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Prognosis for sarcoidosis in a defined geographical area
Br. J. Dir. Chest (1987) 81. 381
PROGNOSIS FOR SARCOIDOSIS IN A DEFINED GEOGRAPHICAL AREA E. HUHTI. ANNELI POUKKULA Department
of Medicine,
Univrrsity
AND M. LILJA
Central Hospital.
Oltlu,
Finland
Summury
One hundred and ninety-nine cases of sarcoidosis were diagnosed from July 1970 to December 1976 in a defined geographical area in northern Finland. At the follow-up examination at least 5 years later (range 5-12 years) a chest riintgenogram was obtained from 179 patients (90%) and lung function tests were performed by 169 patients (85%). A normal r6ntgenogram was achieved by 94 of the 113 patients with stage I sarcoidosis (83%), and by 36 of the 62 patients with stage II (58%). Two patients in the former group (2%) and 14 in the latter (23%) had progressed to the fibrotic stage III, but the fibrosis was usually slight. FEV, and FVC had increased during the follow-up period, D,.,, showing the largest number of abnormal results in the final examination. Lung function largely normalized with a normal r6ntgenogram, whereas the functional outcome was worst where fibrosis had developed. Only two patients had been granted a disability pension because of sarcoidosis. Six patients had died, but none of sarcoidosis. The results show a favourable prognosis for sarcoidosis in this comprehensive series of patients.
INTRODUCTION Sarcoidosis is usually regarded as a benign disease, yet many factors seem to affect its prognosis adversely, such as age and race, mode of onset of the disease, and the r6ntgenological stage at diagnosis (l-5). The symptoms tend to disappear during the course of the disease, even though residual changes are often found in the chest rbntgenograms (4), but some 10% of patients may ultimately receive a disability pension (6). Comparisons between different series of patients are rendered difficult, however, by selective factors affecting the composition of the series. The hospital patients include more with symptoms and probably many with some more severe disease, whereas the cases discovered during mass radiography surveys may have a mild disease and are often completely asymptomatic. To obtain a more comprehensive picture of the prognosis for sarcoidosis, we gathered data on all the patients from a defined geographical area who had received this diagnosis within a given period of time. We have previously discussed the incidence and clinical picture of sarcoidosis in this area (7) and the present paper sets out to describe the Correspondence: Dr Esko Huhti. Department of Medicine. University Central Hospital. SF-90220 Oulu, Finland.
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prognosis among those patients followed up for at least 5 years. The results show that the prognosis remained favourable even after a longer period. Patients and Methods Patients All persons living within the Tuberculosis District of Northern Ostrobothnia in northern Finland and who had sarcoidosis diagnosed between July 1970 and December 1976 were eligible. The district is sparsely populated but includes two sizeable towns, Oulu (population 90000) and Kajaani (population 25000). The total population of the area was about 300000 at that time, and the patients with (suspected) sarcoidosis were examined at two large hospitals, University Central Hospital in Oulu and Paivarinne Hospital. Diagnosis The diagnosis of sarcoidosis was made along common lines. A biopsy specimen was always aimed at, usually through mediastinoscopy unless more easily obtained by some other route. A Mantoux text was performed with 1 TU of PPD-RT23, and if negative, repeated with 10TU. A Kveim test or liver needle biopsy was performed only exceptionally. A large number of other investigations and laboratory tests were also performed but the test pattern varied between the two hospitals, hence the results were not available for each patient and are not taken into account in the present context. Spirometry was performed with a Bernstein-type spirometer (8). At least three acceptable curves were recorded and the best value for the forced expiratory volume in one second (FEV,) and the forced vital capacity (FVC) was used. For certain purposes FEV, has been calculated also in per cent of FVC (FEV,%). Only those spirometries were accepted that had been performed within 3 months of diagnosis. To standardize for sex, age and height, the measured values of FEV, and FVC (but not that of FEV,%) were expressed as percentages of those predicted according to Sobol and Sobol(9). In their method a 10% deviation from the predicted value is equal to one standard deviation (SD). The predicted values were those given by Salorinne (10). The findings from the chest rontgenograms were classified as follows (11): Stage I: enlarged hilar and possibly mediastinal lymph nodes without parenchymal infiltrations; Stage II: parenchymal infiltrations with or without enlarged hilar or mediastinal lymph nodes and without evidence of fibrosis; Stage III: fibrotic parenchymal changes, fibrosis being diagnosed if the shadows in the rontgenogram were consistent with fibrosis and a shrinking of some part or parts of the lung could be demonstrated. Follow-up examination The patients were followed up at the outpatient department of the University Central Hospital, at the tuberculosis dispensary, or at Paivarinne Hospital. From January to March 1982 all patients who could be reached were invited to the outpatient department of the University Hospital, where they were interviewed, a chest riintgenogram was obtained, serum alanine aminotransferase (S-ALAT) and alkaline phosphatase (S-AFOS) were determined and spirometry was performed. The singlebreath diffusing capacity (DcO) was also measured in connection with the follow-up examination (12). If the patient could not be contacted or did not attend the follow-up examination but a chest rdntgenogram was available at least 5 years after diagnosis, then this was used. A few patients were interviewed by telephone. In the caseof those who had died, the causeof death was ascertained from the death certificates.
