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Communications to the Editor |

Sarcoidosis Cycle FREE TO VIEW

David M. Skillrud
Author and Funding Information

Affiliations: Bloomington, IL,  Israel Lung Association Tel Aviv, Israel,  Portland, OR

Correspondence to: David M. Skillrud, MD, FCCP, Carle Clinic-Bloomington/Normal, 1701 East College Ave, Bloomington, IL 61704-2102



Chest. 2004;125(3):1171-1172. doi:10.1378/chest.125.3.1171
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To the Editor:

I read with interest the article by Dr. Reich1 and its editorial comments by Marc Judson2 (July 2003) citing experience and published studies particularly over the past 10 years on the nature of sarcoidosis. Dr. Reich argues, “… there is not any one single agent and that there is not one discrete immunologic defect that causes sarcoidosis” (per Dr. Judson’s comments).

This conclusion seemed to me to be reminiscent of the opinion held by my mentor, Richard A. DeRemee, MD, during my years of residency and fellowship training at Mayo Clinic in the early 1980s. Dr. DeRemee (now retired) was and remains widely recognized as a scholar, and expert in interstitial lung disease (and sarcoidosis). His critical review “The Present Status of Treatment of Pulmonary Sarcoidosis: A House Divided”3 represented the cornerstone of sarcoidosis therapy to me and to many others.

In the June 1969 issue of CHEST, Dr. DeRemee wrote an editorial entitled “The Sarcoid Polemic,”4 comparing the then-existing schools of thought on the issue of the nature of sarcoid: “One, which considers sarcoid a syndrome caused by a number of the inciting agents, and the other which views sarcoid as a unitarian disease of yet-to-be-determined etiology.” He concluded, “It seems more appropriate to ask what the sarcoid reaction means, rather than what causes sarcoid.”

Since 1969, countless studies on the immunologic and biochemical nature of sarcoidosis have transpired. We can certainly characterize the cellular and immunologic events that culminate in the development of the noncaseating granuloma to a far greater extent now, than in years past. But have we really made substantial progress in terms of characterizing the nature of the illness, its etiology, and even its treatment?

The Judson editorial2 suggests that Dr. DeRemee’s 1969 commentary was not only accurate, but was prophetic. Sometimes what goes around, comes around.

Reich, JM (2003) What is sarcoidosis?Chest124,367-371. [CrossRef] [PubMed]
 
Judson, M The etiologic agent of sarcoidosis: what if there isn’t one?Chest2003;124,6-8. [CrossRef] [PubMed]
 
DeRemee, RA The present status of treatment of pulmonary sarcoidosis: a house divided.Chest1977;71,388-393. [CrossRef] [PubMed]
 
DeRemee, RA The sarcoid polemic.Chest1969;55,445-446. [CrossRef]
 
To the Editor:

The thesis of the article by Dr. Reich on sarcoidosis (July 2003)1 is very appealing and could explain the persistent dilemma that has surrounded discussion of the etiology of the disease. Dr. Jan Schwarz, in the 1970s, published articles that dealt with the question of etiology of sarcoidosis, but Dr. Reich did not note them in his bibliography. In one article, Schwarz and Vanek2 noted the appearance of acid-fast bacilli in the biopsy material of > 50 cases previously diagnosed pathologically as sarcoidosis. In another article,2 he, along with Dr. Barlow and myself,3 presented cases of sarcoidosis in which a variety of deep fungal pathogens was found in biopsy material. From this experience, Dr. Schwarz raised the question of possibly perceiving sarcoidosis as an abnormality of the cellular immune response itself rather than something associated with a specific external etiologic agent. I presume to refer to Dr. Schwarz’s two articles, as they were among the first that not only suggested such an etiology for sarcoidosis but provided evidence to support this position.

