Chest Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Full Text (PDF) Free
Right arrow Erratum (v124,p1181)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Reich, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reich, J. M.
(Chest. 2003;124:367-371.)
© 2003 American College of Chest Physicians

What Is Sarcoidosis?

Jerome M. Reich, MD, FCCP

* Dr. Reich is in private practice in Portland, OR.

Correspondence to: Jerome M. Reich, MD, FCCP, 5051 SW Barnes Rd, Portland, OR 97221; e-mail: Reichje{at}dnamail.com

Key Words: drug therapy • granuloma • histoplasmosis • Kveim • sarcoidosis • tuberculosis


   Introduction
TOP
 Introduction
Conclusions
 References
 
I recently consulted on a young woman who had acquired fever, profuse pulmonary shadowing, and liver function abnormalities following a 1997 visit from her residence in upstate New York to the Mississippi Valley. An open-lung biopsy at that time revealed noncaseating epithelioid granulomas (NCG) consistent with sarcoidosis; fungal elements were not evident. The treating physician initiated prednisone therapy, but after a week, a histoplasmosis complement fixation titer of 512, later supplemented by isolation of Histoplasma capsulatum organisms from the biopsy sample, led to its replacement with a short course of amphotericin B, followed by months of itraconazole therapy, with the expectation that her progressive disseminated histoplasmosis would resolve. She was unavailable for follow-up until 2001, when she was re-referred for evaluation of increasingly severe shortness of breath. Prednisone had been provided by her primary physician. A chest radiograph showed profuse pulmonary shadowing; high-resolution CT demonstrated findings characteristic of advanced stage IV sarcoidosis; pulmonary function tests revealed a severe restrictive defect accompanied by a marked reduction in diffusing capacity. Prednisone was discontinued because of the concern that her histoplasmosis had relapsed. BAL fluid was negative for histoplasma antigens and showed no stainable or culturable H capsulatum; her histoplasma complement fixation titer was zero. Her alkaline phosphatase was markedly elevated. CT of her abdomen showed numerous, homogeneously distributed microlucencies in her liver indicative of either micronodules or microabscesses. A percutaneous liver biopsy demonstrated NCG; no organisms were visible and fungal culture showed no growth. A marked progression of the abnormalities identified on her pulmonary function testing, following 1 week of prednisone omission, led to its reinstitution; itraconazole was added to prevent relapse of histoplasmosis. The physicians participating in her care concluded that, whereas previously she had chronic progressive disseminated histoplasmosis, she now had stage IV sarcoidosis.

I cite this vignette not because it is unique—the association of histoplasmosis with systemic NCG indistinguishable clinically and histopathologically from sarcoidosis has previously been reported,1 though the nature of the relationship remains enigmatic2 —but because it raises the issue of what we mean when we state that a patient has sarcoidosis. The descriptive definition provided in the American Thoracic Society statement,3 "Sarcoidosis is a multisystem disorder of unknown cause(s).... The diagnosis is established when clinicoradiologic findings are supported by histologic evidence of noncaseating epithelioid cell granulomas. Granulomas of known causes ... must be excluded ..." leads, in this patient, to a self-contradiction, for it is unreasonable to conclude that identical histopathologic changes in the same organs in the selfsame individual denote different diseases. Scadding and Mitchell,4 providing cogent arguments against this definition, recommended the omission of a priori assumptions about etiology, and defined sarcoidosis histologically: "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." The authors believed that this operational definition would permit nearly all informed observers to arrive at a conclusive diagnosis of sarcoidosis in a doubtful case (such as the one presented). Scadding5 pointed to erythema nodosum as a possibly analogous example of a well-defined clinical syndrome, with equally well-defined and constant histology, which was known to be etiologically heterogeneous. Thomas and Hunninghake6 suggested that "the disease might be triggered by different agents ... the factor that would determine the development of the disease we recognize as sarcoidosis would be the host’s immune response to the inciting agent" [italics added]. Histoplasmosis,1 2 tuberculosis,5 and neoplastic disorders,7 each capable of eliciting local or regional NCG responses, have been associated with systemic responses of the same type.

What, beyond the development of NCG, is known of the "host’s immune response to the inciting agent?" Because Kveim-induced granulomas resemble those of sarcoidosis microscopically, cellular composition, and phenotype as assessed by monoclonal antibodies,8 9 10 11 12 13 the test provides a means of examining the host’s early immune response,14 and may therefore be considered a sarcoidosis paradigm in which cellular and immunologic events recapitulate those of the disease. The Kveim test is analogous in some respects to the late (Mitsuda) reaction to the lepromin test, which is also performed by intradermal injection of a suspension of diseased tissue and requires 4 to 5 weeks to mature; histologically resembling a positive Kveim response, it is typically positive in the paucibacillary tuberculoid form of leprosy (believed to be a T-helper type 1 response) and negative in the multibacillary lepromatous form (believed to be a T-helper type 2 response)—ie, it distinguishes an immunologic response, not an etiologic one.