HUHTI,
Statistical
POUKKULA.
LILJA:
PROGNOSIS
FOR
383
SARCOIDOSIS
methods
The data were processed by computer. The significance levels were mainly determined byX2test but the significances in Table III were derived from the tables of normal distribution. RESULTS Patients
From July 1970 to December 1976 199 cases of sarcoidosis were diagnosed in the area (Table I), 95 men and 104 women. The mean age in the total series was 37 (SD 11.0) years, but men predominated in the two youngest age groups whereas the majority of the older patients were women. Hence the mean age of the men was 33 (SD 10.6) years and of the women, 39 (SD 10.7) years. The diagnosis was confirmed by biopsy in 191 patients (96%). Chest riintgenogram
Out of those 179 patients (90%) who had a chest rontgenogram available both at diagnosis and at follow-up examination, 113 (63%) had stage I and 62 (35%) stage II changes initially (Table II). Normal rontgenograms and stage III changes were uncommon. The Table I. Age and sex of the patients at diagnosis
Sex
15-24
Men Women Total
Total
Age groups
25-34
35-44
45-54
55-64
655
No.
70
No.
96
No.
5% No.
7c
No.
c/o
No.
5%
10 4 14
11 4 7
54 33 87
57 32 44
21 38 59
22 37 27
5 17 12
2 10 12
2 10 6
3 1 4
3 I 2
5 18 23
No.
9%
95 104 199
100 100 100
Table II. Chest rontgenogram at diagnosis and in the follow-up examination Normal No.
At diagnosis Men Women Total At follow-up Men Women Total
Stage I1
Stage I %
-
Stage III
Total
No.
%
No.
%
No.
7c
No.
5%
60 66 63
34 28 62
40 29 35
-
2 2
2 1
84 95 179
100 100 100
7 6 7
8 8 16
10 8 9
8 10 18
10 11 10
84 95 179
100 100 100
1 1
1 1
50 63 113
61 70 131
73 74 73
6 6 12
Only those patients are included who had a chest rontgenogram both at diagnosis and in the follow-up examination. The ‘Total’ column includes one patient at diagnosis and two at follow-up who had ‘other’ changes in the chest rontgenograms and could not be placed with respect to the defined stages.
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follow-up rontgenogram was normal in 73% of the patients, with no significant differences between the men and women. A two-year rontgenogram was available for 155 patients, and this was already normal in 97 patients (63%). Ten per cent of the patients were left with fibrotic changes in the lungs (stage III), but in half of them the fibrosis was slight and localized. The outcome was better for the patients who were diagnosed in stage I than those diagnosed in stage II (Fig. l), 94 of the former (83%) attaining a normal rontgenogram as contrasted with 36 (58%) of the latter (P
STAGE I 113
NORMAL
STAGE 1
STAGE 2
STAGE 3
5 (4%)
2 (2i)
94 (83%) 12 (11%)
STAGE II
62
A\\
NORMAL
STAGE 2
STAGE 3
36 (58%)
11 (18%)
14 (23%)
&R
1 (2%)
Fig. I. Rdntgenological outcome in 113 patients with stage I sarcoidosis on presentation and 62 patients with stage II
HUHTI.
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LILJA:
PROGNOSIS
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Table III. Lung function (% of predicted) and the riintgenological stage in the follow-up examination Test
FEV, No. of patients Mean SD FVC No. of patients Mean SO
DC0 No. of patients Mean SD
RBntgenological stage
Total
Normal
Stage I
Stage II
Stage III
122 99 10
11 94% 6
15 93: 9
I6 85$ 16
169 961 12
122 104$ 9
11 Y8 8
15 98 8
16 93t
169 101 10
121 Y5$
11 863
15
1s
8t-q
80$
10
14
13
11 BIT
15 97
15 8Of
11
14
16
10
12
165 92 12
D,dV,
No. of patients Mean so
121 973 10
165 96$ 11
The ‘Total’ column includes a few patients who had no riintgenogram available or could not be placed with respect to the defined stages. FEV,=forced expiratory volume in one second; FVC=forced vital capacity; D<.,)=diffusing capacity; V,=alveolar volume. Difference from predicted: *P
have had erythema nodosum, and 29 of these (83%) had a normal follow-up rantgenogram, while 102 out of the 141 patients without erythema nodosum (72%) attained a normal riintgenogram. This difference is again not significant. Ten patients out of 179 (6%) had cutaneous sarcoidosis. one with a clear rontgenogram from the beginning, six with stage I initially and three with stage II. The r6ntgenological outcome in this small group was similar to that for the rest of the patients. Lung functiotz tests FEV, was more abnormal at diagnosis than FVC and the function values were worse at stage 11 than at stage I (data not shown: cf. Poukkula et al. (7)). The various values largely normalized in those patients who had a normal rhntgenogram at the follow-up examination (Table 111). The functional outcome was worst among those who ended with stage III, but even so patently unfavourable results were uncommon, only 2-12% of the patients showing values less than 80% of the predicted ones in the various tests (Table IV). Manifest bronchial obstruction was also uncommon, only 10 patients (6%) having an FEV,% less than 70 at the follow-up examination. Only three of these ten were less than 50 years of age, and of the three, one had asthma and another had bronchiectasis.