References
Reich, JM What is sarcoidosis?Chest2003;124,367-371. [CrossRef] [PubMed]
 
Schwarz, J, Vanek, J Demonstration of acid fast rods in sarcoidosis.Am Rev Respir Dis1970;101,395-400. [PubMed]
 
Baum, GL, Schwarz, J, Barlow, PB Sarcoidosis and specific etiologic agents: a continuing enigma.Chest1973;63,488-494. [CrossRef] [PubMed]
 
To the Editor:

Thanks to Dr. Skillrud for his kind comments on my article and Dr. Judson’s accompanying editorial, and for acquainting me with Dr. DeRemee’s 1969 editorial, which eloquently delineated the unitarian vs the syndromic etiologic positions, but provided no evidence favoring either view. He asks, “Have we really made substantial progress in characterizing the nature of the illness, its etiology, and even its treatment?”

Etiology: I imagine that the accepted definition, which includes the term unknown etiology, arose inductively, reflecting that among numerous cases of this distinctive clinicopathologic entity, none was evident. Just as the identification of a single black swan suffices to refute the inductive proposition that “all swans are white,” the unitarian view, the identification of one case of sarcoidosis with an apodictic cause serves to refute this definition. The case I cited in my opinion piece is such a “black swan,” an individual whose sarcoidosis succeeded temporally contiguous, progressive disseminated histoplasmosis (PDH). I cited other articles furnishing plausible evidence of a plurality of causes.

I know of no more penetrating discussion of the difficulties of defining sarcoidosis than that provided by Scadding and Mitchell1 ; their operational definition rejects a priori assumptions about etiology: “Sarcoidosis is a disease characterized by the formation in all of several affected organs or tissues of epithelioid-cell tubercles… proceeding to resolution or to conversion into hyaline fibrous tissue.” I believe that there is currently more widespread acceptance of the possibility of etiologic heterogeneity2 as expressed in Dr. Judson’s accompanying editorial, the article by Thomas and Hunninghake,3 and a written communication from Dr. Jack Lieberman, expressing agreement with this view (July 24, 2003). If sarcoidosis is a syndrome, it follows that the clinicopathologic picture must reflect a shared pathogenetic mechanism.

Nature (pathogenesis): The provocative analysis of Munro et al4 of the Kveim response in normal subjects vs patients with sarcoidosis suggests that the granulomatous response characterizing sarcoidosis is attributable to an antecedent deficit in immune processing. This inference is conformable with and offers a unifying explanation for diverse observations summarized in my article: (1) the propensity of individuals with impaired cellular immune response to acquire sarcoidosis, (2) the favorable outcome in persons with the briskest cellular immune response, and (3) the adverse effect of suppression of the granulomatous response evidenced by (a) stage-adjusted sarcoidosis mortality in referral settings, in which corticosteroid therapy (CST) was furnished to 41% of patients, was sixfold that in population-based settings, in which CST was furnished to only 6%5 ; and (b) unfavorable outcomes were more than twice as frequent in treated individuals in each of five, competent, controlled, CST trials in young persons with recently diagnosed stage II-III sarcoidosis, providing long-term follow-up.6 I find it impossible to account for the spectrum of systemic responses to Histoplasma capsulatum—PDH; seropositive, paucibacillary PDH, failing treatment with amphotericin B and responding to CST; and seropositive, otherwise typical sarcoidosis appearing or recrudescing in a setting of endemic histoplasmosis—other than by postulating a deficiency gradient in cellular immune response.8

Treatment: If sarcoidosis is a granulomatous response to an elusive, persistent antigen (unitarian view), the premise that its suppression would forestall the evolution of fatal or disabling pulmonary fibrosis is reasonable. Proof of principle would reside in demonstration of long-term efficacy. If, however, the granuloma, which is the defining characteristic of sarcoidosis, proves to be a regressive response to inefficient, antecedent, cell-mediated processing—probably to a variety of antigens—then its suppression might be inexpedient. I suspect that the belief that persons with sarcoidosis experience a 10% mortality, cited in several standard references, strongly influences the decision to intervene. However, sarcoidosis mortality in reporting population-based settings, which should resemble clinical practice, is approximately 0.5%.5 It follows under the (doubtful) assumption that, on balance, CST is beneficial long-term in individuals with pulmonary shadowing, sustained treatment of a large number of asymptomatic persons—most of whom would have a self-limited course—would be required to prevent one death. Hillerdal et al9 furnished CST in a population-based setting only to persons exhibiting progressive pulmonary shadowing, and reported a mortality of 0.8% (4 of 409 patients; mean age at death, 74 years). Johnston,10 who employed the same indication in a referral setting, furnished it in only 3% and reported a mortality of 0%. The redoubtable Professor Dame Margaret Turner-Warwick recommended observation for 6 to 12 months without treatment, hoping for spontaneous remission in persons with asymptomatic pulmonary shadowing and normal pulmonary function (written communication; March 30, 1999). Lacking evidence of sufficient benefit to offset the adverse effects of sustained CST in persons with pulmonary shadowing, the majority of whom would experience a favorable outcome in the absence of intervention, the framers of a joint statement on sarcoidosis were unable, absent compelling symptoms, to define its indications.11 I do not know to what extent these conservative indications have influenced physician’s practice. Whether “substantial progress” has been made in understanding the nature of sarcoidosis, its etiology, or its treatment since publication of Dr. DeRemee’s editorial. I leave to the reader and to time to judge.

