was 62 years (52-72)and mean FEV, 1-25 1. After baseline measurements, sal-butamol was inhaled from an MDI or jet or ultrasonicnebuliser at 10 minute intervals to provide a cumulativedose of 5,000 ,ug. FEV,, FVC, and heart rate were meas-ured 10 minutes after each dose. Mean baseline values ofFEV,, FVC, and heart rate were similar on each study day.The mean maximum increase in FEV, and FVC frombaseline was 0*71 and 0-91 1 for the jet nebuliser, 0-74 and0-98 l for the ultrasonic nebuliser, and 0*80 and 0-94 1 forthe MDI. There were no significant differences in AFEV,

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or AFVC at any dose. After 5000 ,ug of salbutamol, heartrate was unchanged with the jet nebuliser (-1 beats/min)and the ultrasonic nebuliser (+ 3 beats/min), but hadincreased by 19 beats/min with the MDI (p<0025). Thegreater increase in heart rate with the MDI is likely to bedue to greater absorption from the lung with this methodof inhalation. For this reason the MDI is unsatisfactory foradministering high doses of f3-agonists.

Progressive exercise training: subjective and objectivechanges

HA BOOKER, DJ HARRIES, MA REHAHN, DV GASKELL, BA WEB-BER, AJ DAVIS, JV COLLINS Improvement in exercise toler-ance following periods of progressive exercise training forpatients with chronic airways obstruction has led to thisbeing a generally accepted form of treatment. Onehundred and twenty-eight patients with severe irreversibleairways obstruction and exercise tolerance limited bybreathlessness took part in a double blind, controlled trial.Objective assessments of lung function and six-minutewalking distance and subjective assessment from a ques-tionnaire were carried out before a nine-week course ofone of three regimens: (1) control (C); (2) exercise train-ing (E); (3) exercise with breathing control (P). Reassess-ments were carried out at three, six, and 12 months follow-ing the initial assessment. While there were severalsignificant changes in lung function within the groups, par-ticularly the P group, the actual changes were clinicallyunimportant. Subjective improvement of both the P andthe E groups was significantly greater than that of the Cgroup (p<0-001) at three months. This difference and theimprovement were maintained at 12 months, and theimprovement in the P group was significantly greater thanthat of the E group at 6 (p<0-01) and 12 months(p<0-05). In the absence of objective improvement, con-siderable subjective benefit obtained with exercise trainingmay be enhanced by teaching breathing control. Thesesubjective changes were maintained without constant clinicvisits for reinforcement.

Response of the pulmonary crculation to oral pirbuterol inpatients with chronic airflow obstruction

AJ PEACOCK, C BUSST, DM DENISON In 1981 the MRC work-ing party reported that domiciliary oxygen therapy reducedmortality from chronic hypoxic bronchitis and emphysema.It is likely that this effect was due in part to a fall in pulmo-nary vascular resistance (PVR). Oxygen therapy is expen-sive and difficult to administer and it would be an advan-tage if oral therapy had a similar beneficial effect. Pir-buterol, a ,2-agonist, has been reported to reduce PVR insuch patients so we studied nine people with chronicairflow obstruction (FEV, 757 + SEM 94 ml) and arterialhypoxaemia (PaO2 8-43 + 0-51 kPa) before and after 15mg oral pirbuterol. Maximum haemodynamic effectsoccurred 30 minutes after the administration of the drug.Mean pulmonary artery pressure was not changedsignificantly but PVR fell by 19% + 6% and cardiac out-put rose by 24% + 8%. However, these changes were


accompanied by a fall in Pao2 of 7-4% + 2*4%. We con-clude that while pirbuterol causes a significant fall in PVR(p<0-02), this occurs at the cost of a significant fall in Pao2(p<0-02). One explanation for this finding is that pir-buterol reverses a functionally necessary vasoconstrictionwhereas oxygen reverses the need for one.

Correlation between a respiratory questionnaire and peakflow measurements in printing workers exposed to acontaminated humidifier

P SHERWOOD BURGE, CAC PICKERING, NIGEL HORSEFIELD Asurvey of a printing works identified 37 workers withhumidifier fever or respiratory symptoms, or both, whoimprove away from work by self-administered respiratoryquestionnaire. An attempt was made to validate the ques-tionnaires by issuing each worker with a peak flow meterwith written instructions to record peak flow every twohours from waking to sleeping for 14 days. Five workersreturned incomplete records, leaving 32 workers withcompleted questionnaires and peak flow records, whichwere assessed blindly by defined criteria. Sixteen workershad records indicating asthma (diurnal variation in peakflow exceeding 20% after the first two days). Of these, onlynine had attacks of wheezing or whistling in the chest withbreathlessness, although all responded to the less specificquestion " Does your chest ever feel tight or your breathingbecome difficult?" Wheezing or whistling in the chest withrest day improvement occurred in 15 workers: consistentdeterioration in peak flow at work was seen in eight ofthese and a further three had a history of humidifier fever.Breathlessness with rest day improvement was present in18 workers: consistent deterioration at work was seen in11, and a further four had symptoms of humidifier fever.Excluding the workers with humidifier fever alone it waspossible to validate the questionnaire with peak flow read-ings in at least 75% of workers.

Effects of exercise on the regional deposition of an inhaledaerosol

HW CLAGUE, D AHMAD, MJ CHAMBERLAIN, WKC MORGAN, SVINITSKI We have investigated the deposition of aninhaled radioaerosol at rest and during moderate exercisein eight normal subjects and five control smokers to deter-mine whether the increased ventilation of exercise has animportant influence on the regional deposition of inhaledparticles. Exercise produced an increase in the totalamount of aerosol deposited with proportionately greatertracheobronchial deposition, especially in smokers. In con-sequence, the central-to-peripheral gradient for aerosoldeposition, which was significant only in smokers at rest(p<0-05), became significant in both groups on exercise(p<0001). The distribution pattern for zonal tracheo-bronchial deposition on exercise was the same in bothgroups, with greatest tracheobronchial deposition in theupper zone, less in the lower zone, and least in the middlezone. In addition, in the upright position at rest there was amarked gradient for alveolar deposition increasing from

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apex to base, which corresponded to the gradient for reg-ional ventilation. On exercise aerosol deposition was moreuniform and the previous interzonal differences disap-peared except in smokers, whose alveolar deposition in theupper zone remained significantly less (p<0-01) than thatin the lower zone. The relative increase in particle deposi-tion which occurs in the upper zones on exercise and thedifference between smokers and non-smokers may beimportant in the pathogenesis of occupationally relateddust-induced lung disease.

Plulmonary effects of experimental exposure of normalsubjects to dust from dew-retted flax and from dew-rettedsteamed flax

JP JAMISON, JHM LANGLANDS, RC LOWRY, CC BODEL Forcedexpiratory measurements were made on 12 normal sub-jects before and after breathing flax dust dispersed in roomair at a concentration of 5 mg m3, with a mean particle sizeof 4 ,um. The subjects were divided randomly into twogroups to breathe the dust from dew-retted flax and fromdew-retted steamed flax in two six-hour periods, twoweeks apart, in a double-blind crossover trial. Probabilitylevels were determined by analysis of variance. The resultsshowed significant diminution of forced expiratory vol-umes and flow rate after exposure to dust (p<0-01). Afterdust from steamed flax the diminution in pulmonary func-tion was significantly less than after untreated flax dust(p<0-05). It is suggested that steaming of flax might helpto prevent byssinosis.

