36 Annals oftheRhewatic Diseases 1991; 50: 36-40

Bronchial hyperresponsiveness to methacholine in Ann Rheum Dis: first published as 10.1136/ard.50.1.36 on 1 January 1991. Downloaded from patients with primary Sjogren's syndrome

Bjorn Gudbjornsson, Hans Hedenstrom, Gunnemar Stalenheim, Roger Hallgren

Abstract inhalation in a consecutive series of patients The prevalence of bronchial hyperresponsive- with primary Sjogren's syndrome. We found ness (BHR) to methacholine inhalation in a that most patients were hyperreactive in the consecutive series of 21 patients with primar test, and we correlated the methacholine test Sj6gren's syndrome was studied prospectively. findings with clinical features and spirometric Slight to severe BHR was seen in 12/20 (60%/o) findings. of the patients. Ten of 12 patients with BHR (83%) had a non-productive , wheezing, or intermittent breathlessness. Bronchial Patients and methods hyperresponsiveness was more common in A consecutive, non-selected series of patients patients with exraglandular symptoms (10/14, (20 women, one man; aged 22-78 years; mean 71%) than in those with only glandular age 53-6) who were admitted to the section of symptoms (29%). Spirometrically 29% (6/21) rheumatology were studied. The diagnosis of of the patients had 'small airways' disease', primary Sjogren's syndrome was based on the and all those had BHR. Of6/21 (29%) who had following findings: each patient had kerato- diffuse interstitial lung disease, two had BHR. conjunctivitis sicca shown by a pathological Three of the four patients with obstructive Schirmer's test (<10 mm/5 min) and positive lung function were challenged with metha- rose bengal staining,7 and xerostomia with a choline and two of them had BHR. Only two total salivary secretion rate stimulated by patients with BHR had normal spirometry chewing of <0 7 ml/min,8 in the absence of findings. The data showed that respiratory other rheumatic diseases. The diagnosis was disease-mostly mild or moderate but even confirmed by a positive lower lip biopsy.9 severe bronchial hyperresponsiveness- is Glandular and extraglandular symptoms of the commonly seen in patients with primary patients were clinically evaluated. All patients Sj6gren's syndrome. underwent serological examinations with the

following tests: Waaler-Rose rheumatoid factor http://ard.bmj.com/ and antinuclear antibodies were measured at the Sjogren's syndrome is a chronic autoimmune department of clinical bacteriology, University inflammatory disease, which mainly affects Hospital, Uppsala. Anti-Ro (SS-A) and anti-La exocrine glands. Sjogren's syndrome can occur (SS-B) were measured by the Western blot alone-primary Sjogren's syndrome, or in technique at the State Bacteriological Laboratory association with other autoimmune diseases, in Stockholm, Sweden.