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Table IV. Patients with lung function 80% of those predicted Test
Men
6
FVC
1
D co
8
4
%
No.
7
7
(81) 1
2
10
12
(80)
examination
5
3
below
Total %
No.
8
13
(88)
(85) (85)
o/c
8 (169)
2
3
14
20
638)
(80) Total number Abbreviations
4
values in the follow-up
(81) DcolV,
81 NO.
Women
No.
FEV,
VOL.
2 (169)
4
7
12 (165)
4
(165)
of patients in parentheses. as in Table III.
Liver function
S-ALAT was elevated more often among the men (20 out of 78, 26%) than among the women (10 out of 87,12%) (PcO.05). S-AFOS was increased in two of the men (3%) and seven of the women (8%) but the difference was not significant. Symptoms, disability and mortality
Eighteen out of 181 patients (10%) complained of symptoms that could have been derived from sarcoidosis, mainly breathlessness and cough. A higher percentage of the women (13%) than of the men (6%) had symptoms, but the difference was not significant. Two patients, one man and one woman, had been granted a disability pension because of sarcoidosis. One of them had sarcoidosis of the central nervous system and sarcoid uveitis. Six patients died during the follow-up period, but none of them from sarcoidosis. Treatment
Thirty-five patients (18%), 19 men and 16 women, were treated with prednisolone for at least 4 months. The mean age was similar among the treated and untreated patients. The length of treatment varied from 4 to over 80 months, being 22 months on average. The indications for treatment varied between the two hospitals. In 22 cases (63%) prednisolone was prescribed on account of intrathoracic changes, in five cases (14%) for symptoms (including erythema nodosum), and in seven cases (20%) for extrathoracic sarcoidosis. In one case the indication was not mentioned. The chest rontgenogram was normal at the start of treatment in one patient, six patients had stage I, 27 stage II and one patient stage III changes. Follow-up rontgenograms were available for 34 of the treated patients. Twenty (59%) finished with a normal rontgenogram and six (18%) with stage II changes. Eight of the
HUHTI,
POUKKULA,
LILJA:
PROGNOSIS
FOR
SARCOIDOSIS
387
treated patients (24%) and 10 of the untreated ones (7%) showed stage III changes at follow-up. These 18 patients were older than the others, but the treated and untreated cases among them were of similar age. Seven patients progressed from lesser stages to stage III during treatment, all of them instances in which treatment had been started more than 2 years after the first manifestations of sarcoidosis. The lung function values at the follow-up examination were worse among the treated patients than among the untreated ones. This stands to reason and no more detailed analysis was carried out.
DISCUSSION All the patients with suspected sarcoidosis in our district were examined at the two hospitals participating in the study, and thus we have been able to exclude the selective factors which often influence or distort the composition of hospital series. We do not claim to have recorded every case of sarcoidosis occurring during the period, however, as a number of symptomless patients may have been cured without ever having been diagnosed, as mass radiography surveys were performed only at 3-year intervals. Hence our results, if anything, tend to give an unduly pessimistic picture of the prognosis for sarcoidosis. The rontgenological staging used (11) differs a little from staging usually used in that it classifies as stage II all cases with parenchymal infiltrates irrespective of whether the hilar lymph nodes are enlarged or not. In our experience it is difficult to detect lymphadenopathy among pulmonary infiltrates and observer variation is considerable. The staging we adopted has also been often used in Scandinavian studies (2, 13-15). Complete disappearance of rontgenological changes seemed to be rather more common among our patients than in many previous series (1, 4-6, 16-19), suggesting that the course of sarcoidosis is mild in Finland. Our results are similar to those obtained by Hannuksela et al. (20)) although their series was obviously selected and included only acute cases, a large proportion of whom had erythema nodosum (46%). The prognosis among the patients described by Selroos (2) was also favourable but few patients had been followed up for as long as 5 years. On the other hand, the rontgenological prognosis was less favourable among the patients studied by Elo (21), but he obtained a participation rate of only 66%. Hillerdal et al. (22) have recently published a follow-up study of sarcoidosis patients from Sweden. Their series comprised 505 patients, also gathered from a limited geographical area, and included all patients with sarcoidosis diagnosed in this area during a 15-year period. The authors used different rontgenological staging but it is shown, or can be calculated, that 82% of the patients with stage I initially and 59% of those with stage II attained a normal rontgenogram. Hence their results were identical to those obtained by us, which lends support to the view that the course of sarcoidosis is benign and relatively similar all over Scandinavia. Lofgren (23) showed that patients with erythema nodosum attain a clear chest rontgenogram more often than those without, and similar observations have been made in subsequent studies. The present results point in the same direction, but the difference was not significant. Similarly, we did not find any significant difference in the rontgenological outcome between the younger and older patients (P
