Function Studies in Diagnostics and Follow-up of Pulmonary

By INGELA BRÅDVIK

Lund 1994 From the Department of Lung Medicine and the Department of Clinical Physiology University of Lund, Sweden

Lung Function Studies in Diagnostics and Follow-up of Pulmonary Sarcoidosis

Ingela Brådvik

Lund 1994 Organization Document name LUND UNIVERSITY DOCTORAL DISSERTATION Department of Lung Medicine Date of issue University Hospital 94 06 09 S-22I 85 Lund CODEN: ISRN LUMEDW/MELL- - 1007- - SE

Authorfj) Sponsoring organization Ingela Brådvik The Swedish Heart Lung Foundation

Title and subtitle Lung function studies in diagnostics and follow-up of pulmonary sarcoidosis

Abstract

In 66 patients the relationship between and lung mechanics in pulmonary sarcoidosis was investigated Lung volumes, static lung mechanics, lung resistance, dynamic lung mechanics and arterial blood gases at rest and during exercise were obtained. Fifteen functionally compromised patients received steroids during one year. They were re-investigated during the treatment and at a follow-up after an average of 7 years.

In another 41 patients with newly diagnosed sarcoidosis, the kinetics of the lung clearance of ^9mTc-DTPA measured over 180 minutes was explored, and compared to kinetics in healthy smokers. The relationship between lung clearance and lung volumes, lung mechanics, arterial blood gases and disease activity assessed with serum angiotensin-converting enzyme and "'Ga scintigraphy was studied.

Reduced lung volumes and compliance, increased resistance and decreased arterial oxygen tension were common. Vital i capacity (VC), and changes of VC at follow-up, corresponded to the slope of the static elastic pressure/volume curve, . and to the variation of it. Other static lung volumes reflected rather the position of the curve along the volume axis Reduced VC also reflected obstruction. Forced expiratory volume in one second revealed to equal extent lung stiffness | and obstruction. Lung mechanics showed abnormalities not always evident from .

In 50% of the patients lung cleaiance of ^m Tc-DTPA disclosed an abnonnally fast mono-exponential clearance or a bi-exponential clearance, which however differed from that in smokers. Lung clearance more readily detected abnormal function than did spirometry. Clearance did not correlate with other investigations 67Ga lung activity was higher in patients with a pathologic lung clearance. J'å il Key words , radionuclide imaging, respiratory function tests, sarcoidosis, , steroid therapy, technetium-99m pentetate Classification system and/or index terms (if any)

Supplementary bibliographical information Unguage English

ISSN and key title ISBN

Recipient's notes Number of pages 1()() Price

Security classification

Distribution by (name and address) Ingela Brådvik, Department of Lung Medicine, University Hospital, S-22185 LUND, Sweden I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all reference sources permission to publish and disseminate the abstract of the above-mentioned dissertation. 940408 Signature Date This thesis is based on the following publications, referred to in the text by their Roman numerals.

I Brådvik I, Wollmer P, Simonsson B, Albrechtsson U, Lyttkens K, Jonson B Lung mechanics and their relationship to lung volumes in pulmonary sarcoidosis Eui Respir J 1989; 2:643-51

II Brådvik I, Wollmer P, Blom-Biilow B, Albrechtsson U, Jonson B Lung mechanics and gas exchange during exercise in pulmonary' sarcoidosis. Chest 1991; 99:572-78

III Brådvik I, Wollmer P, Blom-Bulow B, Albrechtsson U, Jonson B. Lung mechanics and gas exchange in steroid treated pulmonary sarcoidosis. A seven year follow-up Sarcoidosis 1991,8:105-14

IV Brådvik I, Wollmer P, Evander E, Lårusdöttir H, Blom-Bulow B, Jonson B Different kinetics of lung clearance of 99mTc-DTPA in patients with sarcoidosis and smokers. Submitted for publication.

V Brådvik 1, Wollmer P, Evander E, Sloth M, Lårusdöttir H, Blom-Bulow B, Jonson B Lung function and disease activity in sarcoidosis assessed with lung clearance of 99mTc-DTPA, lung mechanics, arterial blood gases, serum angiotensin-converting enzyme and 67Ga scintigraphy. Manuscript. CONTENTS

Introduction

Aims of the Thesis II

Material and Methods 12

Results 17

Discussion 21

Acknowledgements 26

References 27

Summary in Swedish 34

Appendix: Papers I-V

Errata INTRODUCTION

According to The 1991 Descriptive Definition of Sarcoidosis the diagnosis is established when clinico-radiological findings are supported by histological evidence of non-caseating epitheloid cell granulomas (1). The epitheloid cell is a differential form of the alveolar macrophage, which is derived from the mononuclear phagocyte lineage (2). In the the granulomas have a predilection for peribronchial, subpleural and interlobular septa and perivascular connective tissue, but may also be seen in the submucosa of bronchial walls and the adventitia of blood vessels (3). Other histopathologic features are a diffuse inflammatory cell reaction, especially in active disease, and as the disease advances eventually fibrosis (4,5,6).

The multisystemic nature of sarcoidosis became evident when radiography was introduced and disclosed lesions in bone and lungs (7). Intrathoracic involvement has been demonstrated radiographically in about 90 percent of the patients (8). Sarcoidosis is more frequent in some parts of the world, e.g. Scandinavia. The incidence in a Swedish region was reported to be 19/100.000 (9). The prevalence is age-dependent with the highest figures between 18 and 35 years (10). A recent survey of pulmonary sarcoidosis in the Nordic countries showed that about half of the patients have bilateral hilar adenopathy at the time of diagnosis (11). The prognosis is generally regarded to be good, especiaiiy if the onset is acute with fever, erythema nodosum and/or arthritis, i.e. Lofgren's syndrome. Among these patients the radiographic restitution after two years was close to 90 percent (11). In patients with radiographic lung infiltrations without signs of lymphadenopathy normalization occured after five years in about 30 percent (11). The lung involvement may be clinically silent, but 40-60 percent of the patients suffer from cough and/or dyspnoea (12). The latter symptom may occasionally be due to sarcoid cardiac disease. Electrocardiographic abnormalities ' e been described as fairly common in a Swedish series of patients with sarcoidosis (13). Apart from selective involvement of the conducting system, the cardiac disease rray present as a more general involvement of the myo- or pericardium (14). Microangiopathy has recently been brought to light in sarcoid heart pathology (14). Sarcoidosis-related cardiopulmonary complications are the main cause of the threefold increased mortality rate in Nordic sarcoid patients with radiologic pulmonary involvement, compared with the expected death rate in the general population (15).

Lymph node biopsies or the Kveim reaction were previously commonly employed to support the diagnosis. In the latter test a suspension of sarcoid tissue material is in/ected intracutaneously in the patient. A papule develops after 4-6 weeks when the test is positive. On microscopic study the papule reveals epitheloid cell granulomas. The Kveim test is often negative in later stages of sarcoidosis. Transbronchial lung biopsy discloses non-caseating epitheloid cell granulomas in a high percentage of patients (5,16).

Pathogenesis. Studies of different components of (BAL) fluid have increased our knowledge of immunopathologic mechanisms in sarcoidosis, but the cause of the disease is still unknown (4 ) Infectious agents such as mycobacteria, mycoplasma, chlamydia and virus have been suggested as triggers (4,17), but none has been confirmed. Genetic factors are of importance However, human leukocyte antigen (HLA) markers show a variable pattern in the disease (4,18,19) The occurrence of non-familial clusters in the absence of an apparent infectious etiology has led to the suspicion of other environmental factors as causative agents (20). The question why non-smoking is associated with sarcoidosis is unsettled (21). The non- caseating epitheloid cell granulomas are thought to be preceded by a lymphocytic alveolitis (2,22,23) In active disease there is an accumulation and activation particularly of T-helper cells in the lungs (23) The crucial role of macrophages in T-cell activation, granuloma formation and fibrosis has recently been stressed (24). Signs of T-cell activation are elevation of the fraction of interleukin-2 receptor (IL-2R) positive cells and the occurrence of IL-2R in a soluble form in BAL fluid and in serum (22). In BAL fluid there is elevation of other immune mediators promoting further increase and activation of T-lymphocytes, as well as mediators leading to aggregation and activation of macrophages and granuloma formation. Examples are IL-1, IL-2, y interferon, a tumor necrosis factor and monocyte chemotactic factor (2,22) The macrcphages are thought to act as antigen-presenting cells, and secrete different products, e.g. calcitriol and angiotensin-converting enzyme (ACE) (23) Constitutional symptoms associated with sarcoidosis may be mediated by e.g. IL-1 (23). Other types of inflammatory cells such as mast cells may be activated. Increased amounts of histamin in BAL fluid have been found (25). The increased permeability of the alveolo-capillary membrane in sarcoidosis has been postulated to be due partly to mast cell activity (23). The ultimate fibrotic process seen with advancing stage of sarcoidosis is not only regarded as a healing process, but is immediately linked to the immune response (23) Indicators of the fibrotic process, e.g. hyaluronate and type III procollagen peptide, may be found in lavage fluid ( 26).

Assessment of disease activity. A number of biochemical markers have been recognized as potentially useful indicators of disease activity (27) The initial enthusiasm for repeated BAL studies in clinical pract:ce for analysis of different cell populations and immunologic markers nas faded (23). T!v. power of BAL to predict radiographic findings and lung function is poor, although a high BAL lymphocyte count and a high T-helper/T-suppressor (CD4+/CD8+) ratio certainly reflect an intense alveolitis at the time of investigation (28). In active sarcoidosis serum ACE may be elevated in 75 to 90 percent of patients (29). In patients with acute sarcoidosis and erythema nodosum serum ACE is usually normal (30), probably because the granulomatous mass is too small to produce a detectable excess of the enzyme. Serum ACE is elevated particularly in extrathoracic disease and frequently increased in sarcoid patients with hypercalcemia (27) Draw-backs are the elevation of the enzyme in disorders other than sarcoidosis (27) and that the prognostic value of also serum ACE is limited (31). Measurement of local ACE by relating BAL ACE to serum and lavage albumin may provide better information about lung engagement (31) Normalization of ACE levels with steroid therapy may in part be an effect of steroids on ACE independent of the steroid effect on disease activity (32). Obvious reasons in favour of the frequent use of longitudinal ACE determinations are that the method is simple, inexpensive and probably not less efficacious than other methods in monitoring relapse of disease activity (33).