such as , systemic All subjects underwent plain chest radio- on September 25, 2021 by guest. Protected copyright. erythematosus, and systemic sclerosis- graphy and spirometry. The spirometric test secondary Sjogren's syndrome. Several visceral included measurements of the total lung organs, including the lungs,' may be affected in capacity (TLC), residual volume (RV), airways primary Sjogren's syndrome. The respiratory resistance (Raw), and airway conductance manifestations include among others interstitial (Gaw/V) with a body plethysmograph. Vital and Rheumtolgy Section, pneumonitis, 'small airways' disease', capacity (VC), forced vital capacity (FVC), Department of pleuritis.21 Large airway obstruction has been forced expiratory volume in one second (FEVy), Internal Medicine, reported in 8-12% of patients with primary FEVy as a percentage of VC (FEVI/VC) and of Uppsaa University Sjogren's syndrome.5 6In our experience severe TLC (FEV,/TLC), flow volume registrations Hospitl, S-751 85 are to maximal flows Uppala, Sweden obstructive symptoms attributed with exploratory flow Vem.,) and B Gudbj6msson bronchial and the diagnosis of Sjogren's measured at 50%/o (Ve5o) and 25% (Ve25) of FVC R Hiigren syndrome unfortunately does not become were measured with an Ohio spirometer. The Depar met of apparent until the patients develop interstitial slope of the alveolar plateau (phase III), closing Ph lung fibrosis. About one third of patients with volume (CV) as a percentage of VC (CV/VC), UppQla University Hosptl, primary Sjogren's syndrome have a chronic dry and closing capacity (CC) as percentage of TLC Uppsala, Sweden non-productive cough and dyspnoea.2 3 These (CCITLC) were determined with the single H Hedenstr6m symptoms are thought to be due to dryness in breath nitrogen washout test and the transfer Department of the large airways, secondary to a lymphocyte factor of the lung for CO (TLco) was measured Lung Medicine, infiltration of the glands of the mucous mem- with the transfer test. The values obtained were Hospial, Uppsala, brane in the trachea. These so-called xerotrachea compared with those for healthy controls Sweden symptoms may, however, also imitate the matched for age and sex, and abnormal values G Sthienheim symptoms of mild or moderate bronchial hyper- were defined as values outside the 95% con- Correspondence to: us 11 Dr reactivity. This clinical background induced fidence intervals.'0 Gudbj6rnsson. of bronchial The methacholine test was modified from Accepted for publication to investigate the prevalence 1 February 1990 hyperresponsiveness (BHR) to methacholine Hargreave's method.'2 A hand-held deVilbiss Bronchial yperresponsiveness inprina Sjogren's syndrome 37

Tabk I Sex, age, serology, extraglandular mamfestations and respiratory symptoms in 21 patients with primary Sjogren's drome Ann Rheum Dis: first published as 10.1136/ard.50.1.36 on 1 January 1991. Downloaded from Case Sex Age Serolorv Extraglandukir Pulmuny No (years) toms sympom RF* ANA* iiire fire, patern 1 F 22 -t - Sun sensitivity None 2t F 60 1/125 - Raynaud's Dry coughing 3 F 38 1/25 - Raynaud's Dry coughing 4 F 78 1/640 1/100 Raynaud's Exertional dyspnoea Speckled S F 60 - 1/25 BC,* NEAr,* HTh,* Dry coughing Homogeneous Raynaud's 6 F 71 - 1/1600 NEAr, Raynaud's, 'Asthma' Nucleolar kidney stone 7 F 63 - 1/1600 NEAr, Wmgl,* Dry coughing Nucleolar polyneuropathy, kidney stone 8 F 62 - - None Exertional dyspnoea 9t F 55 1/80 1/25 None Dry coughing Homogeneous 10 F 55 - - None None 11 F 40 - 1/400 None None Homogeneous 12tt F 41 1/80 - None 'Asthma' 13 F 63 - - None Exertional dyspnoea 14 F 43 - 1/100 Kidney stone, Dry coughing Homogeneous cutaneous vasculitis 15 F 51 1/25 - Sun sensitivity, Dry coughing Raynaud's 16 F 56 1/25 1/25 HTh, NEAr, None Speckled Raynaud's 17t F 46 - 1/100 Raynaud's Dry coughing Homogeneous 18 F 38 - 1/3200 Kidney stone, Dry coughing Homogeneous non-Hodgkin's lymphoma, leucopenia, neuropathy 19 M 63 - - NEAr, Raynaud's None 20 F 60 - - Raynaud's Exertional dyspnoea 21 F 50 1/160 1/25 None None Speckled 'RF=rheumatoid factor; ANA=antinuclear antibody; BC=biliary cirrhosis; NEAr=non-erosive arthritis; HTh=hypothyroidism; Wmgl=Waldenstr6m's macroglobulinaemia. tSmokers; ttex-smoker. *-indicates a titre <1/25.