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value and the greater age of the patients with stage III at the follow-up examination suggest that the prognosis really is worse for older patients, as deduced in previous studies (3, 4, 20). Both FEV, and FVC increased during the follow-up (data not shown), but even in the latest spirometry FEV, was lower than FVC in relative terms at all the rdntgenological stages (Table III), which implies that some obstruction may remain indefinitely. Although pulmonary sarcoidosis is often regarded as a restrictive disease, the bronchial mucosa may be affected (2, 17,24-26) and physiologically diagnosed bronchial obstruction appears to be common (27, 28). Obstruction seems to diminish during the course of the disease. Initially some 10% of our patients have an FEV, %<70 (7)) whereas in this follow-up study the respective percentage was only 6%. Those patients who progressed to the fibrotic stage III had the lowest FEV,, as could be expected from previous studies (29) and the stage III patients also had the lowest FVC, whereas the patients with a normal chest rontgenogram at the follow-up had recovered their normal ventilatory function. The patients with stages I or II lay in between these extremes. Hence the various rontgenological stages roughly reflect ventilatory function. The relations of the diffusing capacity to the rontgenological stages at the follow-up examination were approximately similar to those of FEV,, only the test results were lower in relative terms. D,, was low among the patients with stage III changes but it also deviated significantly from the predicted level in the patients with a normal rontgenogram (Table III). The low D,, in these cases may reflect the existence of sarcoid granulomas or other histological changes in the lung parenchyma despite the normal rontgenogram (16, 30,31). Sharma et al. (32) found that 17 out of 18 patients with stage I showed a reduction in DC,-,, with further decline in eight patients during the follow-up without any worsening of the rontgenogram, while in the study by Miller et al. (33) 55% of the patients with stage I changes and almost all with stage II had D,, values less than 75% of those predicted. Such profound abnormality was not common in our series. Pathological liver function tests were common at the follow-up examination, but in the absence of a control group it is difficult to evaluate their importance. S-ALAT was more often increased among the men than the women and may indicate higher alcohol consumption among the men. The benign nature of the disease in this series of patients is also attested to by only two patients having been granted a disability pension and by the fact that none of the patients died of sarcoidosis. Mortality was not analysed further because of the small number of deaths. The indications for treatment and its duration varied and no randomization was undertaken, hence any analysis of the results by treatment would also be unprofitable. The patients who progressed to stage III were older than the others, and although the treated and untreated patients in this subgroup were of the same age, all the treated patients who developed fibrosis had a late commencement of steroid administration. This leaves open the possibility that the results might have been better had steroids been given earlier.
ACKNOWLEDGEMENT This work was supported by grants from the Finnish Anti-tuberculosis Yrjo Jahnsson Foundation.
Association and the
HUHTI.
POUKKULA,
LILJA:
PROGNOSIS
FOR
SARCOIDOSIS
389
REFERENCES 1. Sones M, Israel HL. Course and prognosis of sarcoidosis. Am J Med 1960;29:84-93. 2. Selroos 0. The frequency, clinical picture and prognosis of pulmonary sarcoidosis in Finland. Acta Med Stand 1969;Suppl 503. 3. Wurm K, Rosner R. Prognosis of chronic sarcoidosis. Ann NY Acad Sci 1976;278:732-5. 4. Romer FK. Presentation of sarcoidosis and outcome of pulmonary changes. A review of 243 patients followed up for up to 10 years. Dan Med Bull 1982;29:27-32. 5. Neville E, Walker AN. James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q Jl Med 1983;52:525-33. 6. Thygesen K, Viskum K. Manifestations and course of the disease in intrathoracic sarcoidosis. Stand J Resp Dis 1972;.53:174-80. 7. Poukkula A, Huhti E, Lilja M, Saloheimo M. Incidence and clinical picture of sarcoidosis in a circumscribed geographical area. Br J Dis Chest 1986;80:13847. 8. Bernstein L, D’Silva JL, Mendel D. The effect of the rate of breathing on the maximum breathing capacity determined with a new spirometer. Thorax 1952;7:255-62. 9. Sobol BJ. Sobol PG. Per cent of predicted as the limit of normal in pulmonary function testing: a statistically valid approach. Thorax 1979;34:1-3. 10. Salorinne Y. Single-breath diffusing capacity. Reference values and application in connective tissue diseasesand in various lung diseases. Stand J Resp Dis 1976;Suppl96. 11. Wurm K, Reindell H, Heilmeyer L. Der Lungenboeck im Rontgenbild. Stuttgart: Georg Thieme Verlag, 1958. 12. Cotes JE. Lung function. Assessment and application in medicine. 4th ed. Oxford: Blackwell Scientific Publications, 1979. 13. Karma A. Ophthalmic changes in sarcoidosis. Acta Ophthalmol (Copenh) 1979;Suppl 141. 14. Thunell M, Bjerle P, Stjernberg N. ECG abnormalities in patients with sarcoidosis. Acta Med Stand 1983;213:115-18. 15. Stjernberg N, Thunell M. Pulmonary function in patients with endobronchial sarcoidosis. Acta Med Stand 1984;21.5:121-6. 16. Smellie H, Hoyle C. The natural history of pulmonary sarcoidosis. Q Jl Med 1960;29:539-58. 17. Scadding JG. Sarcoidosis. London: Eyre & Spottiswoode, 1967. 18. Siltzbach LE. Sarcoidosis: clinical features and management. Med Clin NAm 1967;51:483-502. 19. Siltzbach LE. James DG, Neville E, et al. Course and prognosis of sarcoidosisaround the world. Am J Med 1974;57:847-52. 20. Hannuksela M, Salo OP, Mustakallio KK. The prognosis of acute untreated sarcoidosis. Ann Clin Res 1970;2:57-61. 21. Elo JJ. Sarkoidoosi. Kliininen tutkimus Varsinais-Suomen tuberkuloosipiirissti vuosilta 19651977. Thesis. Turku: Turun yliopisto. 22. Hillerdal G, Ndu E. Osterman K, Schmekel B. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Resp Dis 1984;130:39-42. 23. Lofgren S. Primary pulmonary sarcoidosis. II. Clinical course and prognosis. Acta Med Stand 1953;145:465-74. 24. Kalbian V. Bronchial involvement in pulmonary sarcoidosis. Thorax 1957;12:18-23. 25. Olsson T, Bjornstad-Pettersen H, Sternberg NL. Bronchostenosis due to sarcoidosis. A cause of atelectasis and airway obstruction simulating pulmonary neoplasm and chronic obstructive pulmonary disease. Chest 1979;75:663-6. 26. Hadfield JW, Page RL, Flower CDR, Stark JE. Localised airway narrowing in sarcoidosis. Thorax 1982;37:443-47. 27. Colp C. Sarcoidosis: course and treatment. Med Clin N Am 1977;61:1267-78. 28. Levinson RS, Metzger LF, Stanley NN, et al. Airway function in sarcoidosis. Am J Med 1977;62:51-59.