Gallium scintigraphy has been available for about two decades. As gallium is accumulated in macrophages and epitheloid cells the method is used in sarcoidosis in the evaluation of the extent and the activity of the granulomas (34). Gallium uptake has been reported in hilar lymph nodes in 90 percent of patients and in lung parenchyma in 60 percent (35), but figures may vary depending on the state of the disease (34). Distinctive distribution patterns of gallium, namely to lacrimal and salivary glands and intrathoracic lymph nodes in a symmetrical fashion, may help in the diagnosis when the chest radiograph is normal (36). The enthusiasm for this method has also been moderated somewhat since no clearcut relation to lung function or final outcome has been proven (37,38). A positive gallium scan does not necessarily indicate a poor prognosis (38), but negative scan findings do suggest that the patient will not show progress of the disease after two years (32).

Radiography. A relationship between the chest radiographic stage and prognosis has already been mentioned. Lymphadenopathy as the only radiologic abnormality thus indicates a favourable prognosis. Parenchymal changes are associated with a greater likelihood of persistent disease. Most classification systems of chest radiographs in sarcoidosis are based on subdivisions according to the sequential fashion of radiographic appearance. They have proven simple and reproducible (39). In some systems parenchymal changes are emphasized more than node involvement (39). In the classification commonly used in Sweden stage 0 implies normal findings, stage I hilar and/or paratracheal lymphoma, stage II parenchymal infiltrations irrespective of lymph node enlargement and stage III signs of shrinkage indicating fibrosis (40). Increasing stage thus corresponds to decreasing likelihood of spontaneous disease remission (39). However, it is well known that even patients with adenopathy as the only radiographic abnormality may have granulomas in transbronchial lung biopsies (16), and that radiologic staging does not give detailed information about the degree of reversible inflammation and irreversible fibrosis (39) Also the relation between radiographic severity and changes in lung function is rather weak, especially in the individual (41) This also holds true for computed tomography (CT) Modifications of the International Labour Office classification scheme, with analysis of profusion scores in different lung zones weighted for the relative volume of the zone, or on individual CT sections, may improve the information gained by radiology, but are hardly applicable in clinical routine (41). Even high-resolution CT may be better in evaluating respone to therapy than in predicting lung function results (42,43). Further studies are needed to confirm this.

Lung function tests. Various methods of directly estimating disease activity are thus often not appropriate in prognosticating the future outcome Lung function evaluation, in sarcoidosis first performed more than 50 years ago in Sweden (44), has remained one of the corner-stones in monitoring pulmonary involvement and in making decision about treatment. The first lung function study revealed reduced VC and TLC (44). Subsequent investigations confirmed this finding and also showed other aberrations including decreased lung compliance, small and large airway disease, reduced and abnormal gas exchange (45,46) Patients with pulmonary sarcoidosis not seldom display , especially at exercise (47). The occurrence of airway obstruction even in non-smoking sarcoid patients is well established (48,49) and may be due to endobronchial lesions, peribronchial granulomas, enlarged lymph nodes compressing the airway lumen, fibrotic scarring and non-allergic hyperresponsiveness (50). Dyspnoea is often associated with physiologic signs of airway obstruction, though the correlation between symptoms and results of function tests is variable (49). Among histopathologic features Carrington found an interstitiell cell index to show the best correlation with arterial oxygen pressure during exercise and a composite index of overall functional impairment (51) In a more recent study a high quotient between the BAL coefficient of excretion of IgG and IgA relative to albumin values was associated with both a poor for carbon monoxide and a low PaC>2 during maximal exercise. This suggests that a reduction of the difrusion capacity is related to cellular interstitial infiltration (52). Part of the functional changes cannot be easily correlated with histopathology, as pointed out by Carrington (51). The ready accessibility and convenience of some rather non-specific physiologic methods certainly explain why, e.g., spirometry and determination of the diffusion capacity for carbon monoxide are the predominating tests (45), both in clinical practice and for study purposes, and why investigations based on lung mechanics and arterial blood gases at maximal exercise are sparse It has previously not been possible to establish accurately the relationship between lung mechanics and lung volumes, nor the role of lung mechanics and arterial blood gases, in clinical long-term follow-up studies of sarcoidosis. It is well recognized, however, that lung volumes and the diffusion capacity can be altered independently of each other (53). Changes in usually parallel compliance changes (54,55). Measurement of gas exchange during exercise is advocated as probably being the most sensitive test to detect changes in interstitial lung disease (56). The sensitivity of gas exchange studies has been attributed in part to alterations in small airways and blood vessels causing functional defects which will become increasingly manifest with the demands of exercise (56).

In the search for new methods that might help in assessing disease activity and outcome, attention has lately been drawn to the lung clearance of inhaled technetium-99m labelled diethylene triamine pentaacetate (99mTc-DTPA). The method implies measurement of the transfer rate of small, water soluble molecules from the air space to the blood. The permeability of the alveolar capillary membrane to inhaled 99mTc-DTPA is increased in a variety of lung disorders such as acute lung injury and different chronic interstitial diseases (57). Smoking also increases the clearance rate of 99mTc-DTPA. After cessation of smoking, reversal is rapid (57). The occurrence of biphasic clearance in smoking has recently been demonstrated (58). There may be different pathogenetic mechanisms behind abnormal clearance. Lung inflammation, hyperinflation and surfactant abnormalities have been regarded as possible explanations (59) In sarcoidosis about 60 percent of patients have shown increased clearance rates (60). In the individual the clearance rate increases with deteriorating lung function as assessed by lung volumes and diffusing capacity for carbon monoxide, and decreases with therapy. Sarcoid patients with stable lung function are thought to have a normal clearance rate (61). Potentially subtle changes not always necessitating treatment may be detected by the method (57).

As already discussed some easily performed physiologic tests are those usually applied in order to assess the function deficit in sarcoidosis and to monitor lung function during therapy. The debate continues about which method provides the most useful clinical information (45,56).

Treatment. The question of when, and for how long, to intervene pharmacologically is not settled (62). Early effects of peroral steroids, e.g. improvement of the vital capacity within ten days of treatment, is well known (63), but to date no controlled long-term follow-up study has been designed in a way allowing definite conclusions about a possible beneficial effect of steroids on mortality (62). Naturally a positive response to treatment can be anticipated predominantly in patients with active disease. The principle of using peroral steroids in pulmonary sarcoidosis only if activity is paired with functional derangement has received increasing support (33,62). Even in patients with extensive fibrosis medication should be considered, as the patients may have coexisting alveolitis (64) The question whether smoking sarcoid patients, apart from 10 refraining from smoking, should be treated more intensely than non-smokers does not seem to have been addressed, though there are indications of synergistic effects of smoking and sarcoidosis. Very high values of serum ACE and gallium uptake have been reported in some sarcoid smokers (65) Small airway disease probably occurs earlier in smoking patients with sarcoidosis than in non-smokers (66) Increased total lung capacity, residual volume and functional residual capacity are reported in smoking sarcoid patients compared with non- smoking patients (66), while in another study a more pronounced reduction of total lung capacity was found in sarcoid smokers compared to non-smokers (48). Others found that the combination of sarcoidosis and smoking was associated with a greater maximal transpulmonary pressure than in sarcoidosis alone, and that the static pressure/volume curve was shifted towards higher pressures and lower volumes (67)

The effect of corticosteroids in sarcoidosis may be explained by a direct effect on macrophages or an indirect effect on T-helper lymphocytes (68). Corticosteroids decrease the T-helper/T- suppressor ratio and local immunoglobuline production, suppress release of eg IL-2 and activity of IL-2 gene and inhibit chemotaxis of predominantly monocytes and neutrophils (24,69). Topical steroids have lately been advocated in sarcoidosis. Lung tissue concentrations of inhaled budesonide are high enough to give a receptor binding (70). When first introduced for therapy in sarcoidosis, budesonide was recommended to be administered in combination with oral steroids for a couple of months prior to maintenance therapy with only inhaled budesonide (70). Inhaled drug used in the early management of patients has been shown to alter BAL alveolar macrophage subpopulations and function, and to keep patients in remission during an 18 month period of follow-up (24). It is unknown whether early treatment with inhaled steroids in patients otherwise not considered for immediate therapy may prevent deterioration and need of high doses of peroral steroids later on. Perhaps topical steroid treatment should be started only in subgroups of patients. In case of severe side effects from steroids, or lack of a positive effect despite evidence of disease activity, chloroquine or methotrexate may be used (64). Azathioprine and chlorambucil could also be tried (71). Cyclosporine seems not to be effective in pulmonary sarcoidosis. In a recent study it neither suppressed T-cell alveolitis or lymphokine release in vivo, nor did the drug improve lung function (72). A few sarcoid patients may be candidates for (64). 11

AIMS OF THE THESIS

To describe the elastic and resistive properties of the sarcoid lung and to show how the mechanical properties are reflected in lung volumes.

To evaluate lung mechanics and arterial blood gases during exercise in pulmonary sarcoidosis

To analyze lung function in steroid-treated patients with pulmonary sarcoidosis with special attention to the late outcome and to find the physiological parameters most useful in follow-up.

To describe the kinetics of lung clearance of 99mTc-DTPA in sarcoidosis and to compare the findings with clearance kinetics in healthy smokers.