646 nebuliser was used. After an initial test with METHACHOLINE CHALLENGE TEST RESULTS

saline the patients were tested with double Twenty patients underwent the methacholine http://ard.bmj.com/ dilutions of methacholine, at three minute inhalation challenge test. One patient (case No intervals, starting with 1-2 mg/ml up to a 12) had an FEV1 lower than 1-0 1/min before maximum dose of 20 mg/ml. The subject methacholine inhalation and was therefore not inhaled for two minutes actuating the nebuliser challenged with methacholine. The bronchial during each inhalation. The nebuliser was response to methacholine inhalation showed weighed before and after each inhalation and that 12/20 (60%) of the patients fulfilled the

the consumed dose calculated. The inhalation criteria for BHR. One patient had severe BHR, on September 25, 2021 by guest. Protected copyright. was discontinued when there was a fall in the five moderate, four mild, and two patients had FEV1 of 20% or more below the lowest post- slight BHR (table 2). In the reference group saline value. The test result was expressed as the only two subjects had mild BHR (their PD20 provocation dose which caused a fall in FEVy values were 3-2 mg and 3-4 mg). of 20% (PD20). The degree of BHR was divided into categories based on the PD20 value: severe (<0-125 mg methacholine), moderate (0-125- CLINICAL SYMPTOMS AND BRONCHIAL 1-2), mild (1-3-5-0), and slight (5-1-9-0). HYPERRESPONSIVENESS Twenty one healthy subjects (19 women, two Dry non-productive coughing and foreign body men; aged 29-63 years; mean age 48 years) sensation in the pharynx were noted in nine of served as controls. One was a smoker and three the 21 patients. No one had productive cough. were ex-smokers. Exertional dyspnoea was seen in six of the 21 patients; in two of these patients asthma had been diagnosed. They suffered from inter- Results mittent wheezing, chest tightness, and breath- The onset of the Sjogren's disease occurred two lessness. Two patients had a history of pleuritis to 21 years (mean 9-5) before respiratory and five patients had frequent respiratory evaluation. Seven of 21 patients (33%) had only infections. Only four patients had smoked glandular symptoms, whereas extraglandular (table 1). Clinical examination showed that two symptoms as well were evident in 14 patients patients had bilateral basal rales and four (67%) (table 1). Fifteen patients (71%) had patients had prolonged expiration, one of whom positive rheumatoid factor or antinuclear had forced expiratory, low pitched rhonchi. antibody titres, or both (table 1). Only three Seven patients had no extraglandular patients were anti-SSA and anti-SSB positive, symptoms; two of these (29%) had evidence of however (case nos 14, 15, and 18). slight to mild BHR. One patient (case No 12) 38 Gudbjomsson, Hedenstr6m, Stdlenheim, Haillgren