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29. Miller A, Teirstein AS, Jackler I, Chuang M, Siltzbach LE. Airway function in chronic pulmonary sarcoidosis with fibrosis. Am Rev Resp Dis 1974;109:179-89. 30. Carrington CB, Gaensler EA, Mikus JP, Schachter AW, Burke GW. Goff AM. Structure and function in sarcoidosis. Ann NY Acad Sci 1976;278:26.5-83. 31. Epler GR, McLoud TC, Gaensler EA, Mikus JP, Carrington CB. Normal chest roentgenograms in chronic diffuse infiltrative lung disease. New Engl J Med 1978;298:934-9. 32. Sharma OP, Colp C, Williams MH, Jr. Pulmonary function studies in patients with bilateral sarcoidosis of hilar lymph nodes. Arch Intern Med 1966;117:436-9. 33. Miller A, Chuang M, Teirstein AS, Siltzbach LE. Pulmonary function in stage I and II pulmonary sarcoidosis. Ann NY Acad Sci 1976;278:292-300. Date accepted 26 November
1986
PROGNOSIS FOR SARCOIDOSIS IN A DEFINED GEOGRAPHICAL AREA E. HUHTI. ANNELI POUKKULA Department
of Medicine,
Univrrsity
AND M. LILJA
Central Hospital.
Oltlu,
Finland
Summury
One hundred and ninety-nine cases of sarcoidosis were diagnosed from July 1970 to December 1976 in a defined geographical area in northern Finland. At the follow-up examination at least 5 years later (range 5-12 years) a chest riintgenogram was obtained from 179 patients (90%) and lung function tests were performed by 169 patients (85%). A normal r6ntgenogram was achieved by 94 of the 113 patients with stage I sarcoidosis (83%), and by 36 of the 62 patients with stage II (58%). Two patients in the former group (2%) and 14 in the latter (23%) had progressed to the fibrotic stage III, but the fibrosis was usually slight. FEV, and FVC had increased during the follow-up period, D,.,, showing the largest number of abnormal results in the final examination. Lung function largely normalized with a normal r6ntgenogram, whereas the functional outcome was worst where fibrosis had developed. Only two patients had been granted a disability pension because of sarcoidosis. Six patients had died, but none of sarcoidosis. The results show a favourable prognosis for sarcoidosis in this comprehensive series of patients.
INTRODUCTION Sarcoidosis is usually regarded as a benign disease, yet many factors seem to affect its prognosis adversely, such as age and race, mode of onset of the disease, and the r6ntgenological stage at diagnosis (l-5). The symptoms tend to disappear during the course of the disease, even though residual changes are often found in the chest rbntgenograms (4), but some 10% of patients may ultimately receive a disability pension (6). Comparisons between different series of patients are rendered difficult, however, by selective factors affecting the composition of the series. The hospital patients include more with symptoms and probably many with some more severe disease, whereas the cases discovered during mass radiography surveys may have a mild disease and are often completely asymptomatic. To obtain a more comprehensive picture of the prognosis for sarcoidosis, we gathered data on all the patients from a defined geographical area who had received this diagnosis within a given period of time. We have previously discussed the incidence and clinical picture of sarcoidosis in this area (7) and the present paper sets out to describe the Correspondence: Dr Esko Huhti. Department of Medicine. University Central Hospital. SF-90220 Oulu, Finland.
382
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.I. DIS.