Means (± SEM) (I and Is ') of three forced expirations by12 subjects before dust inhalation and the changes afterinhalation

Untreated Steamed

FEVy 3-92 ( 0-09) 3-97 (± 0-09Before FVC 5-34 0-11) 5-40 ( 0.11

FEF 50%V 4-04 ±0.16) 4-14 (±0-19AFEV, -0-2 -0.1

After 6 h AFVC -0-22 -0-15minus before AFEF 50%V -0-57 -0-49

Occupational asthma in a printing factory with a

contaminated humidifier

P SHERWOOD BURGE, NIGEL HORSEFIELD, CAC PICKERING

Humidifier fever is now well recognised in workplaces withcontaminated humidifiers. So far there have been no

reports of occupational asthma from this cause. We haveinvestigated a printing works where occupational asthmawas documented in 10 workers. A further five workers hadconsistent deterioration at work and improvement awayfrom work with a diurnal variation in peak flow of less than20%. Workers with maximal reactions on the first day ofwork (four) were the minority. Their reactions were lessconsistent than those with equal deterioration each workday (three), or progressive deterioration during the work-ing week (four). A new pattern of deterioration was seen infour workers, whose maximum deterioration was mid weekwith improvement at the end of the week despite con-

709tinued exposure. Neither immediate skinprick tests norserum precipitins to humidifier antigens were helpful indiagnosis.

Microbiological investigation of farmers lung disease inSomerset 1963-83

JP ANDERSON, FB GREATOREX From 1963 to 1983 46patients with proved farmer's lung disease were studied. Allwere precipitin positive for Micropolyspora faeni and 14also for Thermoactinomyces vulgaris. Thirty two of thepatients had M faeni cultured from their sputum afterincubation at 55°C for four days; from nine of these sputaT vulgaris was also grown. A 12 month survey reportedfrom Taunton Public Health Laboratory Service Laborat-ory in 1976, in which 1300 consecutive non-tuberculoussputa had been cultured for thermophilic organisms, hadproduced 16 isolates ofM faeni and nine of T vulgaris; 14of the 20 patients concerned were precipitin positive, theother six were negative or untested; all were farmers. From1975 to 1983 222 sputa were selectively cultured, withthermophilic isolates from 21 patients, 14 of whom wereprecipitin positive. The two organisms were readily iso-lated from the farm environments of three patients. Fibre-endoscopic bronchial aspirates were obtained from fourpatients with positive sputa, M faeni being isolated fromone specimen. No sputum surveys of the general farmingpopulation are yet available; but the apparent clinicalvalue of thermophilic isolates has been shown. In acutefarmer's lung disease there is the possibility of bron-chopulmonary colonisation. Steroid treatment is of valuein acute farmer's lung disease, and tetracycline has helpedsome patients with chronic farmer's lung disease. Air-stream helmets are an efficient means of prevention.

Small-cell carcinoma of the lung: survival after surgicalresection

GN MORRITT, DJL MALONEY, D LAMB, PR WALBAUM During1968-72 854 thoracotomies for lung cancer were carriedout in the department of thoracic surgery at the City Hos-pital in Edinburgh. The histological sections of all caseshave been reviewed by DJLM and DL. One hundred andthirty-five small-cell carcinomas were identified, of which36 were considered unresectable. Of the 99 cases ofsmall-cell carcinoma resected, there were 40 lobectomiesand 59 pneumonectomies. The overall five-year survivalwas 14%. Of the survivors, six had had lobectomies andeight pneumonectomies. Hilar nodes were affected bytumour in five of the survivors, two of whom had hadlobectomy and three pneumonectomy. The value of surgi-cal treatment of small-cell carcinoma is not adequatelyreflected by the simple percentage five-year survival; it isimportant to relate this to the total number of small-cellcarcinomas. As no absolute data are available, comparisonwith the numbers of patients with other cell types operatedon in the same series gives some guide. Over the samefive-year period 360 squamous-cell carcinomas were resec-ted. As there are about twice as many squamous cell car-

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cinomas as small-cell carcinomas this means that small-cellcarcinomas had half the resection rate of squamous car-cinomas. This value of 10% for the resection rate insmall-cell carcinoma, though small, is greater than currentopinion would suggest.

Effect of erythrapheresis on the gas transfer for carbonmonoxide and its subdivisions in polycythaenda secondaryto hypoxic lung disease

JA WEDZICHA, FE COTrER, PJW WALLIS AC NEWLAND, DWEMPEY We have used the technique of erythrapheresis, amethod of isovolaemic haemodilution, in 10 patients withpolycythaemia secondary to chronic obstructive bronchitis(mean Pao2 6-9 kPa; FEVI 0*85 1) to investigate the effectsof reduction of packed cell volume on the gas transfer forcarbon monoxide and its subdivisions pulmonary capillaryblood volume (Vc) and membrane diffusing capacity(DM). Erythrapheresis was performed without change inblood volume with the Haemonetics V50 blood processor.After removal of a mean red cell volume of 645 ml, themean microhaematocrit fell from 0-58 to 0-47, the meanblood viscosity decreasing significantly at both high andlow shear rates (p < 0.01). After erythrapheresis there wasa trend to increase in the transfer factor (TLco) and in thetransfer coefficient (Kco). The mean pulmonary capillaryblood volume (Vc + SD) was reduced before treatment at30*2 ± 12*2 ml and increased significantly to 51-9 ± 20-9ml after erythrapheresis (p < 0.02). There was no changein membrane diffusing capacity, blood gases, or lung vol-umes. The mean Vc remained unchanged in 10 controlnon-polycythaemic patients (mean Pao2 7.7 kPa; FEV,1-01) who did not have erythrapheresis and were assessedon two corresponding occasions (65.5 ± 22*5 ml; 64*3 ±25*2 ml). Pulmonary capillary blood volume increases fol-lowing erythrapheresis. This may be due to an improve-ment in pulmonary blood flow caused by a fall in bloodviscosity and pulmonary vascular resistance, or it may be aconsequence of a rise in cardiac output.

Hands, feet, and lung function

SH BAIN, P HELMS, JO WARNER Expected values of lungfunction in children with respiratory disease are usuallypredicted from regression equations of the index test onstature or sitting height from cross-sectional data in normalchildren. In children with congenital or acquired scoliosis,arm span or "uncoiled' stature, derived from the observedstature and the degree of spinal angulation, have been usedto predict expected values. We have performed measure-ments of stature, sitting height, and hand and foot length,along with other anthropometric variables and lung vol-umes, maximal inspiratory and expiratory flow volumeloops, and diffusing capacity (TLO) in 455 normal schoolchildren aged 4-18 years. As in previous studies, lung vol-umes, maximal flow rates, and TLCo were found to besignificantly correlated with stature and sitting height, withalmost as good correlations with hand and foot length.Mean residual variances for regressions of lung function

Proceedings of the British Thoracic Societydata on stature, sitting height, and foot and hand lengthwere 26%, 26%, 36%, and 41% respectively. Standarddeviations around these regressions were 15-2% for sta-ture and sitting height, increasing to 18-7% for foot lengthand 19.2% for hand length. In children in whom accuratemeasurements of stature or sitting height cannot be made,hand or foot length should prove to be useful in predictingexpected lung function.

Bronchial reactivity and rate of decline in FEVI in smokersand ex-smokers

RG TAYLOR, E GROSS, H JOYCE, F HOLLAND, NB PRIDE Weexamined the relation between bronchial reactivity andannual rate of decline of height-corrected FEV, (AFEV,/ht3) over 7-5 years in 117 smokers, 71 ex-smokers, and 39non-smokers. Bronchial reactivity was determined as theconcentration (PC20) of inhaled histamine sufficient toreduce FEV, by 20%; subjects were divided into reactors(PC20 , 16 mg/ml) and non-reactors (PC20> 16 mg/ml).Twenty-nine per cent of smokers, 24% of ex-smokers, and5% of non-smokers were reactors. Smokers who reactedhad a lower mean baseline FEV, in 1982 than non-reactors(84-6% (SEM 2-7%) v 108-5% (1-4%) predicted, p <0-001) and a faster A FEV,/ht3 (14.1 (SEM 1-4) v 9-2(0-7) mlly/m3, p < 0.01). Baseline FEVI correlated withPC20 in smokers (rs = 0-51) and ex-smokers (r, = 0-60; p< 0-02)' all subjects with FEV, < 80% predicted werereactors. In ex-smokers AFEV,/ht3 was similar in reactorsand non-reactors (9-0 (1-5) v 7-4 (0-8) ml/y/m3; p > 0.3)despite differences in baseline FEVV. The prevalence ofreactors was slightly increased among smokers with normalbaseline FEV1. The results are compatible with the "Dutchhypothesis" that abnormal bronchial reactivity contributesto accelerated decline of FEVI in smokers, although theassociation could be a consequence of a lower FEV,. Inex-smokers, however, abnormal reactivity persists butdecline in FEV, is not accelerated.