To evaluate the relationship in sarcoidosis between the kinetics of lung clearance of 99mTc- DTPA and the results of other methods assessing lung function and disease activity. 12

MATERIAL AND METHODS

Study Mil Sixty-six patients with radiological signs of pulmonary sarcoidosis and a positive tissue biopsy supporting the diagnosis were included in the examination of lung function at rest in study I. They were consecutive patients referred to the Department of Lung Medicine between September 1974 and December 1981 willing to perform lung function evaluation with a comprehensive set of function tests. All but three of the patients in study I also comprise the population in study II, in which lung function was investigated during exercise. Twenty-nine of the patients showed significant lung function impairment and were prescribed peroral steroids according to a special scheme. The objective was to taper off the steroids during an one year peroid with the guidance of the function tests. Fourteen patients did not fulfill this program because of medication problems or unwillingness to repeat the elaborate function tests. The remaining 15 subjects receiving treatment were included in study HI, which describes the evolution of lung function during the treatment year and at a final follow-up after an average of 7 years. These 15 patients had more pronounced function defects at the beginning of the treatment than the 14 drop-outs. The mean age of the patients at inclusion in study I was 43 years (range 20-71). There were 36 men and 30 women. Forty-one had never smoked, 14 were ex-smokers and 11 were current smokers. Twenty-three patients had no cough or dyspnoea, while the rest showed mild to moderate respiratory symptoms Disease duration was estimated to be less than two years in half of the patients. The mean age of the patients in study III was 38 years (range 22-56). In the latter study disease duration exceeded two years in six patients and five years in three.

Steroid treatment. The treatment scheme in study III was the same as the clinical routine of treatment of sarcoidosis at our department at the time of the study. It began with 30 mg prednisolone once daily for two-three months, followed by 10-20 mg during the next three months. The dose was decreased further during the following 6 months, and treatment was stopped after 12 months provided that lung function remained stable.

Chest radiography. At the time of each physiologic examination standard chest radiographs in anteroposterior and lateral projections were obtained and later re-viewed. A radiographic classification emphasizing parenchymal changes was chosen: stage 0 = normal findings, stage I = lymph node enlargement without parenchymal abnormalities, stage II = interstitial parenchymal changes irrespective of enlarged lymph nodes, stage III = indications of fibrosis apart from other changes (40). According to thir classification 27 patients had stage II disease and 38 stage III with mostly slight to moderate changes. One patient's radiograph at entry into studies I-II was lost Study III comprised 5 stage II patients and 10 patients with stage III radiographs.

Lung function tests. Dynamic lung volumes, i.e. forced expiratory volume in one second (FEVj) and FEVj/VC% were obtained with Bernstein spirometry or advanced electronic equipment. Static lung volumes, i.e. total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV) and vital capacity (VC) were determined with body plethysmography.

Lung mechanics was studied with an interrupted constant flow method (73). The pulmonary static pressure/volume (P/V) curve was determined with body plethysmography and oesophageal pressure The flow was limited to 1 1/s during a long expiration, and the airways were closed at intervals. An oesophageal balloon was used for measurements of transpulmonary pressures, which were recorded at different lung volumes. The static elastic

P/V curve was constructed, and static compliance (CstjJ determined over the pressure interval of 5-15 cm H2O. The static pressure at maximal inspiration (PstLTLc)> by others sometimes denoted as the maximal inspiratory pressure, was noted. The oesophageal balloon was used also for determination of pulmonary resistance (R^), which was measured at an expiratory flow rate of 1 1/s, and at a recoil pressure of 7.5 cm fyO. Dynamic lung mechanics was studied at rest and at each increased work load during a step-wise bicycle exercise test, which was continued until exhaustion. Flow was recorded with a pneumotachograph and transpulmonary pressure with the oesophageal balloon during spontaneous . Ventilation, (Vj) and breathing frequency were calculated from the flow signals by a computer. Dynamic compliance (C^y,^) was assessed as the quotient between Vj and the difference between the end-expiratory to end-inspiratory pressures. The functional lung resistance (RflJ was calculated by relating the resistive work of breathing, obtained by measuring the energy transfer, to ventilation (74). Arterial blood gases were sampled at rest with the patient in the supine and the sitting positions and during work after four minutes at each work load. To take the work load into account in judging PaC«2 at exercise, in study III the degree of was related to the work rate achieved expressed as a fraction of the working capacity (WC) predicted. The hypoxia during exercise was thus expressed as an index (EHI):

EHI = (12.7 - PaO2) x WC predicted/actual work rate. (eq.)

(12.7-PaO2) represents the degree of observed hypoxia referring to the normal value of 14

12.7 kPa in the sitting position (75), and is thus related to the intensity of work ECG was recorded during the exercise test, and a vectorcardiogram (VCG) was obtained at the final investigation in study III

Predicted normal values. Most results are expressed as percent of predicted values obtained from materials of healthy subjects (75-82). Values outside the 95% confidence interval for normal subjects have been regarded as abnormal.

Statistics. Data are mostly presented as mean ± SD. For statistical analysis we used Student's t-test for paired and unpaired comparisons and the chi-square test for comparisons of discrete variables DifTi. i snces with a probability level of p>0.05 were considered nonsignificant

StudyIV-V In study IV 41 never-smoking sarcoid patients with radiologic evidence of intrathoracic disease were studied. All but two of the patients had a positive Kveim test or other tissue biopsy lending support to the diagnosis. The patients were mainly consecutive patients referred to the Department of Lung Medicine because of newly diagnosed disease. In the study lung function was evaluated with spirometry and measurement of the lung clearance of 99mTc-DTPA. The findings of these investigations were compared to lung function results obtained from 16 healthy current smokers and 14 healthy never-smokers. Study V further describes the lung function in the 41 sarcoid patients, and the relationship between lung function and disease activity in these patients assessed with also lung mechanics, arterial blood gases, serum angiotensin-converting enzyme and 67Ga scintigraphy. The mean age of the patients was 44 years (range 22-75). Eighteen patients were men and 23 were women. All but one were Caucasians At the time of the physiologic investigation 20 patients suffered from respiratory symptoms of mild to moderate degree. Another 12 patients complained of some other symptom, mainly arthritis Disease duration was in 31 patients judged to be two years or less None of the patients was receiving steroid treatment. Two patients had earlier been treated with 5-10 mg of prednisolone. The smokers in study I had a mean age of 40 years, and the healthy never-smokers a mean age of 33 years

Chest radiography. The same classification system as in study I-III was used. Standard chest radiographs obtained at the time of the physiologic evaluation were later re-viewed. One patient with a normal chest radiograph was included in the group of eleven patients with stage I findings Seventeen 15 patients showed stage II radiographs and 12 patients stage III. In the stage II group 8 had minor, 2 moderate and 7 extensive parenchymal shadows Of stage III patients 3 had moderate and 8 extensive infiltrations In half of the stage III patients the degree of shrinkage was minor, and in the other half moderate.

Lung function tests. In all patients spirometry was performed. In study V static lung volumes, static lung mechanics and measurement of R[, dynamic lung mechanics and arterial blood gases at rest and during exercise were measured in the same way as in the previous studies The complete set of function tests was mainly obtained in patients with stage II-III disease.

In all patients, and the healthy subjects in study IV, the lung clearance of 99mTc-DTPA was measured. The method has been described earlier (58) An aerosol of 99mTc-DTPA was generated from a commercially available kit and nebulized with an air jet The subjects inhaled the aerosol by quiet tidal breathing for 1 to 2 minutes while seated in front of a gamma camera until a count rate of 2000 counts/s had been reached. The subjects were then immediately placed in the supine position on a thin couch with the camera beneath. Radioactivity over the chest was measured for 180 minutes. After 175 minutes, a small amount of 99mTc-DTP A was injected intravenously to enable correction for background radioactivity. Correction was also made for the physical decay of 99mTc. A region of interest was selected over both lungs, and a time-activity curve was generated. Correction for non-pulmonary 99mTc-DTPA was performed according to the principles of Jones et al (83) and Barrowcliffe et al. (84). Each corrected time-activity curve was analyzed by fitting a mono-exponential (eq. 1) as well as a bi-exponential (eq 2) equation to the experimental data.

A(t)=A(0)e->-t (eq. 1)

A(t)=AF(0)e-i-^+As(0)eV-t (eq. 2)

A(t) is the radioactivity in the lungs at any time, t, A(0) the radioactivity in the lung at time zero and X the decay constant. In the bi-exponential analysis, Ap(0) and A$(0) represent the

amount of radioactivity eliminated with the fast (?iF) ar.d slow (X§) clearance component. Clearance was expressed as the half-life (t'/2=ln2/>.) for the single clearance component in the mono-exponential and for the fast (t'/2p) and slow (f/25) clearance components in the bi- exponential analysis. The relative amount of the tracer cleared by the fast clearance component

(fp) was calculated as Ap(0)/(AF(0)+As(0)). The F-test was used for detecting differences between the mono- and bi-exponential fits 16

Apan from calculating the half-life of 99mTc-DTPA from the measurements over 180 minutes, the half-life of 99mTc-DTPA was also calculated from measurements over the first 30 minutes after peak lung activity

Assessment of disease activity. In study V 67Ga scintigraphy was performed about 10 days after the lung function tests, and 48 hours after an intravenous injection of 175-200 MBq of 67Ga-citrate Radioactivity was measured by a gamma camera linked to a computer system Anterior and posterior views of the head, neck, chest and upper abdomen were obtained The scans were re-viewed by an observer anaware of the clinical information and chest radiographs The gallium uptake in the lungs, and in the including hilar glands, was evaluated visually Activity higher than in the soft tissues above the apex of the lung was regarded as abnormal The lung fields were divided into a left and a right upper and lower region The mediastinum was divided into a left and a right region. For each region, the activity was scored from 0 to 3 (85) 67Ga scans were obtained in 12 stage I patients, 12 stage II patients and 8 patients with stage III radiographs.

Serum angiotensin-converting enzyme (SACE) was in all patients analyzed as a part of the clinical routine at the time of the physiologic examination The assay for ACE is based on a shift of the absorption spectrum that occurs when ACE hydrolyses a synthetic substrate (87).

Predicted normal values. As in previous studies, most results are expressed as percent of predicted values obtained from healthy subjects (58,75-82), and values outside the 95 percent confidence interval for healthy subjects were regarded as abnormal. TVi values for 99mTc-DTPA are presented in minutes.