Table 2 Resul ofpulmonayfinction and methacholine chalknge tests in 21 patients with Table 4 Respiratory fiuction findings and results of primy Sjogren's syndrome bronchial hyperresponsiven (BHR) due to methacholine inhalation tests in 21 patients with primary Sjogren's Ann Rheum Dis: first published as 10.1136/ard.50.1.36 on 1 January 1991. Downloaded from Case VC* (1) FEV,* (1) FEVI/VC TLcO* Medtacholine syndrome No (% predicted) (% predicted) (% predicted) PD20* (mg) 1 4-1 (91) 3-4 (90) 82-9 78-9 4-4 BHR (mglml Spiroety finding* 2 2-2 (64) 1-9 (72) 86-4 63-3 0-62 methcholine) 3 4-5 (117) 3-8 (130) 84-4 71-5 1-8 Normal DILD OLD SAD 4 2-4 (102) 1-7 (89) 70-8 87-4 0-08 5 3-5 (98) 2-4 (89) 68-6 81-7 3-2 Normal (>9 0) 3 4 1 0 6 3-3 (135) 2-2 (108) 66-7 71-7 0-14 Slight (5-1-9-0) 0 1 1 0 7 3-6 (104) 2-6 (99) 72-2 73-4 0-36 Mild (1-3-5 0) 1 1 0 2 8 3 5 (96) 2-1 (77) 60-0 779 1-8 Moderate (0-125-1-2) 1 0 1 3 9 3-7 (99) 2-7 (94) 730 704 6-6 Severe (<0-125) 0 0 0 1 10 2-9 (80) 2-4 (85) 82-8 71P4 >12 Not done 0 0 1 0 11 2-6 (72) 2-2 (73) 84-6 82-8 >9 12 2-3 (56) 07 (21) 304 51-8 Not done *DILD=diffuse interstitial lung disease; OLD=obstructive lung 13 4-1 (107) 3-1 (111) 756 100.1 >11-6 disease; SAD=small airways disease. 14 3-2 (78) 2-7 (84) 84-4 76-7 0-76 15 3-6 (96) 2-7 (92) 750 111.0 >935 16 3.9 (97) 2-4 (81) 61-5 80-7 04 17 2-8 (84) 1-9 (67) 67-9 Not done 7 0 18 3-9 (83) 3-0 (84) 76-9 67-2 >9-3 Group II: Obstructive lung disease shown by 19 6-5 (149) 4-7 (137) 72-3 128-9 12-1 diminished 20 3-4 (100) 2-6 (99) 76-5 51-1 >11 1 FEV, and sGaw (specific Gaw) with 21 3-6 (97) 3-0 (102) 83-3 74-0 >9.5 normal VC and TLC. This group included four patients *VC=vital capacity; FEVI=forced expiratory volume in one second; TLco=transfer factor of the (19%). lung for CO; PD20=provocation dose which caused a fall in FEV1 of 20%. Group III: Small airways disease shown by diminished Ve25 and with normal sGaw, FEVy, FVC, TLC, and TLCO. This group included six without extraglandular symptoms was not patients (29%). tested because of a low postsaline FEV, value Group IV: Patients with clinical respiratory (FEV,<1 1/min). Fourteen patients had symptoms of varying intensity with normal extraglandular symptoms and 10 (71%) of these chest radiograph and normal spirometric lung had BHR (table 3). function. Two patients (10%) were in this Ten of the 12 patients with BHR had group. subjective symptoms: dry non-productive Ten of the 12 patients with BHR (83%) had cough, wheezing, or intermittent breathless- pathological spirometric findings (table 4). Two ness. Two patients who had no subjective of the six patients with spirometrically diffuse respiratory symptoms had mild and moderate interstitial lung disease had evidence of BHR. BHR. Two patients had mild respiratory Four patients had obstructive lung disease and symptoms; one a non-productive cough and the two of three patients challenged with metha- other a mild exertional dyspnoea. Both choline inhalation had slight or moderate BHR. displayed normal spirometry and methacholine All patients with spirometrically 'small airways