Need the airway be ocduded to measure Po,?KEVIN JONES, DOUG SHAW, ANTONIO FORESI, TIM HIGENBOT-TAM Careful analysis of the breathing pattern in criticallyill patients with respiratory disease is important for improv-ing understanding and directing appropriate therapy(Milic-Emili. Lung 1981;160:1-17). Present methodsinvolve the measurement of pressure after a brief but totalairway occlusion at the onset of inspiration (Pr,), whichprecludes simultaneous measurement of the timing ofbreathing events and breath-by-breath analysis. We havedeveloped an automated (on line to a microcomputer)method for measuring, breath by breath, pressure profilefrom the onset of inspiration; tidal volume; instantaneousminute volume; and duration of inspiration, expiration,and the apnoeic pause between breaths. The changes inthese measurements with rising end-tidal carbon dioxidehave been estimated during carbon dioxide rebreathing innine normal subjects on four separate occasions on fourseparate days. End-tidal carbon dioxide correlated withinstantaneous minute volume (r = 0-91), tidal volume (r =

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0.90), and inspiratory pressures measured at 0 1 second (r= 0.76), 0-2 seconds (r = 0.85), and maximum inspiratorypressure (r = 0.85). There was no significant differencebetween these correlation coefficients (p > 0.05). Thismethod may have general value as the early inspiratorypressures (P). and P0.2) appear to reflect respiratory driveand occur before significant change in lung volume occurs.

An optical technique of measunng the change in tninkvolume with breathing

AJ PEACOCK, MDL MORGAN, AR GOURLAY, DM DENISON Wehave developed a particular optical technique of mappingthe size, shape, and position of the thora-.oabdominal wallwith breathing. The subject stands in a reference framewhile a pattern of vertical black and white stripes is pro-jected on to the trunk surface, creating contours of itsshape. These contours are photographed simultaneouslyfrom in front and behind, and encoded digitally to describethe surface in three-dimensional co-ordinates and recon-struct the trunk in order to measure its total volume, par-tial volumes, surface area, and cross-sectional area at anylevel. We have used this method to measure the change involume of the trunk with expiration while simultaneouslymeasuring expired volume at the mouth. In 54 measure-ments of respired volume in the 13 subjects (one of whomwas scoliotic) correlation between optical and spirometricmeasurements was r = 0-985, with an absolute error of0 17 1 (± SEM 0-024 1). We conclude that this method ofmeasuring respired volume is sufficiently accurate for clini-cal purposes and has the advantage that it shows the con-tribution of each region to the breath.

Mechanisms of paradoxical lateral nrbcage motion inpatients with airflow obstruction

JJ GILMARTIN, GJ GIBSON Inspiratory paradox of the lateralribcage margin in chronic airflow obstruction is usuallyattributed to abnormal traction on the lower ribcage bycontraction of the flattened diaphragm. Since direct evi-dence is lacking, we have investigated the relationshipsbetween dimensional changes and pleural (Ppl) and trans-diaphragmatic (Pdi) pressures in 10 patients with demon-strable lateral paradox. The lateral diameter of the ribcagewas measured at two levels by magnetometry during tidalbreathing and voluntary relaxation. Paradox was more evi-dent in the lower ribcage in eight of the 10 patients; ittypically begins at the start of inspiration, but in late inspi-ration the diameter usually increases. Relating the dimen-sional and pressure changes indicated that the maximumdistortion corresponded in most patients to peak values ofboth Pdi and Ppl but the relation to Pdi was more clearcut,consistent with contraction of the flattened diaphragm asthe main mechanism. Paradox of the upper lateral dimen-sion was less clearly attributable to Pdi or Ppl. Duringdiaphragmatic relaxation at full inflation the lateral ribcagediameters increased in all patients, but in some subjects therelaxed dimensions were greater still at volumes below

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TLC, suggesting that distortions may also result from thehyperinflation per se, in addition to the effects of activediaphragmatic contraction.

Respiratory movements before and after high thoradccord compression

P HELMS, D HEAF, S JOLLY, J WARNER, M GREEN During nor-mal inspiration diaphragmatic contraction increasesthoracic volume by displacement of the abdominal con-tents and elevation of the rib cage. Although the effects ofdiaphragmatic paralysis on the pattern of thoracoabdomi-nal motion are well known, opportunities to observe theeffects of chest wall (intercostal and abdominal muscle)paralysis alone are less common. Video recordings of tidalbreathing were made in an otherwise normal 2-month-oldmale infant recovering from staphylococcal pneumonia, aspart of a teaching library of normal and disturbed respirat-'ory patterns. Between the age of 9 months and 1 year thisinfant developed a dense paraplegia with a sensory level atthe second thoracic segment. Radiographs of the spinerevealed a subluxation of thoracic vertebra T2 on T3 withsevere cord compression at this level. Halopelvic tractionwas applied and anterior and posterior spinal fusions wereperformed. We repeated video recordings of his respirat-ory pattern together with measurements of abdominal andribcage motion using magnetometers and intrathoracic andabdominal pressures using catheter-mounted balloons.During inspiration the abdomen moved outwards owing tothe descent of the diaphragm while the ribcage appeared tobe passively driven by the fall in intrathoracic pressure andmoved paradoxically inwards. We present video recordingsof the respiratory movements in this infant taken beforeand after cord compression together with the movementsof a 9 month-old infant with bilateral diaphragmatic para-lysis for comparison.

Is bronchiolectasis reversible after intermittentpositive-pressure ventilation with PEEP?

D LYONS, M NAVARATNARAJAH, JS MILLEDGE, JF NUNNBronchiolectasis (dilatation of terminal and respiratorybronchioles) has recently been described in a postmortemstudy of patients who died during or after intermittentpositive-pressure ventilation (IPPV) (Slavin et al. Br Med J1982;285:931-4). The degree of bronchiolectasis was pre-dictable from the duration and level of positive end-expiratory pressure (PEEP). A very large increase inphysiological dead space was inferred from measurementsof ventilation and arterial carbon dioxide. We studied fivepatients who required IPPV and PEEP and were treatedon the same intensive therapy unit at the same time asthose who died. The mean predicted bronchiolectasis scorein the survivors was 2.6 (range 2-1-3.2) compared with 3-2(range 0-8) for the group that died. All the patients werehealthy adults prior to the development of the conditionrequiring their admission to the intensive therapy unit.None smoked and all appeared to have made a full recov-ery when seen 18-120 months after discharge. We carriedout spirometric testing and measured arterial gases, lung

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volumes, carbon monoxide transfer, and physiologicaldead space. Two subjects had spirometric values of 3%below normal range. Mean dead space was 149 ml (range104-185 ml); in no case was it above the normal range. Weconclude that these subjects do not have measurable evi-dence of irreversible bronchiolectasis.