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prognosis among those patients followed up for at least 5 years. The results show that the prognosis remained favourable even after a longer period. Patients and Methods Patients All persons living within the Tuberculosis District of Northern Ostrobothnia in northern Finland and who had sarcoidosis diagnosed between July 1970 and December 1976 were eligible. The district is sparsely populated but includes two sizeable towns, Oulu (population 90000) and Kajaani (population 25000). The total population of the area was about 300000 at that time, and the patients with (suspected) sarcoidosis were examined at two large hospitals, University Central Hospital in Oulu and Paivarinne Hospital. Diagnosis The diagnosis of sarcoidosis was made along common lines. A biopsy specimen was always aimed at, usually through mediastinoscopy unless more easily obtained by some other route. A Mantoux text was performed with 1 TU of PPD-RT23, and if negative, repeated with 10TU. A Kveim test or liver needle biopsy was performed only exceptionally. A large number of other investigations and laboratory tests were also performed but the test pattern varied between the two hospitals, hence the results were not available for each patient and are not taken into account in the present context. Spirometry was performed with a Bernstein-type spirometer (8). At least three acceptable curves were recorded and the best value for the forced expiratory volume in one second (FEV,) and the forced vital capacity (FVC) was used. For certain purposes FEV, has been calculated also in per cent of FVC (FEV,%). Only those spirometries were accepted that had been performed within 3 months of diagnosis. To standardize for sex, age and height, the measured values of FEV, and FVC (but not that of FEV,%) were expressed as percentages of those predicted according to Sobol and Sobol(9). In their method a 10% deviation from the predicted value is equal to one standard deviation (SD). The predicted values were those given by Salorinne (10). The findings from the chest rontgenograms were classified as follows (11): Stage I: enlarged hilar and possibly mediastinal lymph nodes without parenchymal infiltrations; Stage II: parenchymal infiltrations with or without enlarged hilar or mediastinal lymph nodes and without evidence of fibrosis; Stage III: fibrotic parenchymal changes, fibrosis being diagnosed if the shadows in the rontgenogram were consistent with fibrosis and a shrinking of some part or parts of the lung could be demonstrated. Follow-up examination The patients were followed up at the outpatient department of the University Central Hospital, at the tuberculosis dispensary, or at Paivarinne Hospital. From January to March 1982 all patients who could be reached were invited to the outpatient department of the University Hospital, where they were interviewed, a chest riintgenogram was obtained, serum alanine aminotransferase (S-ALAT) and alkaline phosphatase (S-AFOS) were determined and spirometry was performed. The singlebreath diffusing capacity (DcO) was also measured in connection with the follow-up examination (12). If the patient could not be contacted or did not attend the follow-up examination but a chest rdntgenogram was available at least 5 years after diagnosis, then this was used. A few patients were interviewed by telephone. In the caseof those who had died, the causeof death was ascertained from the death certificates.
HUHTI,
Statistical
POUKKULA.
LILJA:
PROGNOSIS
FOR
383
SARCOIDOSIS
methods
The data were processed by computer. The significance levels were mainly determined byX2test but the significances in Table III were derived from the tables of normal distribution. RESULTS Patients
From July 1970 to December 1976 199 cases of sarcoidosis were diagnosed in the area (Table I), 95 men and 104 women. The mean age in the total series was 37 (SD 11.0) years, but men predominated in the two youngest age groups whereas the majority of the older patients were women. Hence the mean age of the men was 33 (SD 10.6) years and of the women, 39 (SD 10.7) years. The diagnosis was confirmed by biopsy in 191 patients (96%). Chest riintgenogram
Out of those 179 patients (90%) who had a chest rontgenogram available both at diagnosis and at follow-up examination, 113 (63%) had stage I and 62 (35%) stage II changes initially (Table II). Normal rontgenograms and stage III changes were uncommon. The Table I. Age and sex of the patients at diagnosis
Sex
15-24
Men Women Total
Total
Age groups
25-34
35-44
45-54
55-64
655
No.
70
No.
96
No.
5% No.
7c
No.
c/o
No.
5%
10 4 14
11 4 7
54 33 87
57 32 44
21 38 59
22 37 27
5 17 12
2 10 12
2 10 6
3 1 4
3 I 2
5 18 23
No.
9%
95 104 199
100 100 100
Table II. Chest rontgenogram at diagnosis and in the follow-up examination Normal No.
At diagnosis Men Women Total At follow-up Men Women Total
Stage I1
Stage I %
-
Stage III
Total
No.
%
No.
%
No.
7c
No.
5%
60 66 63
34 28 62
40 29 35
-
2 2
2 1
84 95 179
100 100 100
7 6 7
8 8 16
10 8 9
8 10 18
10 11 10
84 95 179
100 100 100
1 1
1 1
50 63 113
61 70 131
73 74 73
6 6 12
Only those patients are included who had a chest rontgenogram both at diagnosis and in the follow-up examination. The ‘Total’ column includes one patient at diagnosis and two at follow-up who had ‘other’ changes in the chest rontgenograms and could not be placed with respect to the defined stages.