Thanks also to Dr. Baum for his kind comments, and for drawing my attention to the two articles co-authored by Dr. Schwarz, with which I was not acquainted. In the first article,12 the authors report on the identification of acid-fast bacilli on tissue stains in a large proportion of patients with putative sarcoidosis. As Dr. Baum points out in his article,13 the clinical and radiographic delineation of these cases was insufficient to draw firm conclusions regarding the certainty of sarcoidosis, and the histologic findings were unsupported by culture confirmation. Additionally, other investigators of well-characterized sarcoidosis have not replicated this finding, and polymerase chain reaction evaluation has shown inconsistent results; most were negative. The provocative 1973 case series13 reported on individuals with respiratory disorders, the majority of which were misdiagnosed sarcoidosis, in which the correct diagnosis—fungal or mycobacterial disease—was delayed due to the confounding effect of histologic similarity. In addition, several cases exhibited an association with a fungal agent in which it appeared that the latter was a consequence of sarcoidosis (semi-invasive aspergillosis), CST (Cryptococcus neoformans), or fortuitous (cutaneous sporotrichosis). Case 5, in which a firm diagnosis of sarcoidosis was succeeded by tuberculosis, is a good example, I think, of the overlap between an immunologic vs an infectious response to Mycobacterium tuberculosis, paralleling the spectrum of PDH cited above. In summary, while I agree that sarcoidosis is etiologically heterogeneous, and an abnormal cellular response its underlying cause, the two articles lack persuasive evidence of the correctness of either proposition.

References
Scadding, JG, Mitchell, DN Definition.Sarcoidosis 2nd ed.1985,36-42 Chapman and Hall. London, UK:
 
Rossman, MD, Kreider, ME Is chronic beryllium disease sarcoidosis of known etiology?Sarcoidosis Vasc Diffuse Lung Dis2003;20,104-109. [PubMed]
 
Thomas, PD, Hunninghake, GW State of the art: current concepts of the pathogenesis of sarcoidosis.Am Rev Respir Dis1987;135,747-760. [PubMed]
 
Munro, CS, Mitchell, DN, Poulter, LW, et al Immunological processes active in developing Kveim responses differ in normal and sarcoidosis subjects [abstract]. Am Rev Respir Dis. 1986;;132(Suppl) ,.:A244
 
Reich, JM Mortality of intrathoracic sarcoidosis in referral vs. population-based settings: influence of stage, ethnicity, and corticosteroid therapy.Chest2002;121,32-39. [CrossRef] [PubMed]
 
Reich, JM Adverse long-term effect of corticosteroid therapy in recent-onset sarcoidosis.Sarcoidosis Vasc Diffuse Lung Dis2003;20,227-234. [PubMed]
 
Wheat, JL, Morris, LV, French,, et al Sarcoidlike manifestations of histoplasmosis.Arch Intern Med1989;149,2421-426. [CrossRef] [PubMed]
 
Reich, JM Deciphering histoplasmosis, systemic noncaseating granuloma, and sarcoidosis in the literature [letter]. Chest. 1998;;113 ,.:1143
 
Hillerdal, G, Nou, E, Osterman, K, et al Sarcoidosis: epidemiology and prognosis: a 15-year European study.Am Rev Respir Dis1984;130,29-32. [PubMed]
 