inhalation tests. Two other patients with mild disease' had BHR. http://ard.bmj.com/ xerotracheitis and exertional dyspnoea respect- ively, had spirometrically interstitial lung disease without BHR (tables 1 and 2). BRONCHIAL HYPERRESPONSIVENESS AND LUNG RADIOGRAPHIC FINDINGS Five (24%) patients had abnormal radiological BRONCHIAL HYPERRESPONSIVENESS AND LUNG findings. Three patients had minimal diffuse FUNCTION interstitial densities in the lungs; two of these on September 25, 2021 by guest. Protected copyright. The pulmonary functional evaluation showed patients had moderate BHR. One patient had that 16 of the 21 patients (76%) had abnormal bilateral nodulary intensities in the lungs. This spirometric findings (table 2). Based on these patient was not challenged with methacholine findings the patients were subgrouped into four because of a low postsaline FEV, (case No 12). groups: One patient had isolated bullae in the right lung Group I: Diffuse interstitial lung disease and no BHR. No patient had pleural thickenings shown by impaired TLCO and without evidence or effusion. of central or peripheral obstruction. This group included six patients (29%). Discussion Bronchial hyperresponsiveness is defined as an Table 3 Twenty one patients with primay Sjogn's syndrome divided into ttw groups: exaggerated bronchoconstrictive response in patet wih glandula and extragkadular symptoms and their response to the methacholine smooth muscles with airway narrowing to a challenge test* small quantity of a non-allergic stimulus that Brmchial rs No (%) of patient No (%) of patients Total does not provoke such a reaction in normal to eith Only with extraglandular subjects.'3 This airway narrowing may manifest PD2Ot (mg) gadua spms ptoms itself as episodes of coughing, dyspnoea, and Normal (>9-0) 4 (57) 4 (29) 8 (38) after to stimuli such as cold Slight (5-1-9-0) 1 (14) 1 (7) 2 (10) wheezing exposure MAid (1-3.-5-0) 1 (14) 3 (21) 4 (19) air, smoke, exercise, and pharmacological Modeate (0 125-1-2) 0 5 (36) 5 (24) agents such as histamine and methacholine. Severe (<0 125) 0 1 (7) 1 (5) Not done 1 (14) 0 1 (5) These symptoms can mimic xerotracheal (FEVI <1.0 I/min) symptoms in patients with primary Sjogren's Total 7 14 21 syndrome. *The Hhlinechallenge test was not aried out in one patient (No 12) who had a low postaline Our of consecutive with FEVy of lss than 1-0 I/min. study patients tFor abbreviations see table 2. primary Sjogren's syndrome showed that 12/20 Bronchial hypearesponsveness inprimary Sjogren's syndrome 39

