Pulmonary Sarcoidosis

preliminary rePOrt Pulmonary Sarcoidosis* Long-term Follow-up of the Effects of Steroid Therapy Lionel E. Harkleroad, Lt Colonel, USAF, BSC; Robert L. Young, Colonel, USAF, MC; Patrick]. Savage, Maior, USAF, MC; Douglas W. Jenkins, Lt. Colonel, USAF, MC, FCCP; and Robert E. Lordon, Colonel, USAF, MC Fifteen years ago we began a prospective study using alternate case treatment with prednisone in patients with pulmonary function abnormalities due to sarcoidosis. Twenty-five patients were divided into treatment and control groups that were similar in sex, age, race, degree of pulmonary dysfunction, and duration of disease. Evaluation included complete spirometric studies, singlebreath carbon monoxide diffusion capacity, and arterial blood gases. FoUow-up studies at six montbs, one to two

T

he value of corticosteroid therapy in sarcoidosis remains controversial.l-7 Some do not believe that therapy is of any benefit, others advocate early treatment to prevent fibrosis, and still others argue that a prolonged course of treatment is necessary. 3 • 7 •8 We initially studied 25 patients with the recent onset of histologically confirmed pulmonary sarcoidosis who were alternately treated with corticosteroids. After one to two years of follow-up, we were unable to detect any benefit from therapy. 8 The same patients were re-evaluated ten to 15 years later. Our results continue to suggest that an early course of corticosteroids has no short- or long-term therapeutic benefit in pulmonary sarcoidosis. MATERIALS AND METHODS

Initially there were 12 treated and 13 untreated pattients. The criteria used for inclusion of a patient in the treatment protocol were a diffusing capacity less than 80 percent of predicted or an arterial Po2 less than 80 mm Hg at rest or after exercise. Alternate patients meeting these criteria were treated with prednisone. They were equally matched for age, sex, pulmonary symptoms, and pulmonary function abnormalities. 8 After ten to 15 years, two patients cannot °From the Pulmonary Department, Division of Medicine, Wilford Hall Medical Center ( AFSC), Lackland Air Force Base, Texas. Research performed at Wilford Hall USAF Medical Center, Lackland AFB, Tex. The opinions expressed are those of the authors and do not necessarily represent official USAF policy. 84

years, and ten to 15 years show no difference between the treated and untreated groups. Improvement or deterioration in pulmonary function of individual patients in the treated group was reftected in the control group, even in those patients witb a diffusing capacity and forced vital capacity less than 65 percent of predicted. Data from this long-term study fail to show any benefit of short-term use of steroids in tberapy for pulmonary sarcoidosis.

be located, and two patients have died of pulmonary sarcoidosis. The remaining 21 pa·tients were personally contacted as to symptoms and subsequent steroid therapy, 16 of whom returned for follow-up evaluation. Twelve patients began receiving steroid therapy for periods of at least six months and for as long as two years. 8 Treatment consisted of 15 mg of prednisone four times per day for one month, then 5 mg four times daily for at least an additional five months. Ten of these 12 patients stopped receiving corticosteroid therapy after their initial treatment, and two patients who died two years and 12 years, respectively, after diagnosis, received nearly continuous therapy with corticosteroids. Follow-up is available in 11 of the original 13 untreated patients. One patient received a two-week course of corticosteroids for hypercalcemia during his 12th year of follow-up. None of the other ten untreated patients received corticosteroids. Seventeen patients returned for evaluation after ten or more years of follow-up. Each patient was examined by one of the authors, and all had a CBC, chest roentgenogram, spirometry, arterial blood gases, and single breath diffusing capacity ( Dsb). Spirometry was performed on a 10-L Stead-Wells spirometer. Forced vital capacity ( FVC), forced expiratory volumes at one second (FEV1 ), forced expired How 0-25$ (FEF0-25$), forced expired How 25-75$ ( FEF25-75$), and forced inspired How ( FIF) were recorded. 9 The Dsb was measured by the method of Krogh as modified by Oglivie et al10 and adapted for use with the Beckman GC-IIA gas chromatograph. 11 Gas concentrations used in the test were 0.3 percent carbon monoxide, 1.0 percent neon, 21.0 percent oxygen, and 77.7 percent nitrogen. Diffusing capacity was measured in triplicate and the Pulmonary Sarcoidosis (Harkleroad et at)