Single-point in vivo calibration improves the accuracy oftranscutaneous oxygen tension (tcPo2) estimations in adultpatients

BJ GRAY, RW HEATON, AF HENDERSON, DCS HUTCHISON Es-

timations of arterial oxygen tension (Pao2) in adults withtranscutaneous electrodes calibrated by in vitro methodslack sufficient accuracy for clinical purposes. We studied14 patients with indwelling arterial cannulas in whom itwas possible to vary the inspired oxygen concentration(Flo2), and thus obtain a range of Pao2 values. An oxygen

electrode heated to 45°C was calibrated in vitro, applied tothe skin, and allowed to reach a stable tcPo2 reading. Invivo calibration was then achieved by adjusting the tcPo2reading to correspond to the Pao2 of a simultaneous arter-ial blood sample. tcPo2 and Pao2 were then compared atseveral points in each patient by altering Flo2 and allowingtcPo2 to reach a new stable level, when it was comparedwith the Pao2 of a simultaneous arterial sample. Followingin vitro calibration the relationship between tcPo2 andPao2 in the 14 patients is given by the regression equation(in mm Hg) tcPo2 = 0*58 Pao2 + 13-4 (r = 0*86: p <0-001). Following in vivo calibration the relationship bet-ween tcPo2 and Pao2 over the range of values for Pao2 of50-294 mm Hg (77 data points) was given by the equationtcPo2 = 0-74 Pao2 + 21-8 (r = 0-986: p <0-001). If thevalues of Pao2 in the range of 50-120 mm Hg (55 datapoints) are considered separately, the relationshipbecomes tcPo2 = 0*98 Pao2+ 1*61 (r = 0-984: p < 0-001).With a single point in vivo calibration values for tcPo2 canfor practical purposes be considered identical to Pao2 inthe range 50-120 mm Hg.

Sputum leukotrienes in obstructive airways diseases

BR ODRISCOLL, 0 CROMWELL, AB KAY Sputum samplesfrom patients with bronchial asthma, chronic bronchitis,and cystic fibrosis were examined for the presence ofleukotrienes B41 C, and D4. After ethanol extraction andpurification on Amberlite XAD-8 leukotrienes wereidentified by high-pressure liquid chromatography (HPLC)using the appropriate markers. Fractions from HPLC werealso tested biologically with both the Boyden chemotaxisassay and FPL 55712-inhibitable contraction of the iso-lated guinea pig ileum. LTB4 was detected in the sputafrom patients with bronchial asthma (7/7), chronic bron-chitis (4/4), and cystic fibrosis (4/4). In contrast, LTC4 andLTD4 were not found in 17 asthmatic sputa, although theywere detected in one of four bronchitics and 16 of 25patients with cystic fibrosis. Sputum from 11/17 asthmatics,4/25 patients with cystic fibrosis, and 2/5 bronchitics con-tained an anaphylatoxin-like substance. The majority ofsputum samples containing LTB4 also possessed an activity

Proceedings of the British Thoracic Societywith chemical and biological characteristics of the 5S,1 2S-6, trans-LTB4 isomer. These studies indicate thatlipoxygenase products of arachidonic acid metabolism arepresent in the sputum in various forms of obstructive air-ways disease. The failure to detect the "SRS-A" leuko-trienes in sputum in bronchial asthma may be attributableto either losses during extraction, the insensitivity of theassay procedure, or more rapid catabolism of LTC4 andLTD4 by bronchial secretions in bronchial asthma than incystic fibrosis.

Sputum histamine in acute asthma, chronic bronchitis, andpneumonia measured by five different assay techniques

DJR MORGAN, I MOODLEY, RJ DAVIES Mediators derivedfrom mast cells are thought to be important in thepathogenesis of extrinsic asthma. Studies on the measure-ment of peripheral blood histamine in patients with asthmahave shown significantly higher levels at the time of admis-sion to hospital than in other acutely ill patients. However,recent work suggests that the histamine measured in bloodmay be derived from circulating basophils. For this reasonmediators have also been measured in secretions. Previousstudies have shown that substantial quantities of histaminecan be found in sputum, though there is disagreement as towhether the levels of this mediator are higher in asthmaticpatients' sputum than in sputum from patients with bron-chitis or pneumonia. We have compared histamine levelsin sputum from patients with acute exacerbations ofasthma, chronic bronchitis, and pneumonia using a biologi-cal assay, a fluorometric assay, two radioenzymatic assays,and a high-pressure liquid chromatography assay. There ismarked variation in the amount of histamine found,depending on the technique employed. The highest quan-tity is found by the fluorometric method, the lowest by thedouble-isotope radioenzymatic assay (DIREA).Significant inter-assay difference is present in measure-ments of histamine in biological fluids, despite a close andsignificant correlation between the assays when histamineis measured in Tyrode's solution (r = 0*9, p < 0-05). His-tamine was measured in the sputum of 10 asthmatic, 10bronchitic, and 10 pneumonic patients with the DIREA,and was found in all groups (109.2 + 27*8 ng/g) with nosignificant inter-group difference. Sputum cytology wasperforlned and cell counts correlated with histamine levels.

Assessment of the dinical value of the measurement ofserum type Ill procolagen peptide levels in cryptogenicfibrosing alveolitis.

JME KIRK, GJ LAURENT, ED BATEMAN, PL HASLAM, MTURNER-WARWICK The variability- of prognosis andresponse to treatment in cryptogenic fibrosing alveolitis(CFA) has led to studies suggesting that patients with"active" CFA have increased type III collagen in the lung(Bateman et al. Thorax 1983;38:93-101), the proportionof which is mirrored by serum levels of its synthetic by-product type III procollagen peptide (PCP) (Kirk et al. AmRev Respir Dis in press). To assess the value of PCP levels

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in the management of CFA we measured levels in 60patients with CFA and 45 controls. In 17 patients, levelswere measured prior to commencement of treatment withsteroids and/or cyclophosphamide and three to six monthsthereafter. Physiological measurements were made at sixand 12 months. The mean PCP in controls was 8-8 + 2*3SD and 12*9 + 3.5 in the untreated CFA group. Followingtreatment 14/17 patients showed a decreased PCP, which ifmore than 25% was accompanied by a greater than 5%improvement in the percentage Kco (the corrected trans-fer factor) (p <0-001) and forced vital capacity (p<0-005). This percentage change in PCP also correlatedsignificantly with the physiological changes found at 12months (p < 0-01). These results suggest that changes inPCP levels follow treatment response, and also imply thatinterference with type III collagen synthesis is important inthe treatment of CFA.

Pulmonary metabolism of immunoreactive prostaglandin Fin the healthy and diseased lung and pulmonary arculation

RM JENKINS Much evidence has now accumulated that thelungs and pulmonary circulation of both mammals andman are responsible for the metabolism of a wide range ofendogenous circulating substances. Included is the removalof a significant proportion of circulating prostaglandins.There is evidence that these normal metabolic activities aredisturbed in pulmonary hypertension and chronic lung dis-ease in man but these previous studies have involved theintravenous administration of bolus pharmacological dosesof tritiated prostaglandins. I estimated plasma concentra-tions of immunoreactive prostaglandin F in pulmonaryartery and left ventricular samples, and calculated trans-pulmonary differences, clearance, and release rates in sixpatients with primary and secondary pulmonary hyperten-sion, six patients with chronic obstructive lung disease withcor pulmonale, and 15 control subjects. A significanttranspulmonary fall was observed in the control group,indicating clearance of prostaglandin F during passagethrough the pulmonary circulation. In both patient groups,however, the transpulmonary differences were reversed,indicating net release of prostaglandin F by their lungs.These data suggest that diseases involving the pulmonarycirculation are associated with a disturbance in the balancebetween uptake and release of prostaglandins by the pul-monary endothelial cells. This disturbance in normalmetabolic activity may aggravate existing pulmonaryhypertension and have important systemic effects.