Statistics. Most data are given as mean±SD. Differences between groups were investigated with Student's t-test, or for discrete variables the Kruskal-Wallis test. The chi-square test was used for comparison of positive lung 67Ga activity scores and lung clearance of 99mTc-DTPA Linear regression analysis was performed with Spearman's rank correlation test Differences with a probability level of p>0.05 were considered nonsignificant 17

RESULTS

Study MM The dominating aberration in lung mechanics was reduced compliance, but nearly 40% of the patients showed increased lung resistance. The static elastic recoil pressure at maximal inspiration was on average normal, but the range was wide. In 20 subjects without signs of was emphysema, PstLTLC abnormally low, which is not expected in a disease with stiff lungs. This finding was seen predominantly in older people and in those with short duration of disease. Lung volumes except RV were reduced. Smokers had lower TLC, RV and FRC than never-smokers. Lung volumes at higher values of PstL tended to be more reduced in stage III than stage II disease in spite of on average equal CstL and spirometric findings This observation was combined with a flat upper part of the PstL/V curve. Compared to TLC, RV and FRC, VC was more closely correlated to compliance, that represents the slope of the P/V curve. TLC, RV and FRC, on the other hand, reflected the position of the P/V curve rather than its slope. Lower values of these volumes were associated with a curve displaced towards lower volumes and higher PslL FEVj reflected lung-parenchyma stiffness and airway obstruction to about the same extent. High resistance was associated with reduced VC

Mechanical variables during maximal exercise were as sensitive indices of lung malfunction as measurements of the static lung pressure/volume curve and of RL Of 28 patients with abnormally low C^L at maximal work load only 10 had an abnormally low CdynL at rest. Twenty-one patients had abnormally high R^ at work, but RJL at rest was abnormally high in not more than 10 of these subjects. Accordingly dynamic mechanics studied during spontaneous breathing at rest had a low sensitivity. Blood gas changes were frequent PaO2 was often reduced both at rest and during exercise. At rest in the sitting position about one third of the patients had a reduced PaO2. In 8 of these, and in another 12 patients, PaO2 fell during exercise In the others PaO2 increased at work. Although reduced PaO2 at rest and/or during exercise was a common finding, the blood gas aberrations seldom deviated from predicted normal values to the same extent as mechanical parameters. In the individual patient exercise PaO2 could not be predicted from PaO2 at rest. Other physiologic variables were also poor predictors of exercise PaO2 Of the lung volumes, FEVj showed the strongest correlation to PaO2 at exercise. C^ynL at maximal exercise also correlated reasonably well to PaO2 at exercise.

Patients complaining of respiratory symptoms in everyday life had on average more pronounced function defects than asymptomatic individuals, i.e. lower WC, CstL, C^L at rest,

VC and FEV], higher resistance and lower PaO2 at rest Lung mechanics could reveal abnormalities, e.g. reduced compliance and increased resistance, not evident from lung volume measurements, especially in patients with symptoms. However, the working capacity could not be accurately predicted from any single parameter, although ventilation was the major limiting factor during exercise. Among lung volumes VC and FEVi showed the strongest correlation to WC. Both compliance and resistance showed a significant relation to WC. No significant ECG changes were noted apart from an abnormal VCG in three patients at the final follow-up. The VCG in two of the patients indicated right ventricular hypertrophy and in the third patient left ventricular hypertrophy.

Treatment did not lead to significant relief of symptoms. Early improvement after the institution of steroids was indicated instead by a decrease in interstitial radiologic changes, and above all by physiologic parameters likely to reflect parenchymal disease, i.e. gas exchange, compliance and VC A significant improvement of the exercise hypoxia index and of dynamic compliance at rest and during maximal exercise was already seen at the first re-investigation after three months of treatment This positive development in puimonary physiology continued throughout short- and long-term follow-up in most of the treated patients. However, at the final investigation several patients had still a function deficit, which was not correlated to the radiographic stage. After the first re-examination the chest radiographs remained almost unchanged No patient showed major functional or radiological deterioration. VC reflected the development of compliance better than did TLC. At inclusion into study III TLC did not correlate significantly to CstL, but the correlation coefficient increased throughout the study. In spite of improved compliance at follow-up, when measured over the pressure interval of 5-15 cm H2O, the upper part of the static elastic P/V curve had become flatter. The increase in VC during follow-up certainly reflects an overall improvement, but also that the patients then generated a higher PstL through a more vigorous inspiration. Parameters reflecting increased resistance, i.e. FEVj/VC%, RL and RJL at maximal exercise showed an on average modest aberration before treatment. Resistance did not appreciably change in the entire study group or in the individual over the study period. In the individual other variables deviating from the predicted normal range at the first physiologic evaluation also tended to remain abnormal at follow-up, despite the modest improvement. In keeping with these findings patients with a normal value of a parameter at follow-up almost always showed only a moderate function deficit at the first investigation.

Study IV-V Lung volumes were on average normal in the healthy subjects and in the sarcoid patients belonging to stage I. There were no significant differences in lung volumes between the radiologic stages, though both in stage II and stage III TLC, VC and FEV| were on average reduced. In all patients investigated with lung mechanics, on average reduced CS1L and C a at at maximal work, and higher than normal PsuvrLC' ^L "d RfL maximal exercise were found Arterial blood gases showed reduced PaO2 both at rest and at maximal exercise. The were reater changes in CdvnL at maximal work and PstLTLC g ••"• stage HI than stage II disease. rove t0 In the present study population, PS1LTLC P d be the parameter, which most frequently was was abnormal. PS1LTLC increased in all stage III patients, and nearly half of the stage II group. In 15 patients lung mechanics disclosed lung malfunction not revealed by lung volumes One patient showed as the only function deficit reduced PaC>2 at maximal exercise

Lung clearance of "mTc-DTPA showed in the healthy smokers a better curve fit with a bi- exponential equation In the healthy never-smokers the bi-exponential curve fit was not better than the mono-exponential one. In 22 of the patients the clearance course was mono- exponential, but with an on average shorter Wi than in healthy subjects. Four patients had an abnormally fast mono-exponential clearance A few stage I patients, and more than half of the patients with radiologic parenchymal changes, had the best curve fit by use of a bi-exponential equation. The fraction of the tracer cleared by the fast component was smaller in sarcoidosis than in smokers, but the rate of clearance by this fraction did not differ between the patients and the smokers. On the other hand, the rate of clearance by the slow component was significantly higher in sarcoidosis, and equal to the mono-exponential clearance rate in healthy non-smoking subjects. Two stage III patients had the individual highest clearance rate among individuals with a mono-exponential clearance course, and the fastest iVi^ of the patients with a bi-exponential clearance, respectively. Patients regarded to have either an abnormally fast mono-exponential clearance of the tracer when calculated from measurements over 180 minutes, or a bi-exponential clearance curve, had on average shorter V/2T,i)mm.

Lung clearance findings did not correlate significantly with other lung function parameters. Spirometry was normal in 17 of the 23 patients with a pathologic lung clearance. Sometimes abnormalities in other function tests were seen though the lung clearance was normal In five patients with normal clearance more than three other function parameters were pathologic showed a weak, significant negative correlation to SACE

SACE was on average just slightly elevated, and without significant differences between the patients when divided into different radiologic stages or according to normal or pathologic lung clearance measured over 180 minutes. In 18 patients SACE was increased above the upper normal limit. SACE did not correlate with 67Ga scores or lung function parameters other l 67 than weakly negative with VC and, as mentioned, with t /23()mjn. A positive Ga scintigraphy was a frequent finding. The lung activity score was significantly higher in stage III than stage I patients, and in those with pathologic lung clearance compared with patients showing a normal clearance course Lung sc ores did nor correlate to lung function variables apart from RL. 20

Of the 32 patients who had a 67Ga scan, 26 were symptomatic. SACE was abnormal in only 13 of the 32 patients and lung clearance of 9&mTc-DTPA abnormal in 16 of ihem. SACE was normal in all but one of the patients with a negative 67Ga scan. A distinct, positive lung 67Ga activity score above 1 was more often found in patients with a pathologic lung clearance than in those with a normal clearance. All 32 patients had either symptoms and/or signs of disease activity as assessed with 67Ga scintigraphy, SACE and lung clearance of 99mTc-DTPA. 21

DISCUSSION

Study Mil In our studies lung mechanics provides information about both compliance, reflecting the elastic properties of lung tissue and the number of functioning alveoli, and bronchial resistive properties. Recording the complete pressure/volume curve enables estimation of the pathophysiologic significance of reduced lung volumes. In our sarcoid patients reduced lung volumes, decreased compliance and increased resistance were all frequent findings. In study I and III VC, and changes of VC at follow-up, were shown to correspond mainly to the slope of the P/V curve and to the variation of the slope during the study period. To a higher degree TLC, RV and FRC reflected the position of the curve along the volume axis. The increase of RL in a number of patients in study I could not be anticipated from spirometric data, although there was a correlation between RL and VC, FEVj and FEVi/VC%.

In clinical work the information gained in study I and III can be used for an improved interpretation of spirometry results. In sarcoidosis a high elastic recoil pressure relative to lung volume is the main reason behind low values of TLC. Particularly early in the disease when inflammation is active, TLC was also reduced because the patients did not inspire as forcefully as expected. This is illustrated by low values of PstLTLC. The mechanism is thought to be inhibition of inspiration by reflexes from stretch or irritation receptors (87). Patients with muscle granulomas may also have decreased inspiratory muscle strength (88). The reduced TLC is reflected in a reduction of VC. However, VC reflects to a greater extent compliance rather than the value of PstL. During follow-up of patients, e.g. when treatment is given, in most subjects changes in VC follows changes in compliance. However, there are two other factors determining VC. The more vigorous distension of the lungs at later stages of the disease might lead to overestimation of the improvement of lung compliance. In extreme cases the improvement of VC can be fully explained by a more forceful inspiration. This probably reflects training of inspiratory muscles and attenuation of reflexes hindering a forceful inspiration. Airway obstruction is ai.other factor of some importance for VC, as increased resistance may result in airway closure. FEVi and FEVj/VC% did not adequately reveal airway obstruction. The reason is certainly that the high elastic recoil hampers dynamic compression during expiration, as has previously been explored (89).