(60%) had BHR of varying severity and that the may be present in patients with primary

BHR correlated strongly with their subjective Sjogren's syndrome, who may have an in- Ann Rheum Dis: first published as 10.1136/ard.50.1.36 on 1 January 1991. Downloaded from symptoms. In a control population of similar flammatory cell infiltration of the glands in the age and sex only 10% had mild BHR. All tracheal and bronchial mucosal membrane. patients, except two, with a chronic dry cough Additionally, increased cell counts in broncho- and exertional dyspnoea had severe, moderate, alveolar lavage fluid are seen in 50%/o of patients or mild BHR when challenged with metha- with primary Sjogren's syndrome.22 choline. The two patients with mild so-called Our observations on BHR in primary xerotracheitis and exertional dyspnoea and Sjogren's syndrome seem to have some practical without BHR were spirometricaily abnormal clinical implications. The strong correlation with an impaired diffusion capacity. Only two between BHR and symptoms of xerotracheitis patients with evidence of BHR were without sicca suggests that either BHR is secondary to any subjective respiratory symptoms. dryness ofthe bronchial mucus or, alternatively, In clinical studies the severity of BHR due to that symptoms due to BHR contribute to or histamine or methacholine correlates strongly mimic tracheitis sicca. Studies are in progress to with the intensity of asthma or with the determine whether or not pharmacological bronchial obstructive symptoms'4 and remains bronchodilators or inhaled stable over long periods in asthmatics in the reduce the troublesome symptoms of tracheitis absence of exacerbating factors.'5 The BHR sicca. Furthermore, the observation that all also correlates with the amount of treatment patients with small airways' disease but not all required to control the symptoms of the of the patients with spirometrically obstructive obstructive lung disease.'6 Asthma may exist lung function have BHR may reflect the fact without BHR, however,'7 and vice versa, BHR that it is the small airways that are affected and may exist in patients without bronchial hyperresponsive to external stimuli. Thus asthma-for example, in those with chronic repeated methacholine testing with progressive bronchitis or upper respiratory tract infections; increases in BHR may be a better indicator than patients with atopy or without asthma spirometry of patients at risk for developing may also have a mild or slight BHR.'620 None progressive small airways' disease. Finally, the ofour patients had an active respiratory infection high incidence of impaired gas diffusion in at the time of evaluation and none had a history primary Sjogren's syndrome might to some of atopy or allergy. Thus it is interest- extent be influenced by an obstruction of the ing that all the patients with spirometrically airways. Airway obstruction may induce an small airways' disease had BHR, while one of uneven distribution of alveolar ventilation,28 three tested patients with spirometrically which in turn may contribute to reduced TLCO obstructive lung function had no evidence of values. BHR. In conclusion, we have shown that BHR is Several studies have shown that the respiratory the major respiratory disease in patients with system is affected in primary Sjogren's syn- primary Sjogren's syndrome. The respiratory http://ard.bmj.com/ drome.l 4 21-24 In secondary Sjogren's syn- evaluation of these patients with symptoms of drome lung disease is often dominated by the chronic coughing and breathlessness should associated .4 25 There- therefore include not only spirometry and chest fore, we studied only patients with primary radiographs but also a methacholine or hista- Sjogren's syndrome, thus avoiding confusion mine challenge test. Furthermore, the presence with respiratory manifestations of concomitant of primary Sjogren's syndrome should be autoimmune disorders. Our study showed that considered in patients complaining of a chronic on September 25, 2021 by guest. Protected copyright. 19/21 (91%) of patients with primary Sjogren's cough and obstructive lung symptoms and, in syndrome, with or without extraglandular particular, when the lung radiograph is symptoms, had respiratory system disease, in abnormal and pulmonary physiological findings which the major abnormality was a variable are not fully compatible with the findings in BHR response to methacholine in 12/20 (60%), bronchial asthma. followed by diffuse interstitial lung disease in 6/21 (29%) and small airways' disease in 6/21 We thank Eva Persson and Sonia Nordstr6m for their excellent technical assistance. This work was supported by grants from the (29%) and, finally, obstructive ventilatory Sitra Brunns Fund, the Swedish Medical Research Council, and function in 4/21 (19%). Previous studies have the Swedish National Heart and Lung Fund. also reported that diffuse interstitial lung disease and small airways' disease are commonly 1 Moutsopoulos H M, Chused T M, Mann D L, et al. seen in patients with primary Sjogren's syn- Sjogren's syndrome (sicca syndrome): current issues. Ann drome.2 Others have described obstructive Intern Med 1980; 92: 212-26. 2 Oxholm P, Bundgrd A, Birk Madsen E, Manthorpe R, ventilatory defects as the major abnormality.5 6 VejI6 Rasmunssen F. Pulmonary fuction in patients with The mechanism behind BHR in patients with primary SjOgren's syndrome. Rhewmatol Int 1982; 2: 179-81. primary Sjogren's syndrome is not known but 3 Constantopoulos S H, Drosos A A, Maddison P J, Mout- may be related to bronchial or tracheal in- sopoulos H M. Xerotrachea and interstitial lung disease in primary Sren's syndrome. Respaiton 1984; 46: 3104. flammation. Bronchial hyperreactivity in other 4 Constantopoulos S H, Moutsopoulos H M. Respiratory conditions has been explained as an activation of involvement in patients with Si6gren's syndrome: Is it a problem? ScandI Rheumatol [SupJ 1986: 61: 146-50. various cell types in the airways: mast cells, 5 Newbali H H, Brahim S A. Chronic obstructive airway alveolar macrophages, eosinophils, and neutro- disease in patients with Sj6gren's syndrome. AmRevRespir Dis 1977; 115: 295-304. phils. The release of inflammatory mediators 6 Sega I, Fink G, Machtey I, Gura V, Spitzer S A. Pulmonary may alter the function of nerves or the response function abnormalities in Sjogren's syndrome and the sicca compkx. Thox 1981; 36: 286-9. of smooth muscle cells to reflex bronchial 7 van Biisterveldvan O P. Diagnostic test in the sicca syndrome. constriction.26 27 Such postulated mechanisms Arch Ophthamol 1969; 82: 10-14. 40 Gudbjornsson, Hedenstrom, Stdknheim, HdUgren