Effect of gas phase of dgarette smoke on lung epithelialpermeability

CDI! BORLAND, AT CHAMBERLAIN, TIM HIGENBOTrAMCigarette smokers have increased lung epithelial permea-bility, demonstrated by low clearance half-times from lungto blood (T1hLB) of diethylene triamine penta-acetic acidlabelled with technetium-99 m (99mTc-DTPA). On absten-tion from smoking T1h LB rapidly returns towards normal(Minty BD, Jordan C, Jones JG. Rapid improvement in

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abnormal pulmonary epithelial permeability after stoppingcigarettes. Br Med J 1981;282:1183-6). Six normal malecigarette smokers who wished to stop smoking wererecruited. They received nicotine chewing gum (Nicorette)throughout the study. Subjects continued to smoke for thefirst week, all cigarettes being smoked via a Cambridgefilter, which effectively excludes particulate matter. Duringthe second week subjects completely abstained fromcigarettes. T1/2LB was measured at recruitment and at theend of weeks 1 and 2. Abstinence at the end of week 2 wasconfirmed by measuring expired carbon monoxide. MeanT/2LB was 11-8 minutes at recruitment, 10.7 minutes atthe end of week 1 (NS), and 19-8 minutes at the end ofweek 2 (p <0*001 with two-way analysis of variance). Ourresults suggest that the gas phase of cigarette smoke isresponsible for the increased lung epithelial permeabilityobserved in smokers. We do not yet know, however,whether abnormal lung permeability is related to subse-quent development of lung disease in cigarette smokers.

Immunofluorescence studies of panetal pleural capillariesin patients with pleural effusion

EW BENBOW, BC LEAHY, KJ WOOD, E BENJAMIN, G WILLIAMS,TB STRETTON We have investigated the possibility that,pleural capillary damage by immune complexes may par-ticipate in the pathogenesis of exudative pleural effusion ofvarious aetiologies. Pleural biopsy samples were obtainedfrom 26 patients with pleural effusion. These wereexamined by conventional light microscopy and byimmunofluorescence; for the latter method fluorescein-tagged antibodies to immunoglobulins IgG, IgA, and IgMand to Clq and C3 components of complement were used.Of the 26 biopsy samples examined, 17 were suitable forstudy as intact pleural capillaries were seen in the tissuesample. Nine samples showed capillary deposits. Of thenine, five showed deposits of IgM; these were all frompatients with malignant effusions. The four other positivesamples revealed complement only; they were frompatients with tuberculosis, pulmonary infarction, andempyema and a patient whose effusion was labelled"idiopathic" after full investigation. Eight biopsy samplesdid not reveal capillary deposits. Four were from the fourpatients with transudative effusion, two were from patientswith malignant disease, and two from "idiopathic" cases.Thus immune complexes are seen in pleural capillary wallsof patients with exudative effusions and may have a role inthe pathogenesis of the effusion.

Effects of inhaled histamine, salbutamol, andbeclomethasone dipropionate on lung epithelialpermeability

PJ REES, D SHELTON, N EISER, TJH CLARK NM MAISEY Lungepithelial permeability has been shown to be increased incigarette smokers and in asthmatic subjects. We haveinvestigated the effects of inhaled salbutamol, bec-lomethasone dipropionate (BDP), and histamine on lung

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permeability. Permeability was measured with a scintilla-tion counter over the right upper lobe after inhalation ofdiethylene triamine penta-acetic acid labelled withtechnetium-991Tc-DTPA). An estimate of background tis-sue activity was obtained by comparing counts from thelung probe and a scintillation counter over the left thigh.Permeability was measured as the half-time clearance of99mTc-DTPA from the right upper lobe. The coefficient ofvariation of the clearance was 14%. In six normal subjectsinhalation of 1 mg salbutamol from a metered-dose inhaler20 minutes before "mTc-DTPA had no effect on the clear-ance, neither did inhalation of salbutamol 200 ,ug fourtimes a day for one week or BDP 100 ,ug four times a dayfor two weeks. Inhalation of histamine 20-40 minutes after99mTc-DTPA produced a mean peak flow decrease of60%, while half-time clearance fell by a mean of 30%. Anincreased epithelial permeability in asthmatic subjectsmight allow increased penetration of inhaled antigen orinflammatory mediators. Our results show that a similarincrease in permeability occurs on bronchoconstrictionwith inhaled histamine. Inhaled asthma therapy with sal-butamol and BDP has no effect on permeability in normalsubjects.

Can the spread of bronchial carcnoma be predicted by asingle blood test?

MARY CARROLL, MARGARET E HODSON, AB KAY A testof leucocyte function (complement receptor enhance-ment-CRE) was performed on blood monocytesfrom 38 patients with suspected bronchial carcinoma inwhom this diagnosis was subsequently substantiated. In 31(81.5%) the values were below a normal range previouslyestablished for monocytes from healthy controls (37) andpatients with other non-malignant respiratory diseases (9).By chest radiography and a combination of tomography,liver scan, bone scan, brain scan, computed tomographyscan, mediastinoscopy, and operative assessment whereappropriate, it was ascertained that all of the 31 patientswith reduced CRE had either local or widespread meta-stasis. In contrast, abnormalities in a single routinehaematological or biochemical test in the 38 patients at thetime of presentation were as follows: haemoglobin 15(39%), ESR 11 (29%), bilirubin 7 (18%), aspartate trans-aminase 7 (18%), y-GGT 12 (31.6%), alkaline phosphat-ase 11 (29%), and calcium 3 (7%). These results suggestthat CRE is a reliable predictor of the extent of this diseasesince low values were associated with extension within thechest and very low values with widespread metastasis.

Tumour growth and cell loss in human pulmonaryneoplasms

KM KERR, D LAMB Actual volume doubling time (DTact)can be obtained for human pulmonary neoplasms by thetechnique established by VP Collins et al (Am J Roentgenol1956;76:988), using measurements taken from lesions onserial chest radiographs. Tumour growth can be investi-gated at a cellular level after radioactive labelling of


S-phase cells in vitro with tritiated thymidine. The percen-tage of cells labelled with thymidine, autoradiographicallydetected on histological sections, is termed the thymidinelabelling index (TLI). TLI relates to tumour cell prolifera-tion within a neoplasm and from this a theoretical orpotential doubling time (DTpot) may be derived (SteelGG Eur J Cancer 1967;3:381). Differences betweenDTact and DTpot are attributed to cell loss from thetumour. The cell loss factor, 4, derived by Steel, expressingcell loss as a fraction of cell production, has not previouslybeen estimated for human pulmonary tumours. We havemade such estimates for 14 primary and three secondarycarcinomas of the lung. All primary bronchogenic car-cinomas have 4 values over 70%. Sixty four per cent havevalues of 90% or more. A correlation exists between 4 andboth degree of tumour differentiation and tumour TLI.Cell loss from the tumour is a major determinant of theactual growth rate of human pulmonary tumours.

Effect of cysteine derivatives on glycoprotein secretioninto the rat trachea

NC TURNER, C MARRIoTT R Martin et al (Am Rev RespirDis 1980;121:495) have reported that in vitroN-acetylcysteine (NAC) decreases the elasticity of mucus,resulting in an improved mucociliary transport rate. In con-trast, S-carboxymethylcysteine (SCMC) has no effect oneither mucus properties or mucociliary transport rate andits reported effectiveness in vivo must be due to a mechan-ism unrelated to direct mycolytic activity. In the studydescribed here the effects of systemically administeredSCMC and NAC on the basal rate of glycoprotein secre-tion and on the increase in glycoprotein secretion elicitedby intravenous infusion of pilocarpine (4 x 10-6 mol/kg/min) have been investigated in the rat trachea. A segmentof trachea with the collateral arteries and nerves intact wasisolated in situ and perfused with physiological saline solu-tion warmed to 37°C and pregassed with 95% 0,2 5%CO2. NAC or SCMC was given by continuous intravenousinfusion immediately after surgery and pilocarpine infusionwas commenced two hours later. The tracheal perfusateswere changed every 30 minutes and assayed for glycopro-tein and protein content. The basal rate of glycoproteinsecretion into the tracheal segment was 94 ± 13 ,ughexose/30 mins, this rate of secretion was reached withinthe two-hour control period and remained in this range forthe remainder of the experiment (3 hours). Intravenousinfusion of pilocarpine elicited an increase in secretoryrate, which reached a peak usually within 90 minutes. Themean maximum increase in secretory rate was 108-25 ±23-4 ,ug hexose/30 min. Neither SCMC (5.5 x 10-6, 5-5 x10-5, and 2-8 x 10-4 mol/kgfh) nor NAC (3 x 10-- and 3x 10- mol/kg/h) caused any reduction in the basal rate ofglycoprotein secretion; however, SCMC 5-5 x 10-5 and2-8 x 10-4 mol/kg/h and NAC 3 x 10-' mol/kg/h pro-duced a significant reduction in the secretory response topilocarpine. Neither drug had any effect on the amount ofprotein in the perfusates. In conclusion, both cysteinederivatives produced a reduction in glycoprotein secretionwhich is unrelated to their direct effects on mucus. SCMCwas approximately 10 times more potent than NAC.