Study II was focused on pathophysiologic findings during exercise. In about half of the 63 patients PaC>2 was reduced during rest and/or exercise. There were two different blood gas

reactions during exercise. Several patients showed a fall in PaO2 at work while in others PaC«2 increased. Changes in arterial blood gases in sarcoidosis could be due to diffusion limitation as well as to ventilation/ inhomogeneity (90). A fall in Pa(>2 during exercise can be 22

explained by reduced time for diffusion of oxygen into single blood cells An increase of PaO2 during exercise is often seen in patients with airway obstruction, who improve their ventilation/perfusion matching at work In study III we introduced an exercise hypoxia index, representing the degree of hypoxia at exercise in relation to the achieved work rate expressed as a fraction of the predicted working capacity. It was thus constructed to permit consideration of the exercise level when comparing PaO2 during exercise on different occasions. Like others

(91) we found no single parameter to be a good predictor of exercise PaO2, nor could exercise

PaO2 predict working capacity

In the foilow-up of steroid-treated patients in study III the earliest physiological improvement was noted in PaO2 during exercise and in dynamic compliance VC followed the positive course of compliance changes The degree of improvement of TLC was less than that of VC. The correlation between TLC and compliance, which was non-significant at the inclusion to study III, also improved during follow-up The relationship between VC and CS1L pointed out in study I is in keeping with other reports (54). In SDite of the positive trend throughout the follow-up, the final examination revealed that there was still a function deficit in most parameters, eg in lur.g volumes, lung mechanics, gas exchange at work and working capacity The lung function at entry into the study indicated the future prognosis As a rule, in the individual a variable with a normal value at follow-up deviated only slightly at the first investigation, while a more severe initial malfunction seldom became quite normalized. Parameters other than physiological ones, such as chest radiography and above all symptoms, proved less useful in predicting the long-term result. The usefulness of function evaluation in predicting vital prognosis has recently been stressed (92) A low FEVj in sarcoidosis is thus associated with increased mortality (92) The constantly elevated RL throughout our study III, and the increase of transpulmonary pressure at maximal inspiration at follow-up, may be indicators of persistent granulomas and /or fibrosis after suppression of the active inflammation The possibility of a poorer prognosis in smoking sarcoid patients, due to synergism between the damage caused by sarcoidosis and by smoking, has only lately been pointed out (48,66,67), and is consistent with the lower TLC, RV and FRC in sarcoid smokers in study I compared to the never-smoking patients in the same study

Corticosteroids are still ihe therapeutical mainstay in sarcoidosis, albeit up to now none of the few controlled treatment studies have shown long-term benefit of the therapy (62). Viskum et al. have even proposed an association between a poor prognosis and steroid treatment (92) Their study was retrospective, and their results may simply reflect that patients with overall more severe disease were prescribed steroids. In study II we tried to suppress inflammatory activity in patients with lung function deficit with the intention of preventing further development of irreversible fibrosis. No other study has evaluated both the Psti7V curve and lung resistance, as well as exercise arterial blood gases during follow-up. Like many other studies, ours was not designed to provide definite conclusions about the efficacy of therapy Even though our treatment group comprised the patients with the most pronounced lung malfunction referred to us during seven years, many improved during the follow-up An investigation another 8 years after the final physiological examination has revealed progressive sarcoid pulmonary disease in only three patients, all reluctant to receive therapy One patient had died from liver cirrhosis Accordingly, we treated patients with the most severe disease judged from lung function tests The immediate response was positive. The outcome after several years was largely favourable. The data show that steroid treatment modified the disease process and probably contributed to a favourable prognosis. The study supports the strategy of treating patients under the guidance of physiological tests.

Reduced VC was noted in th^ first physiologic study of sarcoidosis more than 50 years ago (44). Spirometry remains the most frequent test in the evaluation of lung function, but offers limited information about the pathophysiology. In our study I static lung mechanics and RL revealed a greater number of abnormal values than the lung volumes, especially in symptomatic individuals. The same study showed that the complete P/V curve added further information. The groups of stage II and III patients thus had almost equal static compliance, but tended to differ in lung volumes at higher PstL. Our method could thus serve as a sensitive test to detect functional aberrations not otherwise obvious. However, study III showed the commonly used way of investigating lung mechanics, i.e. dynamic mechanics at rest, to be less sensitive than our method. In contrast, in the same study dynamic lung mechanics at maximal exercise, previously not reported in sarcoidosis, was as sensitive as the technically more difficult tests at rest in study I. The exercise test was combined with measurement of arterial blood gases. Analysis of the diffusing capacity for carbon monoxide was not performed, as the method was not available in our hospital at the time of our studies. Moreover, the diffusing capacity for carbon monoxide at rest has been shown to be an insensitive predictor of abnormal gas exchange during exercise (93,94). Indeed, some sarcoid patients with a normal diffusing capacity may during exercise develop hypoxia, in spite of a statistical correlation between the diffusion capacity and the difference between PaO2 at rest and during maximal exercise (52). The still limited availability of our complete set of lung function tests, and its relative expense, may be argued as disadvantages. Some drop-out in study III was due to the patient's reluctance to repeat the comprehensive set of function tests. In spite of these draw-backs, we advocate especially our set of physiological tests during exercise in patients with pulmonary sarcoidosis when referred for their first lung function evaluation. The results of the tests provide a firm basis for the patient's future management and prognosis Our findings do, 24 however, support spirometry as being a reasonably accurate and simple method in the follow- up of the sarcoid patient

Study IV-V Lung mechanics and arterial blood gases were confirmed to be more sensitive means of revealing lung function deficit than lung volumes alone In some contrast to study I, in study V the static elastic recoil pressure at maximal inspiration was frequently increased However, in was w e A n sta e tnan the former study, the range of PS1LTLC '^ higher PS1LTLC ' S M in stage II disease is also in keeping with our earlier investigation

Abnormal lung clearance of 99mTc-DTPA was evident in more than half of the patients. Figures in previous series have varied, 'vith increased clearance rate in 25 to nearly 60 percent of patients Our measurements over 180 minutes enabled disclosure of a bi-exponential clearance course in many of our patients. In sarcoidosis a bi-exponential clearance of 99mTc- DTPA has not before been demonstrated Moreover, we found differences in the kinetics of the bi-exponential clearance in sarcoidosis compared with healthy smokers. This suggests at least partly different mechanisms behind pathologic clearance in sarcoidosis and smoking. In smokers surfactant dysfunction has been proposed to alter lung clearance (95). In sarcoidosis changes in phospholipids in BAL fluid may be found (96), indicating surfactant abnormalities. Another proposed cause of abnormal lung clearance in sarcoidosis is increase of the permeability of the respiratory epithelium, due to inflammation (61,97). The tendency in our study towards a relationship between SACE and the lung clearance rate, verified by others, speaks in favour of the latter hypothesis. Although in study V 67Ga lung activity was on average higher in patients with an abnormal lung clearance of 99mTc-DTPA than in patients with a normal clearance, there was no significant correlation between 67Ga scores and the results of 99mTc-DTPA clearance, or other lung function parameters than R^ This might imply lung clearance of 99mTc-DTPA and 67Ga scintigraphy to be influenced by mainly independent mechanisms (60) The lack of correlation between lung clearance of 99mTc-DTPA and other lung function variables is in keeping with another report (98), but in contrast to the findings of Dusser et al. who showed a relationship between the clearance rate and FEVj, PaC>2 at rest, the alveolar-arterial PO2 difference and the diffusion capacity for carbon monoxide (99). Possible explanations for the different results may be heterogeneity in study populations, and differences in the methods employed Indeed, in other studies the clearance measurements were calculated over a considerably shorter time-peroid after the peak activity had been reached. E.g. Dusser et al determined the regression line of the counts during the first 10 minutes after peak lung activity We found lung clearance of 99mTc-DTPA frequently pathologic in the presence of a normal spirometry result Thus lung clearance more readily than spirometry indicates abnormal lung function in sarcoidosis Similar findings have been reported in allergic alveolitis (100). On the other hand, in a few patients a number of other function variables could reveal function defects in patients with a normal lung clearance

The high percentage of positive 67Ga scans are in agreement with earlier reports (34). Though not a uniform finding, also others were unable to demonstrate any significant correlation between intrathoracic 67Ga activity and SACE (101). Absence of, or only weak significant correlations between 67Ga activity scores and lung function parameters, is a general experience (102). The relative lack of a relationship is not surprising, as lung function is prone to be deranged not merely by active inflammation, but by other structural and functional changes (102). With the methods used in study V, measurement of only SACE does obviously not exclude current disease activity. Adding 67Ga scintigraphy appreciably augments the number of patients regarded to have active disease. Including also lung clearance of 99mTc-DTPA may further increase the sensitivity of assessment of disease activity

Lung clearance of 99mTc-DTPA has, at least with our method, a fairly wide normal range, which naturally is a draw-back in validating the relevance of individual results Though on a group basis the kinetics of lung clearance of 99mTc-DTPA in sarcoidosis differed from clearance findings in smokers, again in the individual even our method does not accurately separate abnormal lung clearance caused uy sarcoidosis and smoking. Measurements over 180 minutes may be argued to be less feasible in clinical routine. Despite these disadvantages, our studies give encouragement to continued use of lung clearance of 99mTc-DTPA as a complement to other lung function tests and activity parameters in sarcoidosis. There is a need of further establishment of which way of performing the clearance measurements is the most appropriate 26

ACKNOWLEDGEMENTS

My sincere gratitude to my tutors and the staff at the Department of Lung Medicine and the Department of Clinical Physiology for assistance and encouragement throughout the study. I also wish to thank the Swedish Heart Lung Foundation for support, and the Swedish Medical Research Council (grant No 2872). 27

REFERENCES

1 Yamamoto M, Sharma OP, Hosoda Y. The 1991 descriptive definition of sarcoidosis. Sarcoidosis Suppl 1; 1992; 9:33-34

2 Saitini C, Crystal RG Pulmonary sarcoidosis: pathogenesis, staging and therapy Int Archs Allergy Appl Immunol 1985; 76 Suppl 1:92-100

3 Cole SR, Johnson KJ, Ward PA. Pathology of sarcoidosis, granulomatous and other idiopathic granulomatous diseases of the lung. In: Fanburg BL, ed. Sarcoidosis and other granulomatous diseases of the lung. New York: Marcel Dekker, 1983; 149-202