Johnston, RN Pulmonary sarcoidosis after ten to twenty years.Scott Med J1986;31,72-78. [PubMed]
 
Hunninghake, GW, Costabel, U, Ando, M, et al ATS, ERS, WASOG statement on sarcoidosis.Am J Respir Crit Care Med1999;160,736-755. [PubMed]
 
Schwarz, J, Vanek, J Demonstration of acid fast rods in sarcoidosis.Am Rev Respir Dis1970;101,395-400. [PubMed]
 
Baum, GL, Schwarz, J, Barlow, PB Sarcoidosis and specific etiologic agents: a continuing enigma.Chest1973;63,488-494. [CrossRef] [PubMed]
 

Figures

Tables

References

Reich, JM (2003) What is sarcoidosis?Chest124,367-371. [CrossRef] [PubMed]
 
Judson, M The etiologic agent of sarcoidosis: what if there isn’t one?Chest2003;124,6-8. [CrossRef] [PubMed]
 
DeRemee, RA The present status of treatment of pulmonary sarcoidosis: a house divided.Chest1977;71,388-393. [CrossRef] [PubMed]
 
DeRemee, RA The sarcoid polemic.Chest1969;55,445-446. [CrossRef]
 
Reich, JM What is sarcoidosis?Chest2003;124,367-371. [CrossRef] [PubMed]
 
Schwarz, J, Vanek, J Demonstration of acid fast rods in sarcoidosis.Am Rev Respir Dis1970;101,395-400. [PubMed]
 
Baum, GL, Schwarz, J, Barlow, PB Sarcoidosis and specific etiologic agents: a continuing enigma.Chest1973;63,488-494. [CrossRef] [PubMed]
 
Scadding, JG, Mitchell, DN Definition.Sarcoidosis 2nd ed.1985,36-42 Chapman and Hall. London, UK:
 
Rossman, MD, Kreider, ME Is chronic beryllium disease sarcoidosis of known etiology?Sarcoidosis Vasc Diffuse Lung Dis2003;20,104-109. [PubMed]
 
Thomas, PD, Hunninghake, GW State of the art: current concepts of the pathogenesis of sarcoidosis.Am Rev Respir Dis1987;135,747-760. [PubMed]
 
Munro, CS, Mitchell, DN, Poulter, LW, et al Immunological processes active in developing Kveim responses differ in normal and sarcoidosis subjects [abstract]. Am Rev Respir Dis. 1986;;132(Suppl) ,.:A244
 
Reich, JM Mortality of intrathoracic sarcoidosis in referral vs. population-based settings: influence of stage, ethnicity, and corticosteroid therapy.Chest2002;121,32-39. [CrossRef] [PubMed]
 
Reich, JM Adverse long-term effect of corticosteroid therapy in recent-onset sarcoidosis.Sarcoidosis Vasc Diffuse Lung Dis2003;20,227-234. [PubMed]
 
Wheat, JL, Morris, LV, French,, et al Sarcoidlike manifestations of histoplasmosis.Arch Intern Med1989;149,2421-426. [CrossRef] [PubMed]
 
Reich, JM Deciphering histoplasmosis, systemic noncaseating granuloma, and sarcoidosis in the literature [letter]. Chest. 1998;;113 ,.:1143
 
Hillerdal, G, Nou, E, Osterman, K, et al Sarcoidosis: epidemiology and prognosis: a 15-year European study.Am Rev Respir Dis1984;130,29-32. [PubMed]
 
Johnston, RN Pulmonary sarcoidosis after ten to twenty years.Scott Med J1986;31,72-78. [PubMed]
 
Hunninghake, GW, Costabel, U, Ando, M, et al ATS, ERS, WASOG statement on sarcoidosis.Am J Respir Crit Care Med1999;160,736-755. [PubMed]
 
Schwarz, J, Vanek, J Demonstration of acid fast rods in sarcoidosis.Am Rev Respir Dis1970;101,395-400. [PubMed]
 
Baum, GL, Schwarz, J, Barlow, PB Sarcoidosis and specific etiologic agents: a continuing enigma.Chest1973;63,488-494. [CrossRef] [PubMed]
 
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