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Histologcal features of small-cell carcnomas and survivalafter surgical resection

DJL MALONEY, GN MORRITr, PR WALBAUM, D LAMB Sectionsfrom 854 thoracotomies for lung cancer from 1968 to 1972have been reviewed. One hundred and thirty-five small-cell carcinomas were identified, of which 99 had beenresected. The identification of 135 small-cell carcinomasrequired a change from the histological cell type originallyallocated in over 20% of cases. The small-cell carcinomaswere subdivided into the two main subgroups recognised inthe 1981 2nd edition of the WHO Classification of LungTumours: "oat-cell carcinoma"' and "intermediate celltype." Other histological features such as tumour necrosis,presence of DNA cuffing around vessels, and the presenceof differentiation as shown by rosette formation werestudied and an attempt was made to correlate the histolog-ical features with survival after resection. Comparing the14 survivors with the patients who had resections but didnot survive five years showed similar proportions of oat-cell and intermediate cell type but the survivors includedmore who showed necrosis with DNA cuffing, particularlyamong the oat-cell subgroup. Problems in diagnosingsmall-cell carcinoma are discussed, particularly theidentification of the group of atypical carcinoid tumourswhich have histological features in common with small-cellcarcinoma but a much better prognosis-namely 45%five-year survival after surgery.

Quaity of life after surgical treatment for oesophagealcardnoma

R COX, CE NEWMAN, HR MAT1HEWS Quality of life follow-ing surgical treatment has been quantitated prospectivelyin 100 consecutive new cases of oesophageal carcinoma.Physical activity was graded 0-5 on a scale of increasingdisability, and eating ability similarly. The general sense ofwellbeing was graded subjectively and objectively as"good," "fair," or "poor." Parameters were assessed priorto treatment and for a minimum of two years or untildeath. The principal findings are: (1) Only 19 patientsreached a good quality of life following treatment. Seven-teen of these were among the 28 patients who were resec-ted, and two were among 18 patients treated initially bydilatation. (2) Only four patients resumed paid employ-ment. All were from the 17 with a good result followingresection, of whom 14 were of preretirement age. (3)Recovery time following oesophagectomy for these 17ranged from six weeks to nine months (mean 3-8 months).(4) Of 29 patients treated by endoscopic intubation, noneachieved good parameters and results for quality of life andsurvival were better in 18 patients treated initially by dila-tation alone. This study confirms the generally poor resultsin this disease except in patients who have complete resec-tion of their tumours, and should provide a baseline for asearch for better methods of treatment.

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Modified Pearson gastroplasty in the management of theshort oesophagus

MK REILLY, HRJ PAYNE, K JEYASINGHAM Surgical treatmentof the strictured and shortened oesophagus remains adifficult problem. The desirability of preserving a func-tional oesophagogastric junction led to development ofoesophageal lengthening procedures. Since 1980 12patients with dilatable stricture and shortening of theoesophagus have undergone Collis-Belsey (Pearson) gas-troplasty at Frenchay Hospital. A criticism of Pearson'sprocedure is loss of fundal area coupled with distortionproduced by the longitudinal suture line, making an ade-quate wrap difficult. Modification by transverse closure ofthe gastric suture line has been developed in order toincrease the available surface. Five patients underwent themodified procedure while seven had a standard Pearsongastroplasty. Postoperative evaluation included man-ometry, barium studies, and oesophagoscopy. Bariumstudies revealed reduction of the hernia and adequateangulation of the neo-oesophagogastric junction in all butone. Manometry in patients undergoing the modified Pear-son gastroplasty identified a lower oesophageal sphincterzone of high pressure with normal relaxation. Acid clear-ance was normal. Only one patient who had a standardPearson procedure had a normal sphincter pressure zonewith normal relaxation. Acid studies gave normal results inonly one. While full evaluation must await long-termresults, early indications are that this modification is a use-ful alternative to the standard Pearson gastroplasty.

Postintubation tracheal injuries

K MOGHISSI Postintubation tracheal injuries are infre-quent considering the frequency with which intubation andtracheostomies are carried out. The number of patientshandled by any surgeon is therefore likely to be limited.During a period of 12 years 70 patients with tracheallesions were treated surgically in our centre; 49 of thesehad benign and malignant tumours. The remaining 21patients, who are the subjects of this presentation, hadpostintubation injuries. There were 14 men and 7 women.Their ages ranged from 20 to 76 years (average 57-2years). Anatomopathological studies of the lesion placedthem in five groups: subglottic stenosis (2 patients), steno-tic lesion at the site of the tracheostomy (5), stenoticlesions below the tracheostomy (9), tracheomalacia belowthe tracheostomy (2) and low tracheal stenosis (3). Threepatients had stenotic lesions in two places; the aetiologywill be discussed. In all cases circumferential excision andreconstruction were undertaken; only in one patient wascardiopulmonary bypass used. One patient died in hospitalsix weeks after operation (mortality 4.7%); one patientwith subglottic stenosis and tracheostomy for 20 yearsdeveloped restenosis six months after operation andrequired retracheostomy; one patient died four years afteroperation from unrelated bronchial carcinoma. All others(18) are alive and symptom free from one year to 10 yearsafter operation.

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Inddence and recurrence of spontaneous pneumothorax ina defined population

HUGH J THOMSON, ANDREW V FOOTE Many oil companiesand airlines stipulate a one-year recurrence-free periodafter a spontaneous pneumothorax before allowing returnto work. A comprehensive survey of first spontaneouspneumothoraces occurring in Grampian Region betweenJanuary 1977 and July 1982 found a total of 227 cases,with an average annual incidence of 87-3/million popula-tion. Eleven patients had fibrotic or malignant lung diseaseor acute infections, and the remainder fell into two groupsaccording to age. One hundred'and twenty-two patientswere under 40 years old: 13 were managed conservatively,and 109 by intercostal drainage; 11 required poudrage orpleurectomy for continuing air leak, and the recurrencerate at five years was 30%. Ninety-four patients were aged 40years or more; six were managed conservatively and 88 byintercostal drainage; nine died and 14 required poudrageor pleurectomy for persistent leak. A quarter of survivorshad a recurrence within five years. Recurrences continuedta occur throughout the follow-up period, and it is clearthat a one year recurrence-free period in industry is inade-quate.

Common childhood respiratory illnesses and subsequentdevelopment of lung function

P HELMS, SH BAIN, JO WARNER There is evidence thatrespiratory illnesses in early childhood may result inresidual disturbances of lung function. We have performedmeasurements of static and dynamic lung volumes, airwaymechanics, gas mixing, and gas exchange in a cross-sectional study of apparently fit schoolchildren. To date,401 children aged 4-18 years have been studied, on whoma detailed questionnaire of birth history, subsequentdevelopment, respiratory illnesses, and atopic symptomshad been completed by each child's parents. Of this group,210 (52-3%) had a history of at least one significantrespiratory or atopic illness. The separate categories andtheir incidence in the whole group were as follows:"croup" 13 (3.2%); "wheezing, asthma, or bronchitis" 28(7%); "hay fever and/or eczema" 39 (9.7%); "pertussis"30 (7-5%); any combination of the above 93 (23-2%). Nosignificant differences were found between the symptom-free and symptomatic groups for lung volumes, peakinspiratory and expiratory airflow, airflow at 50% and25% of expired vital capacity (VC), accessible lung vol-ume, or carbon monoxide diffusing capacity. However, in91 children above the age of 9 years a significantly lowerairflow at 25% VC was observed in the respiratory illnessgroup (p < 0-02). The divergence of the two groups in midto late childhood suggests a subtle but significant distur-bance of lung function, which further cross-sectional andlongitudinal studies should clarify.