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follow-up rontgenogram was normal in 73% of the patients, with no significant differences between the men and women. A two-year rontgenogram was available for 155 patients, and this was already normal in 97 patients (63%). Ten per cent of the patients were left with fibrotic changes in the lungs (stage III), but in half of them the fibrosis was slight and localized. The outcome was better for the patients who were diagnosed in stage I than those diagnosed in stage II (Fig. l), 94 of the former (83%) attaining a normal rontgenogram as contrasted with 36 (58%) of the latter (P
STAGE I 113
NORMAL
STAGE 1
STAGE 2
STAGE 3
5 (4%)
2 (2i)
94 (83%) 12 (11%)
STAGE II
62
A\\
NORMAL
STAGE 2
STAGE 3
36 (58%)
11 (18%)
14 (23%)
&R
1 (2%)
Fig. I. Rdntgenological outcome in 113 patients with stage I sarcoidosis on presentation and 62 patients with stage II
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Table III. Lung function (% of predicted) and the riintgenological stage in the follow-up examination Test
FEV, No. of patients Mean SD FVC No. of patients Mean SO
DC0 No. of patients Mean SD
RBntgenological stage
Total
Normal
Stage I
Stage II
Stage III
122 99 10
11 94% 6
15 93: 9
I6 85$ 16
169 961 12
122 104$ 9
11 Y8 8
15 98 8
16 93t
169 101 10
121 Y5$
11 863
15
1s
8t-q
80$
10
14
13
11 BIT
15 97
15 8Of
11
14
16
10
12
165 92 12
D,dV,
No. of patients Mean so
121 973 10
165 96$ 11
The ‘Total’ column includes a few patients who had no riintgenogram available or could not be placed with respect to the defined stages. FEV,=forced expiratory volume in one second; FVC=forced vital capacity; D<.,)=diffusing capacity; V,=alveolar volume. Difference from predicted: *P
have had erythema nodosum, and 29 of these (83%) had a normal follow-up rantgenogram, while 102 out of the 141 patients without erythema nodosum (72%) attained a normal riintgenogram. This difference is again not significant. Ten patients out of 179 (6%) had cutaneous sarcoidosis. one with a clear rontgenogram from the beginning, six with stage I initially and three with stage II. The r6ntgenological outcome in this small group was similar to that for the rest of the patients. Lung functiotz tests FEV, was more abnormal at diagnosis than FVC and the function values were worse at stage 11 than at stage I (data not shown: cf. Poukkula et al. (7)). The various values largely normalized in those patients who had a normal rhntgenogram at the follow-up examination (Table 111). The functional outcome was worst among those who ended with stage III, but even so patently unfavourable results were uncommon, only 2-12% of the patients showing values less than 80% of the predicted ones in the various tests (Table IV). Manifest bronchial obstruction was also uncommon, only 10 patients (6%) having an FEV,% less than 70 at the follow-up examination. Only three of these ten were less than 50 years of age, and of the three, one had asthma and another had bronchiectasis.
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Table IV. Patients with lung function 80% of those predicted Test
Men
6
FVC
1
D co
8
4
%
No.
7
7
(81) 1
2
10
12
(80)
examination
5
3
below
Total %
No.
8
13
(88)
(85) (85)
o/c
8 (169)
2
3
14
20
638)
(80) Total number Abbreviations
4
values in the follow-up
(81) DcolV,
81 NO.
Women
No.
FEV,
VOL.
2 (169)
4
7
12 (165)
4
(165)
of patients in parentheses. as in Table III.
Liver function
S-ALAT was elevated more often among the men (20 out of 78, 26%) than among the women (10 out of 87,12%) (PcO.05). S-AFOS was increased in two of the men (3%) and seven of the women (8%) but the difference was not significant. Symptoms, disability and mortality
Eighteen out of 181 patients (10%) complained of symptoms that could have been derived from sarcoidosis, mainly breathlessness and cough. A higher percentage of the women (13%) than of the men (6%) had symptoms, but the difference was not significant. Two patients, one man and one woman, had been granted a disability pension because of sarcoidosis. One of them had sarcoidosis of the central nervous system and sarcoid uveitis. Six patients died during the follow-up period, but none of them from sarcoidosis. Treatment
Thirty-five patients (18%), 19 men and 16 women, were treated with prednisolone for at least 4 months. The mean age was similar among the treated and untreated patients. The length of treatment varied from 4 to over 80 months, being 22 months on average. The indications for treatment varied between the two hospitals. In 22 cases (63%) prednisolone was prescribed on account of intrathoracic changes, in five cases (14%) for symptoms (including erythema nodosum), and in seven cases (20%) for extrathoracic sarcoidosis. In one case the indication was not mentioned. The chest rontgenogram was normal at the start of treatment in one patient, six patients had stage I, 27 stage II and one patient stage III changes. Follow-up rontgenograms were available for 34 of the treated patients. Twenty (59%) finished with a normal rontgenogram and six (18%) with stage II changes. Eight of the
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PROGNOSIS
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treated patients (24%) and 10 of the untreated ones (7%) showed stage III changes at follow-up. These 18 patients were older than the others, but the treated and untreated cases among them were of similar age. Seven patients progressed from lesser stages to stage III during treatment, all of them instances in which treatment had been started more than 2 years after the first manifestations of sarcoidosis. The lung function values at the follow-up examination were worse among the treated patients than among the untreated ones. This stands to reason and no more detailed analysis was carried out.