Table !--Clinical Feature. of Palientl 111i1la PulmoruJrr Sarcoidom•

Patients Treated I 2 3t 4 5 6 7 8 9 10 11

Nontreated I 2 3 4 5 6 7 8 9 IO 11

Followup, yrs 10

12 IO I5 11 11

13

11 10 10

I2 11

I2

11

12

10 11 11

I3 12 I3 I3

Symptoms

Chest X-ray Stage

,----

Age

Sex

Race

Initial

Follow-up

32 45 31 54 3I 35 36 41 43 32 46

M M M M F M M M M M M

Black White Black White Black Black White White Black Black White

Weight loss, fever, cough None None None Fever, cough None Weight loss, SOB, cough Fever DOE, cough Cough DOE

None None SOB, weight loss, cough None None None SOB SOB, cough None None None

I 2 2 I 2 I 2 2 I 2 2

36 46 37 35 40 32 32 54 36 35 54

F M M F M M M M M M F

White Black Black Black White Back Black White Black Black Back

None None None Cough, photophobia None None Weight loss, SOB, cough None Cough, SOB None DOE, pleuritic chest pain

None Hypercalcemia None None None None SOB, chest pain None None None None

I 2 2

Initial Follow-up

I

3 2 3 I

2 2

I

2 3 2 I 3 I 2 ND ND ND Normal 2 2 Normal Normal 3 3 Normal 3 ND ND

*SOB=Shortness of breath, DOE=dyspnea on exertion, and ND =not done. tPatient died I2 years after diagnosis of progressive respiratory failure. effective lung volume, calculated from the neon gas dilution, was used as alveolar volume. Values for Dbs are expressed as percent predicted. Arterial blood was drawn at rest and immediately after exercise. Resting blood gas levels were determined in the sitting position after a five- to ten-minute stabilization period. Exercise consisted of a 90-second modification of Master's two-step procedure. Blood gases and hydrogen ion concentrations were measured in the Instrumentation Laboratories blood gas analyzers, which were calibrated with known gas concentrations. Linearity and stability were also checked three times daily with tonometered blood samples. The alveolar-arterial oxygen difference P( A-a )0 2 was calculated from the alveolar-air equation, substituting arterial carbon dioxide tension, PaC0 2 , for alveolar carbon dioxide tension, PAC0 2 , and the values reported are expressed in millimeters of mercury (mm Hg). Respiratory quotients used in calculating P(A-a)0 2 were assumed to be one (1.0). Predicted values for spirometric measurements are from Morris's spirometric standards for healthy nonsmoking adults.12 These standards were also used in the recomputation of the baseline data in all patients. Diffusing capacity values were compared with the predicted normals from Cotes.l3 Hemoglobin corrections of Dsb were not required since our patients were not anemic. All patients' chest roentgenograms from the initial and present study were staged according to the following criteria: stage 1, hilar adenopathy; stage 2, hilar adenopathy with parenchymal infiltrates; or stage 3, parenchymal infiltrates. Student's t test was used to statistically compare pulmonary function group means as well as mean values of the percentage of change from baseline with each patient serving as his/her own control. These data were also compared using

Fisher's exact test.H Any calculated P values of less than 0.05 were considered significant. REsULTS

The clinical features of the 22 patients in whom long-term follow-up was obtained are shown in Table 1, including the one patient who died after 12 years but not the patient who died at two years. The treated and untreated patients had similar results in every measurement. The length of follow-up was 11.5 years and 10.8 years in the treated and untreated patients, respectively. Both groups were similar in age, predominantly men, and 60 to 70 percent were black. The incidence of pulmonary symptoms has decreased compared with the initial study in both groups of patients. Two patients in the treated group continued to have mild exertional dyspnea, and a third patient with progressive dyspnea ultimately died of pulmonary failure. Only one untreated patient continued to have mild exertional dyspnea. All other patients were free of pulmonary or systemic symptoms. No difference in radiologic staging was noted between the two groups either initially or at the last follow-up exam (Table I). Both groups had five patients with stage 2 or stage 3 changes at the long-term follow-up study. A normal chest roentgenogram was seen in only four of 17 patients returning for follow-up, all of whom were in the nontreated group. Results of pulmonary function tests in the patients who returned for follow-up examinations are shown in CHEST I 82 I 1 I JULY, 1982

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Pulmonary Sarcoidosis (Harkleroad el a/J

tients. Similar results were noted with the measurement of P(A-a)0 2 and Dsb as shown in Figure 2. There was also no significant difference in arterial Pa0 2 at rest or after exercise between the treated and rmtreated patients initially or after ten to 15 years. An initial Dsb value of 65 percent of predicted or less was measured in five patients, two in the treated, and three in the untreated groups. All five patients showed improvement in their Dsb measurement in the follow-up study. DISCUSSION