4. Van Gundy K, Sharma OP. Pathogenesis of sarcoidosis West J Med 1987; 147:168-74

5 Poletti V, Patelli M, Spiga L, Ferracini R, Manetto V. Transbronchial lung biopsy in pulmonary sarcoidosis. Is it an evaluable method in detection of disease activity? Chest 1986; 89:361-65

6 Rosen Y, Athanassiades TJ, Moon S, Lyons HA Nongranulomatous interstitial pneumonitis in sarcoidosis. Chest 1978, 74:122-25

7. James DG. The battlefield called sarcoidosis. West J Med 1987; 147:193-94

8 Katz S. Clinical presentation and natural history of sarcoidosis. In: Fanburg BL, ed. Sarcoidosis and other granulomatous diseases of the lung New York: Marcel Dekker, 1983,3-36

9 Hillerdal G, Nöu E, Österman K, Schmekel B. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis 1984; 130:29-32

10 Forsen KO, Milman N, Pietinalho A, Selroos O. Sarcoidosis in the Nordic Countries 1950-1987. Sarcoidosis 1992; 9:142-44

11 Milman N, Selroos O. Pulmonary sarcoidosis in the Nordic Countries 1950-1982. II. Course and prognosis. Sarcoidosis 1990, 7:113-18

12 Johns CJ. Sarcoidosis. Ann Rev Med 1989; 40:353-71

13. Thunell M, Bjerle P, Stjernberg N. ECG abnormalities in patients with sarcoidosis. ActaMedScand 1983; 213:115-18

14 Fleming HA Symposium on cardiac sarcoidosis: introduction Sarcoidosis Suppl 1; 1992; 9:227-29

15 James DG. Epidemiology of sarcoidosis. Sarcoidosis 1992; 9:79-87

16 Koerner SK, Sakowitz AJ, Appelman RI, Becker NH, Schoenbaum SW. Transbronchial lung biopsy for the diagnosis of sarcoidosis N Engl J Med 1975; 293:268-70 28

17 Grönhagen-Riska C, Saikku P, Riska H, Froseth B, Grayston JT Antibodies to TWAR-a novel type of chlamydia-in sarcoidosis. In: Grassi C, Rizzato G, Pozzi E, eds Sarcoidosis and other granulomatous disorders. Amsterdam: Elsevier Science Publishers, 1988; 297-300

18 Pasturenzi L, Martinetti M, Cuccia M, Cipriani A, Semenzato G, Luisetti M, the Pavia- Padova Sarcoidosis Study Group. HLA I, II, and HI polymorphism in Italian patients with sarcoidosis. Chest 1993; 104:1170-75

19. Nowack D, Goebel KM. Genetic aspects of sarcoidosis. Class II histocompatibility antigens and a family study. Arch Intern Med 1987; 147:481-8.3

20. Kem DG, Neill MA, Wrenn DS, Varone JC Investigation of a unique time-spacer duster of sarcoidosis in firefighters. Am Rev Respir Dis 1993; 148:974-80

21. Douglas JG, Middleton WG, Gaddie J, Petrie GR, Choo-Kang YFJ, Prescott RJ, Crompton GK Sarcoidosis: a disorder commoner in non-smokers9 Thorax 1986, 41:787-91

22. Muller-Quernheim J, Pfeifer S, Strausz J, Ferlinz R. Correlation of clinical and immunologic parameters of the inflammatory activity of pulmonary sarcoidosis. Am Rev Respir Dis 1991; 144:1322-29

23. Thomas PD, Hunninghake GW. Current concepts of the pathogenesis of sarcoidosis. Am Rev Respir Dis 1987; 135:747-60

24. Spiteri MA. Inhaled corticosteroids in pulmonary sarcoidosis Postgrad Med J 1991; 67:327-29

25. Casale TB, Trapp S, Zehr B, Hunninghake GW. Bronchoalveolar lavage fluid histamine levels in interstitial lung diseases. Am Rev Respir Dis 1988; 138:1604-08

26. Bjermer L, Engström-Laurent A, Thunell M, Hällgren R. The mast cell and signs of pulmonary fibroblast activation in sarcoidosis. Int Archs Allergy Appl Immun 1987; 82:298-301

27. Sharma OP. Markers of sarcoidosis activity. Chest 1986; 90:471-73

28. Verstraeten A, Demedts M, Verwilghen J, van den Eeckhout A, Marién G, Lacquet LM, Ceuppens JL. Predictive value of bronchoalveolar lavage in pulmonary sarcoidosis. Chest 1990, 98:560-67

29. Liebennan J, Nosal A, Schlessner LA, Sastre-Foken A. Serum angiotensin-converting enzyme for diagnosis and therapeutic evaluation in sarcoidosis. Am Rev Respir Dis 1979; 120:329-35

30. Grönhagen-Riska C, Selroos O, Wägar G, Fyhrquist F. Angiotensin-converting enzyme II. Serum activity in early and newly diagnosed sarcoidosis Scand J Resp Dis 1979,60:94-101 29

31. Prior C, Barbee RA, Evans PM, Townsend PJ, Primett ZS, Fyhrquist F, Grönhagen- Riska C, Haslam PL Lavage versus serum measurements of lysozyme, angiotensin converting enzyme and other inflammatory markers in pulmonary sarcoidosis. Eur RespirJ 1990; 3:1146-54

32 Baughman RP, Shipley R, Eisentrout CE. Predictive value of gallium scan, angiotensin- converting enzyme level, and bronchoalveolar lavage in two-year follow-up of pulmonary sarcoidosis. Lung 1987; 165:371-77

33. Rizzato G. The management of sarcoidosis Newsletter SEP 1986, 9:5-9

34. Abe S, Munkata M, Nishimura M, Tsuneta Y, Terai T, Nakano I, Ohsaki Y, Kawakami Y. Gailium-67 scintigraphy, bronchoalveolar lavage, and pathologic changes in patients with pulmonary sarcoidosis. Chest 1984; 85:650-55

35. Heshiki A, Schatz SL, McKusick KA, Bowersox DW, Singh Soin J, Wagner HN. Gallium 67 citrate scanning in patients with pulmonary sarcoidosis Am J Roentgenol 1974; 122:744-49

36. Sulavik BS, Spencer RP, Palestro ChJ, Swyer AJ, Teirstein AS, Goldsmith SJ Specificity and sensitivity of distinctive chest radiographic and/or 67Ga images in the noninvasive diagnosis of sarcoidosis. Chest 1993; 103:403-09

37. Hollinger WM, Staton Jr GW, Fajman WA, Gilman MJ, Pine JR, Check IJ. Prediction of therapeutic response in steroid-treated pulmonary sarcoidosis. Evaluation of clinical parameters, bronchoalveolar lavage, gallium-67 scanning, and serum angiotensin- converting enzyme levels. Am Rev Respir Dis 1985, 132:65-69

38. Turner-Warwick M, McAllister W, Lawrence R, Britten A. Corticosteroid treatment in pulmonary sarcoidosis: do serial lavage lymphocyte counts, serum angiotensin converting enzyme measurements, and gallium-67 scans help management? Thorax 1986;41:903-13

39. DeRemee RA. The roentgenographic staging of sarcoidosis; historic and contemporary perspectives. Chest 1983; 83:128-33

40. Eklund A. Alveolitis in sarcoidosis. Studies on markers of diesease activity. (Doctoral thesis). Stockholm, Sweden, Karolinska Institute, 1986

41. Austin JHM. Pulmonary sarcoidosis: what are we learning from CT? Radiology 1989; 171:603-04

42. Brauner MW, Grenier P, Mompoint D, Lenoir S, de Crémoux H. Pulmonary sarcoidosis: evaluation with high-resolution CT. Radiology 1989; 172:467-71

43. Batra P. Role of high-resolution CT in the diagnosis and evaluation of pulmonary sarcoidosis. Sarcoidosis 1993; 10:95-97

44 Bruce T, Wassén E. Clinical observations on the course and prognosis of lymphogranulomatosis benigna Schaumann, particurlarly in regard to pulmonary lesions. Acta Med Scand 1940; 104:63-104 30

45. Winterbauer RH, Hutchinson JF. Use of pulmonary function tests in the management of sarcoidosis. Chest 1980; 78:640-47

46. Benjamin RG, Sackner MA. Pulmonary function in sarcoidosis. Sarcoidosis 1984, 1 50- 52

47. Gluskowski J, Hawrylkiewicz I, Zych D, Zielinski J. Effects of corticosteroid treatment on pulmonary haemodynamics in patients with sarcoidosis. Eur Respir J 1990, 3:403-07

48. Lamberto C, Saumon G, Loiseau P, Battesti JP, Georges R. Respiratory function in recent pulmonary sarcoidosis with special reference to small airways. Bull Eur Physiopathol Respir 1985; 21:309-15

49. Levinson RS, Metzger LF, Stanley NN, Kelsen SG, Altose MD, Cherniack NS, Brody JS. Airway function in sarcoidosis. Am J Med 1977; 62:51-59

50. Lewis MI, Horak DA. Airway obstruction in sarcoidosis. Chest 1987; 92:582-84

51. Carrington CB. Structure and function in sarcoidosis. Ann NY Acad Sci 1976, 278:265-83

52. Martinot J-B, Delaunois L, Rahier J, Dehennin J-P, Sibille Y. Relationship between inflammatory processes and gas exchange in pulmonary sarcoidosis Chest 1989, 96:550-56

53. Dunn TL, Watters LC, Hendrix C, Cherniack RM, Schwarz MI, King TE. Gas exchange at a given degree of volume restriction is different in sarcoidosis and idiopathic pulmonary fibrosis Am J Med 1988; 85:221-24

54. Marshall R, Karlish AJ. Lung function in sarcoidosis. Thorax 1971; 26 402-05

55. De Troyer A, Yernault JC, Dierckx P, Englert M, DeCoster A. Lung and airway mechanics in early pulmonary sarcoidosis. Bull Eur Physiopathol Respir 1978; 14:299- 310