DISCUSSION All the patients with suspected sarcoidosis in our district were examined at the two hospitals participating in the study, and thus we have been able to exclude the selective factors which often influence or distort the composition of hospital series. We do not claim to have recorded every case of sarcoidosis occurring during the period, however, as a number of symptomless patients may have been cured without ever having been diagnosed, as mass radiography surveys were performed only at 3-year intervals. Hence our results, if anything, tend to give an unduly pessimistic picture of the prognosis for sarcoidosis. The rontgenological staging used (11) differs a little from staging usually used in that it classifies as stage II all cases with parenchymal infiltrates irrespective of whether the hilar lymph nodes are enlarged or not. In our experience it is difficult to detect lymphadenopathy among pulmonary infiltrates and observer variation is considerable. The staging we adopted has also been often used in Scandinavian studies (2, 13-15). Complete disappearance of rontgenological changes seemed to be rather more common among our patients than in many previous series (1, 4-6, 16-19), suggesting that the course of sarcoidosis is mild in Finland. Our results are similar to those obtained by Hannuksela et al. (20)) although their series was obviously selected and included only acute cases, a large proportion of whom had erythema nodosum (46%). The prognosis among the patients described by Selroos (2) was also favourable but few patients had been followed up for as long as 5 years. On the other hand, the rontgenological prognosis was less favourable among the patients studied by Elo (21), but he obtained a participation rate of only 66%. Hillerdal et al. (22) have recently published a follow-up study of sarcoidosis patients from Sweden. Their series comprised 505 patients, also gathered from a limited geographical area, and included all patients with sarcoidosis diagnosed in this area during a 15-year period. The authors used different rontgenological staging but it is shown, or can be calculated, that 82% of the patients with stage I initially and 59% of those with stage II attained a normal rontgenogram. Hence their results were identical to those obtained by us, which lends support to the view that the course of sarcoidosis is benign and relatively similar all over Scandinavia. Lofgren (23) showed that patients with erythema nodosum attain a clear chest rontgenogram more often than those without, and similar observations have been made in subsequent studies. The present results point in the same direction, but the difference was not significant. Similarly, we did not find any significant difference in the rontgenological outcome between the younger and older patients (P
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value and the greater age of the patients with stage III at the follow-up examination suggest that the prognosis really is worse for older patients, as deduced in previous studies (3, 4, 20). Both FEV, and FVC increased during the follow-up (data not shown), but even in the latest spirometry FEV, was lower than FVC in relative terms at all the rdntgenological stages (Table III), which implies that some obstruction may remain indefinitely. Although pulmonary sarcoidosis is often regarded as a restrictive disease, the bronchial mucosa may be affected (2, 17,24-26) and physiologically diagnosed bronchial obstruction appears to be common (27, 28). Obstruction seems to diminish during the course of the disease. Initially some 10% of our patients have an FEV, %<70 (7)) whereas in this follow-up study the respective percentage was only 6%. Those patients who progressed to the fibrotic stage III had the lowest FEV,, as could be expected from previous studies (29) and the stage III patients also had the lowest FVC, whereas the patients with a normal chest rontgenogram at the follow-up had recovered their normal ventilatory function. The patients with stages I or II lay in between these extremes. Hence the various rontgenological stages roughly reflect ventilatory function. The relations of the diffusing capacity to the rontgenological stages at the follow-up examination were approximately similar to those of FEV,, only the test results were lower in relative terms. D,, was low among the patients with stage III changes but it also deviated significantly from the predicted level in the patients with a normal rontgenogram (Table III). The low D,, in these cases may reflect the existence of sarcoid granulomas or other histological changes in the lung parenchyma despite the normal rontgenogram (16, 30,31). Sharma et al. (32) found that 17 out of 18 patients with stage I showed a reduction in DC,-,, with further decline in eight patients during the follow-up without any worsening of the rontgenogram, while in the study by Miller et al. (33) 55% of the patients with stage I changes and almost all with stage II had D,, values less than 75% of those predicted. Such profound abnormality was not common in our series. Pathological liver function tests were common at the follow-up examination, but in the absence of a control group it is difficult to evaluate their importance. S-ALAT was more often increased among the men than the women and may indicate higher alcohol consumption among the men. The benign nature of the disease in this series of patients is also attested to by only two patients having been granted a disability pension and by the fact that none of the patients died of sarcoidosis. Mortality was not analysed further because of the small number of deaths. The indications for treatment and its duration varied and no randomization was undertaken, hence any analysis of the results by treatment would also be unprofitable. The patients who progressed to stage III were older than the others, and although the treated and untreated patients in this subgroup were of the same age, all the treated patients who developed fibrosis had a late commencement of steroid administration. This leaves open the possibility that the results might have been better had steroids been given earlier.
ACKNOWLEDGEMENT This work was supported by grants from the Finnish Anti-tuberculosis Yrjo Jahnsson Foundation.
Association and the
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29. Miller A, Teirstein AS, Jackler I, Chuang M, Siltzbach LE. Airway function in chronic pulmonary sarcoidosis with fibrosis. Am Rev Resp Dis 1974;109:179-89. 30. Carrington CB, Gaensler EA, Mikus JP, Schachter AW, Burke GW. Goff AM. Structure and function in sarcoidosis. Ann NY Acad Sci 1976;278:26.5-83. 31. Epler GR, McLoud TC, Gaensler EA, Mikus JP, Carrington CB. Normal chest roentgenograms in chronic diffuse infiltrative lung disease. New Engl J Med 1978;298:934-9. 32. Sharma OP, Colp C, Williams MH, Jr. Pulmonary function studies in patients with bilateral sarcoidosis of hilar lymph nodes. Arch Intern Med 1966;117:436-9. 33. Miller A, Chuang M, Teirstein AS, Siltzbach LE. Pulmonary function in stage I and II pulmonary sarcoidosis. Ann NY Acad Sci 1976;278:292-300. Date accepted 26 November
1986