8 Heintze U, Birkhed D, Bj6rn H. Secretion rate and buffer Mechanisms of bronchial hyperreactivity in normal affect of resting and stimulated whole saliva as a function of subjects after upper respiratory tract infection. Am Rev age and sex. Swed DentJ 1983; 7: 227-38. RespirDis 1976; 113: 131-9. Ann Rheum Dis: first published as 10.1136/ard.50.1.36 on 1 January 1991. Downloaded from 9 Chisholm b M, Mason D K. Labial salivary glands biopsy in 19 Mapp C E, Di Giacomo G R, Omini C, Broseghini C, Fabbri Si6gren's disease. J Clin Pathol 1968; 21: 656-62. L M. Late, but not early, asthmatic reactions induced by 10 Hedenstr6m H, Malmberg P, Agarwal K. Reference values toluene-diiocyanate are associated with increased airway for lung function tests in females. Regression equations responsiveness to methacholine. Eurj Respir Dis 1986; 69: with smoking variable. BuU Eur Physiopathol Respir 1985; 276-84. 21: 551-7. 20 Richardson J B. Airways smooth muscle. J Allergy Clin 11 Hedenstrom H, Malmberg P, Fredriksson H. Reference Imnuwl 1987; 80: 409-11. values for pulmonary function tests in men. Regression 21 Constantopoulos S H, Papadimitrious C S, Moutsopoulos equations which include tobacco smoking variable. Ups H M. Respiratory manifestations in primary Sjogren's J Med Sci 1986; 91: 299-310. syndrome. A clinical, functional and histologic study. 12 Hargreave F E, Ryan G, Thomson N C, O'Byrne P M, Chest 1985; 88: 226-9. Latimer K, Juniper E F. Bronchial responsiveness to 22 Harton P-Y, Wallaert B, Gosset D, et al. Subclinical lung histamine or methacholine in asthma: measurement and inflammation in primary Sjogren's syndrome. Arthritis clinical significance. EurJ RespirDis 1982; 63 (suppl 121): Rheun 1987; 30: 1226-31. 79-88. 23 Anderson L C, Talal N. The spectrum of benign to malignant 13 Curry J J. Comparative action ofacetyl-betamethacholine and lymphoproliferation in Siogren's syndrome. Clin Exp histamine on respiratory tract in normals, patients with Immunol 1972; 10: 199-221. hayfever and subjects with bronchial asthma. J Clin Invest 24 Ziza J M, Kaplan G, Salomon C, Kahn M F. Fibroses 1947; 26: 430-8. pulmonaries graves revelatrices d'un syndrome de Gougerot 14 Cockroft D W, Killian D N, Mellon J J A, Hargeave F E. Sjogren primitif. Ann MedInterne (Paris) 1986; 137: 46-50. Bronchial reactivity to inhaled histamin: a method and 25 Andonopoulos A P, Constantopoulos S H, Drosos A A, clinical survey. Clin AlLergy 1977; 7: 23543. Moutsopoulos H M. Pulmonary function of non-smoking 15 Juniper E F, Frith P A, Hargreave F E. Long-term stability patients with rheumatoid arthritis in presence and absence of bronchial responsiveness to histamine. Thorax 1982; 37: of secondary Sjogren's syndrome, a controlled study. 288-91. Respiration 1988; 52: 251-8. 16 Juniper E F, Frith P A, Hargreave F E. Airway responsive- 26 Chung K F. Role of inflammation in the hyperreactivity of ness to histamine and methacholine: relationship to the airways in asthma. Thorax 1986; 41: 657-62. minimum treatment to control symptoms of asthma. 27 Barnes P J. Asthma as an axon reflex. Lancet 1986; i: 242-5. Thorax 1981; 36: 575-9. 28 Dal Negro R, Turco P, Pomari C, Zaccatelli 0, Serra R. 17 Giffon E, Orehek J, Vervloet D, Arnaud A, Charpin J. Bronchial hyperreactivity to fog challenge checked by a Asthma without airway hyperresponsiveness to carbachol. multiple parametrical method in FEV, non-responders Eur J Respir Dis 1987; 70: 229-33. atopic workers. Wien Med Wochenschr 1985; 135 (suppl 92): 18 Empey D W, Laitinen L A, Jacobs L, Gold W M, Nadel J A. 20-1. http://ard.bmj.com/ on September 25, 2021 by guest. Protected copyright.