56. Keogh BA, Crystal RG. Pulmonary function testing in interstitial pulmonary disease What does it tell us? Chest 1980; 78:856-65

57. O'Brodovich H, Coates G. Pulmonary clearance of 99mTc-DTPA a noninvasive assessment of epithelial integrity. Lung 1987; 165:1-16

58. Wollmer P, Evander E Biphasic pulmonary clearance of 99mTc-DTPA in smokers. Accepted for publication in Clin Physiol

59. Wollmer P. Transfer of 99mTc-DTPA, lung surfactant and lung injury: a review of the literature. AppI Cardiopulm Pathophys 1991, 4:155-60

60. Jacobs MP, Baughman RP, Hughes J, Fernandez-Ulloa M. Radioaerosol lung clearance in patients with active pulmonary sarcoidosis. Am Rev Respir Dis 1985; 131:687-89. 61 Chinet T, Dusser D, Labrune S, Collignon MA, Chretien J, Huchon GJ Lung function declines in patients with pulmonary sarcoidosis and increased respiratory epithelial permeability to 99mTc-DTPA Am Rev Respir Dis 1990, 141:445-49

62 DeRemee RA, Offbrd KP. The treatment of pulmonary sarcoidosis: the house revisited. Sarcoidosis Suppl 1; 1992; 9:17-29

63. Goldstein DS, Williams MH. Rate of improvement of pulmonary function in sarcoidosis during treatment with corticosteroids. Thorax 1986; 41:473-74

64. Sharma OP. Pulmonary sarcoidosis and corticosteroids. Am Rev Respir Dis 1993, 147:1598-1600

65. Valeyre D, Soler P, Clerici C, Pré J, Battesti JP, Georges R, Hance AJ Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax 1988; 43:516-24

66. Dutton RE, Renzi PM, Lopez-Majano V, Renzi GD Airway function in sarcoidosis: Smokers versus nonsmokers. 1982,43:164-73

67. Hanley ME, King TE, Schwarz MI, Watters LC, Shen AS, Cherniack RM The impact of smoking on mechanical properties of the lungs in idiopathic pulmonary fibrosis and sarcoidosis. Am Rev Respir Dis 1991; 144:1102-06

68. Baughman RP, Strohofer SA, Buchsbaum J, Lower EE. Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990; 115:36-42

69. Stern BJ, Schonfeld SA, Sewell C, Krumholz A, Scott P, Belendiuk G. The treatment of neurosarcoidosis with cyclosporine. Arch Neurol 1992; 49:1065-72

70. Selroos O. Inhaled corticosteroids and pulmonary sarcoidosis Sarcoidosis 1988; 5:104-05

71 Pacheco Y, Marecal C, Marechal F, Biot N, Perrin Fayolle M. Azathioprine treatment of chronic sarcoidosis. Sarcoidosis 1985; 2:107-13

72. Martinet Y, Pinkston P, Saltini C, Spurzem J, Miiller-Quernheim, Crystal RG. Evaluation of the in vitro and in vivo effects of cyclosporine on the lung T-lymphocyte alveolitis of active pulmonary sarcoidosis. Am Rev Respir Dis 1988; 138:1242-48

73. Jonson B. A method for determination of pulmonary elastic recoil and resistance at a regulated flow rate. Scand J Clin Lab Invest 1969, 24:115-25

74 Otis AB, McKerrow CB, Bartlett A, Mead J, Mcllroy MB, Selverstone NJ, Radfors EP. Mechanical factors in distribution of pulmonary ventilation. J Appl Physiol 1956, 8:427-43

75 Malmberg P, Hedenström H, Fridriksson HB. Reference values for gas exchange during exercise in healthy nonsmoking and smoking men. Bull Eur Physiopathol Respir 1987; 23:131-38 76. Jonson B. Pulmonary mechanics in normal men, studied with the flow regulator method. Scand J Clin Lab Invest 1970; 25:363-73

77. Knudson RJ, Clark DF, Kennedy TC, Knudson DE Effects of ageing alone on mechanical properties of the normal adult human lung. J Appl Physiol: Respirat Environ Exercise Physiol 1978; 43:1054-62

78. De Troyer A, Yernault JC. Inspiratory muscle force in normal subjects and in patients with interstitial lung disease. Thorax 1980, 35:92-100

79. Åstrand I. Aerobic work capacity in men and women with special reference to age. Acta Physiol Scand 1960; Suppl 169:1-92

80. Nordenfelt I, Adolfsson L, Nilsson JE, Olsson S. Reference values for exercise tests with continuous increase in load. Clin Physiol 1985; 5:161-72

81. Berglund E, Birath G, Bjure J, Grimby G, Kjellmer I, Sandqvist L, Söderholm B Spirometric studies in normal subjects. I. Forced expirograms in subjects between 7 and 70 years of age. Acta Med Scand 1963; 173:185-92

82. Grimby G, Söderholm B. Spirometric studies in normal subjects III Static lung volumes and maximum voluntary ventilation in adults with a note on physical fitness. Acta Med Scand 1963; 173:199-206

83 Jones JG, Minty BD, Lawler P, Hulands G, Crawley JCW, Veall N Increased alveolar epithelial permeability in cigarette smokers. Lancet 1980; 1:66-68

84. Barrowcliffe MP, Otto C, Jones JG. Pulmonary clearance of 99mTc-DTPA: influence of background activity. J Appl Physiol 1988; 64:1045-49

85. Alberts Chr, van der Schoot JB, Groen AS. 67Ga scintigraphy as an index of disease activity in pulmonary sarcoidosis Eur J Nucl Med 1981; 6:205-12

86. Holmqvist B, Bunning P, Riordan JF. A continuous spectrophotometric assay for angiotensin converting enzyme. Anal Biochem 1979; 95:540-48

87. Harris S, Jonson B. Lung function before and after . Acta Otolaryngol 1974; 78:287-94

88. Baydur A, Pandya K, Sharma OP, Kanel GC, Carlson M. , respiratory muscle strength, and granulomatous involvement of skeletal muscle in patients with sarcoidosis. Chest 1993; 103:396-402

89. Jonson B. Pulmonary mechanics in patients with pulmonary disease, studied with the flow regulator method. Scand J Clin Lab Invest 1970, 25:375-90

90 Eklund A, Broman L, Broman M, Holmgren A V/Q and alveolar gas exchange in pulmonary sarcoidosis. Eur Respir J 1989; 2:135-44 91. Keogh B A, Lakatos E, Price D, Crystal RG Importance of the lower in oxygen transfer. Exercise testing in patients with interstitial and destructive lung disease. Am Rev Respir Dis 1984; 129:Suppl S76-S8O

92. Viskum K, Vestbo J. Vital prognosis in intrathoracic sarcoidosis with special reference to pulmonary function and radiologic stage Eur Respir J 1993, 6:349-53

93 Ries AL, Farrow JT, Clausen JL. Pulmonary function tests cannot predict exercise- induced in chronic obstructive pulmonary disease Chest 1988, 3:454-59

94. Sue DY, Oren A, Hansen JE, Wasserman K Diffusing capacity for carbon monoxide as predictor of gas exchange during exercise N Engl J Med 1987; 316:1301-06

95 Schmekel B, Bos JAH, Kahn AR, Wohlfart B, Lachmann B, Wollmer P. Integrity of the alveolar-capiliary barrier and alveolar s irfactant system in smokers. Thorax 1992, 47:603-08

96 Baughman RP, Strohofer S, Dohn M. Decreased phosphatidylcholine in the lung fluid of patients with sarcoidosis. Lipids 1985, 20:496-99

97 Schmekel B, Wollmer P, Venge P, Linden M, Blom-Bulow B Transfer of DTPA and bronchoalveolar lavage findings in patients with asymptomatic extrinsic allergic alveolitis. Thorax 1990; 45:525-29

98. Thunberg S, Larsson K, Eklund A, Blascke E 99mTc-DTPA clearance measured by a dual head camera in healthy subjects and patients with sarcoidosis Eur J Nucl Med 1989; 15:71-77

99 Dusser DJ, Collignon MA, Stanislas-Leguern G, Barritault LG, Chretien J, Huchon GJ Respiratory clearance of 99mTc-DTPA and pulmonary involvement in sarcoidosis Am Rev Respir Dis I986; 134:493-97

100 Bourke SJ, Banham SW, McKillop JH, Boyd G Clearance of yi;mTc-DTPA in pigeon fancier's hypersensitivity pneumonitis Am Rev Respir Dis 1990, 142:1168-71

101 Schoenberger CI, Line BR, Keogh B A, Hunninghake GW, Crystal RG Lung inflammation in sarcoidosis: comparison of serum angiotensin-converting enzyme levels with bronchoalveolar lavage and gallium-67 scanning assessment of the T lymphocyte alveolitis. Thorax 1982; 37:19-25

102. Line BR, Hunninghake GW, Keogh BA, Jones AE, Johnston GS, Crystal RG Gallium- 67 scanning to stage alveolitis of sarcoidosis correlation with clinical studies, pulmonary function studies, and bronchoalveolar lavage. Am Rev Respir Dis 1981, 123:440-46 34

SAMMANFATTNING (Summary in Swedish)