Does whooping cough damage the lungs?

IDA JOHNSTON, S PATEL, HR ANDERSON, HP LAMBERT Therecent large increase in the incidence of whooping cough


has provoked concern about possible long-term effects onthe lungs. We have investigated this question by comparingthree groups of primary school children with previouswhooping cough with controls of the same sex and schoolclass by means of a respiratory questionnaire completed byparents, physical examination, and spirometry (Vitalo-graph). The three groups comprised 148 children who hadbeen hospitalised with whooping cough, 135 who had beennotified by their GP, and 77 reported as having had whoop-ing cough by their parents in the self-completed question-naire. Previous chest illnesses other than whooping coughand current respiratory symptoms were more frequentamong whooping cough children than controls-for exam-ple croup (18% v 9%, p < 0.05) and wheeze in the past 12months (25% v 12%, p < 0-001). Analysis of the ages atwhich other chest illnesses occurred relative to the age atwhich whooping cough occurred suggested that childrenwho have the disease have a pre-existing susceptibility tochest disease, not that whooping cough itself increases therisk of chest disease. When height was controlled for asnecessary, analysis of covariance showed no significant dif-ferences in FEVO.75, FEV, , FVC, FEV. 0G%, FEF2_,75,, ormean transit time between cases and controls in any of thethree whooping cough groups. We conclude that in thegeneral population whooping cough is unlikely to causesubsequent lung disease.

Prolonged effects of erythrapheresis in patients withpolycythaemia secondary to hypoxic lung disease

JA WEDZICHA, FE COTTER, RM RUDD, AC NEWLAND, DWEMPEY With erythrapheresis, a method of isovolaemichaemodilution, we can obtain satisfactory reductions ofpacked cell volume in patients with polycythaemia secon-dary to chronic obstructive bronchitis, with increases in-exercise tolerance and mental alertness. To investigatewhether these improvements are maintained, we assessed16 patients (mean FEV, 0-841; Pao27-0 kPa) at monthlyintervals following erythrapheresis. After treatment themean microhaematocrit decreased from 0-59 to 0-46 with arise to only 0.51 at the three-month follow-up. The meanblood viscosity at both high and low shear rates was stillsignificantly lower than the pretreatment values at threemonths (p < 0.01), with no change in platelet count. Therewere significant decreases in mean corpuscular volume(MCV) (from 93 to 87 fl; p < 0-001) and mean cellhaemoglobin concentration (MCHC) (from 32-1 to 30-5g/100 ml; p < 0-05); iron supplements were not adminis-tered. Following erythrapheresis the mean six-minutewalking distance increased from 351 m to 429 m (p <0-01), and at three months it was still significantly greater(400 m) than the pre-treatment walking distance (p <0.05). Improvement in scores for three tests of mentalalertness was maintained at the three-month follow-upassessment (p < 0.05). By six months after the originalerythrapheresis polycythaemia (PCV > 0.54) had recurredin eight patients and further treatments were required.Reduction in packed cell volume is, however, maintainedfor a prolonged period following erythrapheresis with sus-tained benefit in exercise capacity and mental alertness.

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Almitrine reduces the frequency and severity of recurrentbansient nocturnal hypoxaemia in chronic bronchitis andemphysema

JJ CONNAUGHTON, AD MORGAN, NJ DOUGLAS, CM SHAPIRO, NPAULY, Dc FLENLEY Almitrine is a triazine derivativewhich significantly improves arterial gas tensions with min-imal change in resting ventilation in hypoxic patients withchronic bronchitis and emphysema. Episodes of recurrenttransient hypoxaemia, which may be important in thedevelopment of pulmonary hypertension and cor pul-monale, are frequent during nocturnal sleep in such "blueand bloated" patients. In a placebo-controlled double-blind crossover study we have measured ear oxygen satura-tion (Sao2) and EEG sleep during nocturnal sleep in sixpatients (3M: 3F; 50-68 years) with chronic bronchitis andemphysema FEV, 0*66 + 0*22 1, VC 2-08 ± 1*0 1, Pao27*15 + 1.02 kPa, Paco2 6*38 + 0 35 kPa) after two weeksof almitrine (50 mg twice daily). Arterial Po2 when theywere awake improved significantly (p <0.01) .after almit-rine (Pao2 7*92 + 0*94 kPa after almitrine, Pao2 7*10 ±1.0 kPa after placebo). Mean Sao2 awake was higher (NS)after almitrine (89% ± 9.6%) than after placebo (84% ±13%). The mean lowest Sao2 recorded during a night'ssleep rose significantly (p < 0.05) from 62% ± 22% afterplacebo to 76% ± 10% after almitrine. The mean numberof transient hypoxaemic episodes (fall in Sao2 : 10%)each night was significantly reduced from 2*5% ± 1-6 afterplacebo to 0*7% ± 0.5 after almitrine. The patients slepton average 199 minutes after almitrine and 191 minutesafter placebo. Less time on average was spent in wakeful-ness and drowsiness (Stages 0 and 1) after almitrine (225minutes) than after placebo (308 minutes). We concludethat oral almitrine may be of value in reducing the numberand severity of recurrent transient hypoxaemic episodesduring sleep in patients with hypoxic chronic bronchitisand emphysema.

Is mood change linked to improvement of chronic airflowlimitation after corticosteroid therapy?

DM MITCHELL, P GILDEH, WAC MCALLISTER, M REHAHN, KDIMOND, P NOBLE, IV COLLINS Corticosteroids may pro-duce mood changes. This might account for improvementin chronic airflow limitation following a trial of steroids asmood elevation could improve performance in objectivemeasurements. This was tested in 21 patients who haddetailed psychological assessment during a randomised andcontrolled double-blind crossover study of the effect ofprednisolone 40 mg/day and placebo on chronic airflowlimitation. Patients rated themselves on visual-analoguescales for cheerfulness, optimism, speed of thought, activ-ity, sociability, sexual activity, depression, and anxietybefore the study and after each phase. Patients also com-pleted a questionnaire designed to detect depression andanxiety. With placebo there was a significant increase onvisual-analogue ratings in cheerfulness (p < 0-01) andsociability (p < 0-01) and a decrease in depression (p <0-01). There was also a decrease in depression detected byquestionnaire (p < 0.001). Following prednisolone the

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only changes in the group as a whole were decreases indepression (p < 0.01) and anxiety (p < 0.05). A smallnumber of patients showed significant (>20%) improve-ments in PEFR, FEVI and/or FVC. Nearly all hadimprovement in one or more of the nine psychological testsfollowing both prednisolone and placebo regardless ofphysiological response. We conclude that in chronic airflowlimitation psychological changes are no more likely withprednisolone than placebo, and that physiologicalimprovement in chronic airflow limitation followingprednisolone is not tied to psychological changes.

Controlled study of etoposde and bleomycin combinationchemotherapy in squamous-cel carcinoma of the bronchus

PA CORRIS, KW WOODHOUSE, MD RAWLINS, S NARIMAN, GJGIBSON Non-surgical treatment of squamous-cell car-cinoma of the bronchus has had little effect on long-termsurvival and is usually reserved for symptomatic use. Fewcontrolled studies of chemotherapy have been reportedand we have therefore carried out such a study using thetheoretically synergistic combination of etoposide andbleomycin. All 43 patients entered were unfit for surgerybut on clinical and biochemical criteria disease was local-ised to the thorax and supraclavicular glands. The patientswere randomly allocated to either continued observationor treatment with intravenous etoposide 100 mg/m2 fol-lowed six hours later by intravenous bleomycin 10 mg onthree successive days; the pulses were given monthly to atotal of five. If after randomisation any patients developeda clear indication for radiotherapy this was given to theappropriate site. Of 22 patients in the treatment group, theradiological response was assessable in 17. Completeradiological remission was achieved in three patients andpartial remission in four, while in the control group therewas no evidence of tumour regression in any case. Perfor-mance status during and after the study was better in thetreatment group and the drugs were well tolerated. Mediansurvival was greater than 12 months in the treatment groupcompared with six monthsihn the control group.