The effectiveness of corticosteroid therapy in pulmonary sarcoidosis has not been established despite its use for more than 20 years. Several studies have not supported the use of corticosteroids. 1 • 2 •8 Many others, however, continue to advocate their use, even though a prospective controlled study showing their therapeutic benefit has not been done. 3 • 7 In addition, those who support the use of corticosteroids vary widely in their indications for therapy and in their recommendation for dosage and duration of treatment. Some recommend that only those with stage 2 or 3 roentgenographic changes be treated. 7 Others limit treatment to those with "severe" pulmonary function impairment as measured by a Dsb or an FVC of 65 percent of predicted or less. 4 Some have stressed early treatment to prevent fibrosis, and others advocate prolonged therapy of two years or longer. ft Some have suggested that continuous therapy may be more important in black patients, since they seem to have a higher incidence of relapse. 7 Our studies have not shown a beneficial effect of early corticosteroid therapy in pulmonary sarcoidosis. Our treated and untreated patients were studied prospectively. Both groups had prep:mderantly black patients and were equal in number of patients with pulmonary function impairment, roentgenographic findings, and symptoms. The treated patients received corticosteroids early in the course of their disease for at least six months and as long as two years, except for the two patients who died of their disease. 8 These two patients died at two years and 12 years, respectively, despite nearly continuous therapy. Only two patients have been lost to follow-up, both untreated. Even if we were to assume that these two patients died of their disease, the rmtreated patients would still have a clinical course similar or equal to the treated patients. Although our study has been well controlled, the small number of patients precludes us from making any definitive recommendation for the general use of corticosteroids in pulmonary sarcoidosis. Our failure to demonstrate any therapeutic benefit from corticosteroids in a small group

of patients at least suggests that such therapy should be used discriminately rmtil a controlled study of a large population of patients is done. ACKNOWLEDGMENT: The authors express their appreciation to Mr. Donald C. Hudson and Ms. Stephanie Klein for technical assistance and to Mrs. JoAnn Honn for preparing the manuscript REFERENCES

1 Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis 1973; 107:609-14 2 Eule H, Roth I, Weide W. Clinical and functional results of a controlled clinical trial of the value of prednisone therapy in sarcoidosis Stage I and II. In: Williams W, Davies B, eds. Proceedings of the eighth international conference on sarcoidosis and other granulomatous diseases. Cardiff, Wales: Alpha Omega Publishing Ltd, 1980; 624-28 3 Refvem 0. Long-term corticosteroid treatment of pulmonary sarcoidosis. In: Iwai K, Hosoda Y, eds. Proceedings of the sixth international conference on sarcoidosis. Baltimore: University Park Press, 1974; 533-38 4 Colp C, Park SS, Williams MH Jr. Pulmonary function followup of 120 patients with sarcoidosis. Ann NY Acad Sci 1976; 278:301-07 5 Johns CJ, Macgregor IM, Zachary JB, Ball WC. Extended experience in the long-term corticosteroid treatment of pulmonary sarcoidosis. Ann NY Acad Sci 1976; 278:722-31 6 Miller A, Teirstein AS, Chuang MT. The sequence of physiologic changes in pulmonary sarcoidosis: correlation with radiographic stages and response to therapy. Mt. Sinai J Med NY 1977; 44:852-65 7 DeRemee RA. The present status of treatment of pulmonary sarcoidosis: a house divided. Chest 1977; 71: 388-93 8 Young RL, Harkleroad LE, Lordon RE, Weg JG. Pulmonary sarcoidosis: a prospective evaluation of glucocorticoid therapy. Ann Intern Med 1970; 73:207-12 9 Kory RC, Rankin J, Snider GL, Tomashefski JF. Clinical spirometry: recommendations of the section on pulmoll&IY function testing. Dis Chest 1968; 43:214-19 10 Ogilvie CM, Forster RE, Blakemore WS, Morton JW. A standardized breath-holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide. J Clin Invest 1957; 36:1-7 11 Smith JR, Hamilton JH. DLCO measurements with gas chromatography. J Appl Physiol 1962; 17:856-60 12 Morris JF, Koshki A, Johnson LC. Spirometric standards for healthy non-smoking adults. Am Rev Respir Dis 1971; 103:57-67 13 Cotes JE. Lung function, 2nd ed. Oxford: Blackwell Scientific Publications, 1968; 342 14 Fleisk JL. Statistical methods for rates and proportions. New York: John Wiley and Sons, 1973

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