Sarkoidos är en inflammatorisk sjukdom, som främst angriper lymfkörtlar, luftvägar och lungor. Diagnosen ställs genom sammanvägning av kliniska och laboratoriemässiga fynd Vävnadsprov visar i typiska fall epiteloidcellig granulomatos. Bakomliggande etiologi är okänd, trots att sjukdomen finns beskriven for över 100 år sedan. Vid akut sarkoidos föreligger oftast fotledsarthriter, hudförändringar i form av erythema nodosum och lungröntgenologiskt hiluslymfkörtelförstoring, dvs röntgenstadium I enligt skandinavisk klassifikationstradition. Vid kronisk sarkoidos upptäcks sjukdomen i regel pga hosta och/eller andnöd, eller av en slump hos symptomfria patienter. Lungröntgen visar vid kronisk sjukdom oftast stadium II-III, vilket innebär interstitiella lungparenchymförändringar, och vid stadium III också tecken på bindvävsbildning. Hos c:a 80 procent av patienterna med akut insjuknande har sjukdomstecknen även hos obehandlade försvunnit inom två år. Förloppet vid kronisk sarkoidos är också i regel godartat, men dödsfall förekommer pga andningssvikt, eventuellt med sekundär hjärtpåverkan, eller primärt hjärtengagemang. Lungfunktionsnedsättningen betingas av att lungvävnadens stelhet ökar, speciellt om inflammationen övergår i bindvävsbildning. Luftvägsobstruktion förorsakas av endobronkiella förändringar, distorsion och tillklämning av luftvägar utifrån, eller av icke-allergisk bronkiell hyperreaktivitet. Blodgasrubbning förekommer pga diffusionshinder eller ojämn ventilation/perfusion. Behandling med kortisontabletter ges enligt aktuell policy främst vid påverkan av olika organs funktion parad med pågående inflammatorisk sjukdomsaktivitet. Som mått på aktivitet används fn rutinmässigt mätning av angiotensin-converting enzyme i serum (SACE), som produceras i granulomen. Scintigrafiundersökning med radioaktivit märkt gallium, 67Ga, visar också, om sjukdomen är aktiv. Intravenöst injicerat 67Ga ansamlas i kroppen i inflammatoriska härdar, och radioaktiviteten lokaliseras med en gammakamera

Lungfunktionspåverkan vid sarkoidos har i mer än 50 år mätts med spirometri, som ger information om vitalkapacitet (VC) och forcerad expiratorisk volym under 1 sekund (FEVj). Spirometri är lättillgänglig även på en vanlig mottagning. Ibland har också bestämning av diffusionskapaciteten för kolmonoxid utförts som rutin. Metoden ger dock osäker upplysning om blodets syresättning. För kartläggning av totala lungkapaciteten (TLC), residualvolymen (RV) och funktionella residualkapaciteten (FRC) används ofta kroppspletysmograf. Lungmekanikundersökning utförd som i Lund ger direkt information om lungornas mekaniska, dvs elastiska och resistiva, egenskaper. Nackdelar är, att metoden inte är tillgänglig överallt, och är förhållandevis kostnadskrävande. Vid lungmekanikundersökning bestäms lungornas statiska elastiska tryck/volym (PstL/V)-kurva med hjälp av kroppspletysmografi och oesophagustryck. Flödet regleras till 1 1/s under en lång utandning, och avbryts intervallvis. En oesophagusballong används för bestämning av transpulmonellt tryck. PstL/V-kurvans registreras, och lungornas statiska tänjbarhet, compliance (Csl]J, mäts inom tryckintervallet noteras 5-15 cm H2O. Statiska elastiska återfjädringstrycket vid maximal inandning (P^yix)

Oesophagusballongen används även för mätning av lungmotstandet (RL) vid ett värde av PslL av 7.5 cm H2O Dynamisk lungmekanik studeras i vila och vid symptombegränsat arbetsprov på ergometercykel Flödet under spontanandning registreras med pneumotackograf och transpulmonellt tryck med oesophagusballong. Med hjälp av dator bestäms sedan ventilation, tidalvolym och andningsfrekvens. Dynamisk compliance (C^L) beräknas som kvoten mellan tidalvolym och tryckskillnaden mellan slutet av ut- respektive inandning Funktionellt lungmotstånd (RflJ fås genom att relatera andningmotståndet, skattat genom energiupptaget i lungorna, till ventilationen. Artärblodgasanalys utförs med patienten liggande respektive sittande i vila, och på varje arbetsbelastning under det stegvisa arbetsprovet För att ta hänsyn till aktuell arbetsbelastning vid värderingen av partialtrycket av syrgas i artärblod (PaO2) i arbete, beräknas skillnaden mellan normalt PaO2 sittande i vila och patientens PaO2 vid maximal arbetsbelastning Skillnaden i PaO2 relateras till aktuella arbetsförmågan uttryckt i procent av förväntad maximal arbetsförmåga. Den erhållna kvoten har kallats för exercise hypoxia index (EHI) EKG registreras i anslutning till arbetsprovet. Lungclearance av inhalerat technetium-99m-märkt diethylen triamin pentaacetat (99mTc- DTPA) är en relativt ny metod för lungfunktionsvärdering Den innebär, att en aerosol av små, vattenlösliga molekyler inandas Mätning av hastigheten för transporten av 99mTc-DTPA från luften i lungorna till blodet sker genom att en gammakamera registrerar radioaktiviteten över lungorna. Vanligen har registreringstiden varit 10-30 minuter. En semilogaritmisk tids- radioaktivitetskurva för aktiviteten över lungorna konstrueras, och halveringstiden för 99mTc- DTPA beräknas. Normalt är clearancefbrloppet monoexponentiellt. Ökat lungclearance av 99mTc-DTPA har tidigare visats vid förutom interstitiell lungsjukdom exempelvis även infektioner och rökning. Exakta mekanismen bakom förändrat lungclearance vid sarkoidos är okänd.

Syftet med studierna I-III var, att hos 60 konsekutiva patienter med lungsarkoidos kartlägga lungornas mekaniska egenskaper samt visa, hur dessa återspeglas i mätningar av lungvolymer. I studie I har resultat från lungvolymmätningar, statisk lungmekanik och bestämning av RL jämförts. Studie II fokuserades mot relationen mellan fynd i vila och arbete, dvs studier av dynamisk lungmekanik och artärblodgaser i vila och arbete. Studie III är en långtidsuppföljning av lungfunktionen hos de patienter, som hade sämst lungfunktion, och som därför fick kortisonbehandling under ett år Hos 41 konsekutiva patienter med nydiagnostiserad sarkoidos har i studie I V-V lungclearance av 99mTc-DTPA mätts under 180 minuter, dvs betydligt längre tid än brukligt 36

Sarkoidospatienternas lungclearance har i studie IV jämförts med clearance hos friska rökare I studie V beskrivs relationen mellan lungclearance och lungvolymer, lungmekanik och artärblodgaser i vila och arbete, samt sjukdomsaktivitet skattad med SACE och 67Ga- scintigrafi.

I studie I var såväl sänkt compliance som ökat lungmotstånd vanligt. Alla lungvolymer utom

RV var sänkta. PstL/V-kurvan hade ett flackare förlopp vid högre återfjädringstryck hos patienter med röntgenstadium III än stadium II, trots lika stor reduktion av CstL- Registrering av hela PstjyV-kurvan, och inte bara dess början, kan således tillföra ytterligare information PstLTLC var *om abnormt lågt hos vissa individer, främst hos äldre och patienter med kort sjukdomsduration. En av förklaringarna härtill kan vara inhibition av inandningen genom reflexer från sträckreceptorer, som aktiveras vid inflammation. TLC, RV och FRC var lägre hos rökare och exrökare än aldrigrökare, vilket indikerar samverkan mellan inflammatorisk vävnadsskada förorsakad av sarkoidos och rökning. Sänkt VC återspeglade i huvudsak sänkt compliance, men också bronkoobstruktion. TLC, RV och FRC relaterade mer till Psti/V- kurvans läge längs volymaxeln. FEVj återspeglade lungstelhet och luftvägsobstruktion i lika mån. Speciellt hos patienter med symptom avslöjade lungmekanik funktionsdefekter trots normala lungvolymer. Lungmekaniska variabler vid maximal fysisk ansträngning var lika känsliga mått på funktionsnedsättning som mer resurskrävande mätningar av Ps(L/V-kurvan och RL Dynamiska lungmekaniska mätningar i vila var däremot mindre sensitiva. Trots avvikande PaC»2 i vila och/eller arbete hos c:a hälften av patienterna, var blodgasrubbningen sällan markant. Ingen enskild variabel förutsade särskilt väl PaC«2 i arbete eller fysisk prestationsförmåga. FEVj visade den starkaste korrelationen till PaO2 i arbete, och bland lungmekanikparametrar CdynL vid maximalt arbete. Arbetsförmågan predikterades bäst av VC och FEV|, men även av compliance och motstånd. Under behandling och uppföljning efter terapi sågs måttlig förbättring av flertal parametrar. Subjektiva besvär förändrades dock knappt. Lungröntgen, EHI och C^L förbättrades tidigast. VC följde ökningen av compliance. TLC visade sämre korrelation till förändringar i compliance. Motståndsökningen kvarstod oförändrad, och övre delen av PstL/V-kurvan flackade av ytterligare med tiden. Fynden talar för i viss mån bestående vävnadsdestruktion trots kortisonterapi. Detta är inte förvånande med tanke på, att det var de sämsta patienterna, som behandlades. Lungclearance av 99mTc-DTPA var patologiskt hos hälften av patientens En del hade abnormt snabbt monoexponentiellt clearance. Andra hade en biexponentiell clearancekurva med en snabbare och en långsammare komponent. Alla rökare hade biexponentiellt clearance Hos sarkoidospatienterna var den långsamma komponentens hastighet högre än hos rökarna, och den snabba fraktionen av 99mTC-DTPA mindre. Detta talar för olika mekanismer bakom 37 förändringar av lungclearance vid sarkoidos och rökning. Lungclearance av 99mTc-DTPA var oftare avvikande än spirometri. Andra lungfunktions- och aktivitetsparametrar korrelerade inte till clearance. 67Ga-scintigrafi visade ofta aktivitetsökning i lymfkörtlar/lungor, och högre lungaktivitet hos patienterna med patologiskt lungclearance. Kombinationen av klinisk symptomvärdering, lungclearance, galliumscintigrafi och SACE föreföll vara känsligt mått på sjukdomsaktivitet.

Studierna pekar på lungfunktionsundersökningars centrala roll vid handläggandet av sarkoidos. Lungmekanikundersökning ger information om patofysiologi och funktionsawikelser, som inte alltid framkommer med andra metoder. Främst lungmekanik i arbete kan förordas som bas för initial funktionsvärdering och ställningstagande till behandling. För uppföljning räcker oftast spirometri. Också lungclearance av 99mTc-DTPA är mer sensitiv metod än spirometri. Även sensitiviteten i aktivitetsvärdering torde ökas av att lungclearance inkluderas i bedömningen.