Are transbronchial biopsies cdinicafy valble ?

PETER BOFFA, RICHARD DENT, TIM HIGENBOTTAM, CHRISFLOWER, JOHN STARK, JOHN SHNEERSON, PETER STOVINWhile it is our practice to use percutaneous needle biopsyaspiration for the diagnosis of discrete peripheral lunglesions, we have performed 204 transbronchial biopsies viathe fibreoptic bronchoscope for bilateral diffuse lung dis-ease (n = 114) and ill-defined lobar opacities (n = 90). Inthe past two years a follow-up of from 4 to 24 months hasenabled us to calculate sensitivity (true positive/true posi-tive + false negative) and predictive value of negativeresults (true negative/true negative + false negative). Allpatients were analysed, including the 28% from whommaterial for histological examination was inadequate.There was one death from pulmonary haemorrhage(hairy-cell leukaemia) and two pneumothoraces. In diffusedisease sensitivity was 84% for sarcoid (n = 31), 75% for

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malignancy (n = 16), and 84% for infection (mainly in theimmunosuppressed) (n = 15), but it was 34% (n = 22) forfibrosing alveolitis and only 10% for vasculitic andgranulomatous disease (n = 10). Sensitivity in lobar dis-ease was 52% for malignancy (n = 42), 55% for infections(n = 9), and zero for vasculitic lesions (n = 2). Transbron-chial biopsy is valuable in diagnosing sarcoidosis, malig-nancy, or infections producing diffuse lung shadowing. Thepredictive value of negative results in cases of diffuseshadowing was poor (=0.38), but with lobar opacitiesnegative results had more predictive value (=0.58) thoughthe method was not particularly sensitive in diagnosis.

Open lung biopsy in patients with diffuse intrpulmonaryshadowing

GRAHAM E VENN, PHILIP H KAY, CAROLINE J MIDWOOD, PETERGOLDSTRAW The radiological appearances of diffusepulmonary shadowing are not specific and usually histolog-ical examination is necessary to provide diagnosis and todemonstrate the activity of the disease process. From July1980 to May 1983 we performed open lung biopsy in 101patients. Biopsy was performed through a limited (3-10 cm) submammary incision. Twenty-seven patients hadundergone prior invasive investigations (transbronchial ordrill biopsy). Twenty-seven patients were taking steroids atthe time of biopsy (10-60 mg prednisolone/day). In 92patients the histological appearances of the biopsy weresufficiently specific to permit diagnosis. Chest infectionsoccurred in six patients, and in eight there was somesuperficial infection of the wound. These complicationswere more frequent in those patients taking cortico-steroids. The chest drain was removed usually on the firstpostoperative day. In three patients who were extremely illwith advanced lung disease air leak recurred. There werefour deaths in the series, all in patients with severe pre-existing lung disease. Death in all cases was related toprogression of the underlying pulmonary disease. Openlung biopsy can be performed with minimal morbidity andhigh diagnostic yield. The approach we have used providesa safe and reliable operation with good cosmetic results.

Open lung biopsy: 158 cases surveyed

DE STABLEFORTH, KM CITRON, M TURNER-WARWICK Onehundred and fifty eight open lung biopsies were carried outon patients ranging in age from 11 months to 74 years(mean 45 years) over a five-year period at the BromptonHospital. The procedures were performed to make a diag-nosis or for staging, sometimes when less invasive methodshad failed, principally in patients found to have fibrosingalveolitis (26%), malignancy (36%), and tuberculosis orsarcoidosis (11%). Overall 31 (20%) biopsies were com-plicated (surgical 11%, anaesthetic 2%, and medical orincidental 8%) and three (1-9%) patients died within 30days. Significant wound infection (5%), prolongedpneumothorax (5%), chest infection, extensive lung col-lapse, and respiratory failure (5%) and contralateral ten-sion pneumothorax (1 %) during anaesthesia were the


main events. Seventeen patients were taking corticosteroiddrugs at the time of surgery; of these, four (24%)developed a pneumothorax requiring prolonged tubedrainage and four (24%) had "medical" complications,including chest infection. None developed wound infec-tions in this group. The remaining 141 patients received nocorticosteroids; of these, only six (4%) acquired a pro-longed pneumothorax, eight (6%) had significant woundinfection, and 10 (7%) "medical" complications (p <0.01). Patients in whom surgical staples were used for lungclosure (29) fared no differently from those not so treated(129), 6% of them having prolonged pneumothorax.Likewise the overall complication rate occurring inpatients having biopsy through full-sized and limited inci-sions was not significantly different. Open lung biopsy mustclearly be considered in the light of possible benefit, clini-cal urgency, alternatives if any, and local surgical expertiseand then embarked on with the knowledge that there is asignificant rate of complications.

Percutaneous Trucut lung biopsy in the diagnosis oflocalised pulmonary lesions

BDW HARRISON, RS THORPE, PG KITCHENER, BG McCANN, JRPILLING Seventy-seven patients with localised lesions onchest radiographs have had percutaneous Trucut biopsiesunder local anaesthetic and with x-ray screening. Tissuewas obtained from 74 patients and was diagnostic in 70(95%) (57 malignant and 13 non-malignant). Objectivehistological or cytological confirmation of the diagnosiswas obtained for 32% of the malignant and 38% of thenon-malignant problems. Corroborative clinical evidencewas obtained in the remainder. Complications includedpneumothorax in 21 patients (27%), requiring a tube infour patients; haemorrhage, usually trivial, in 19, requiringtransfusion in one patient; and two needle-track secon-daries. The sizes of the masses ranged from 1 5 to > 10 cmmost being 5 cm in diameter or less; and all but three were3-10 cm from the skin surface. This is the largest series ofcutting needle biopsies performed for diagnosis of localisedlesions since 1960. Recent reviews have emphasised thedangers of this technique on the basis of fatalities, whichalmost all occurred in patients with diJfuse lung disease.Advantages of biopsy over aspiration cytology include celltyping of tumours, accurate diagnosis of benign lesions,and the fact that an expert cytopathologist is not needed.These and important technical details, including indica-tions and contraindications, will be discussed.

Transbronchial biopsies for diffuse lung disease: is x-rayscreening necessary?

D MITCHELL, JE SELF, JG HAY Transbronchial lung biopsyvia the fibreoptic bronchoscope is used in some centres toobtain tissue for diagnosis of diffuse lung disease.

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Radiological screening has been recommended to allowaccurate forceps placement and to minimise the risk ofcomplications. While screening is clearly necessary for thebiopsy of local disease, its role in the diagnosis of diffusedisease has not been established. We have analysed theresults of transbronchial lung biopsy without screening in70 patients at the London Chest Hospital by review of casenotes, and assessed the incidence of complications in afurther 65 patients at other centres by questionnaire.Blood loss was recorded at the time of the bronchoscopyand a chest radiograph was taken one to four hours afterthe biopsy in every case. Histological diagnosis wasobtained in 42 out of 70 patients (60%) overall. The diag-

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nosis was sarcoidosis in 20 cases, fibrosis in 10, malignancyin eight, and other conditions in four; the procedure wasnon-diagnostic in 28 cases. A definite diagnosis was madeless frequently-in six out of 14 cases (43%)-when theradiographic shadowing was limited to the upper zones.Only three patients had significant complications-namelypneumothorax, pneumonia, bleeding greater than 50 mlrespectively. Review of a further 65 transbronchial lungbiopsies performed at two other centres without screeningrevealed no significant complications. This retrospectivesurvey suggests that transbronchial lung biopsy withoutscreening is a reasonably safe procedure with an acceptablediagnostic yield.

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