To elucidate the pathogenesis of the sarcoid granuloma, Munro et al15 employed immunohistologic techniques16 comparing the early responses to intradermal Kveim suspension in known Kveim-negative sarcoidosis patients and healthy control subjects with Kveim-positive sarcoidosis patients. At 11 days and 18 days (ie, 3 to 4 weeks prior to maturation), the majority of Kveim-negative sarcoidosis patients and healthy control subjects responded with features characteristic of delayed-type hypersensitivity reactions (as typified by the tuberculin test): a dense perivascular infiltrate of mononuclear cells composed of T cells of helper and suppresser types, with markers of activation (Tac+, Leu9+), and dendritic Langerhans cells (OKT6+, RFD+) with strong human leukocyte antigen (HLA)-DR expression. In contrast, among Kveim-positive sarcoidosis patients, a comparable infiltrate developed in only one patient. In the more gradual response developed, characterized by close associations of phagocytic macrophages and helper T cells, some of which were also Tac+, dendritic Langerhans cells were not seen. Thus, persons who respond positively to the Kveim test differ qualitatively from those who do not, by failing to exhibit the features of delayed-type hypersensitivity at 11 days and 18 days.

This observation suggests that the fundamental abnormality of sarcoidosis is "upstream" of the granuloma, and that the latter therefore may represent an "immunologic fallback position" or "alternative pathway" in persons constitutionally unable to respond to the putative etiologic agent(s) by more efficient means (C.S. Munro, MD; personal communication; 1996)—ie, that the granulomas of sarcoidosis are a more primitive and inefficient host immune response, a response to a deficit in antigen processing that comes into play when the demonstrably immunoparetic T-cell mechanism fails (C.S. Munro, MD; written communication; 1994) The joint hypotheses that sarcoidosis represents an idiosyncratic response to a variety of antigens, and that the granulomas reflect an antecedent deficit in cellular immune processing would both predict and provide a unifying conceptual framework for the following diverse observations:

  1. The putative etiologic agent of sarcoidosis would elude identification, for a variety of antigenic exposures in predisposed persons—as suggested by Thomas and Hunninghake6 —might elicit a systemic granulomatous response. Berylliosis is the best characterized example of this phenomenon: it develops in only 1 to 3% of exposed persons, and it is strongly associated with HLA-DPB1 glutamate 69 allele, suggesting a genetic predisposition.17 The percentage of normal individuals who respond positively to the Kveim test (0.7 to 2%),14 of persons identified with sarcoidosis in association with histoplasmosis outbreaks (0.7%),1 and malignant neoplasia (2.5%),7 is of the same order. Scadding5 reported a case series of sarcoidosis associated with tuberculosis; however, the proportion of individuals with sarcoidosis in whom this organism appeared to be etiologically linked is not known. Drent et al,18 employing electron microscopy and dispersive radiograph analysis, reported, among their Netherlands sarcoidosis population of 50 individuals, that there was strong association of pulmonary sarcoid-like granulomas with intragranulomatous deposits of silica, aluminum, and titanium in persons with a work history of exposure to man-made mineral fibers (MMMFs) [rock wool]. Their radiographic pattern was distinguished from that in unexposed individuals with sarcoidosis by being exclusively stages II, III, and IV, and clinically, by their lack of response to therapy. Unfortunately, the authors were unable to provide a percentage figure for this response in MMMF-exposed individuals. This response appears to be quite unusual, as Hughes et al19 found no evidence of clinically relevant respiratory health effects in a survey of > 1,000 US workers exposed to MMMF, though, whether the mineral exposures in the two countries are identical is unknown.
  2. A favorable outcome would be expected in affected individuals exhibiting a brisk granulomatous response. Patients with an acute onset of stage I disease with erythema nodosum, who are known to have a highly favorable prognosis, characteristically exhibit high-intensity lymphocytic alveolitis.20 21 Conversely, persons with high-intensity lymphocytic alveolitis at any stage exhibit more favorable outcomes.22 23 This observation led Haslam23 to hypothesize that patients "with more efficient inflammatory responses may be better able to eliminate an unknown agent or antigenic stimulus in sarcoidosis."
  3. Conversely, one would expect the outcome in patients to be adversely affected by the suppression of the granulomatous response. Milburn et al24 demonstrated that corticosteroid therapy (CST) in sarcoidosis down-regulates the T-helper type 1 response (granulomatous inflammation followed by resolution) in favor of the T-helper type 2 (pulmonary fibrosis) cytokine response. Cumulative sarcoidosis mortality in referral settings (4.8%), which provided CST to 41% of their patients, was 10-fold that in population-based settings (0.5%), in which CST was provided to 6%. After correction for adverse selection (as indicated by the proportion with stages III and IV), the difference in mortality was sixfold.25 In an analysis (J. Reich, MD; unpublished data; 2001) of five competent controlled studies of CST in early stage II and III disease,26 27 28 29 30 31 long-term adverse outcomes—radiographic deterioration, progressive multisystem sarcoidosis—were consistently higher (range of odds ratios, 2.0 to 6.9) in the treated cohorts and deaths due to sarcoidosis were seen only in CST recipients.
  4. The conclusions of Munro would lead one to predict that persons with CD4+ T-lymphocyte deficiencies would be at increased risk of acquiring sarcoidosis. Fasano et al32 reported the occurrence of sarcoidosis in 8 of 80 patients (10%) with common variable immunodeficiency in the combined case registries of Johns Hopkins University and Children’s Hospital of Philadelphia, and identified an additional 22 cases of this association in a literature survey. Common variable immunodeficiency (acquired hypogammaglobulinemia) is a rare disorder of unknown cause, in which up to 50% of affected individuals have an associated deficiency in T lymphocytes. Notably, all eight of the reported patients had chronic sarcoidosis, and T-lymphocyte deficiency was identified in the seven patients in whom subset characterization was reported. This 10% prevalence is seven times the estimated lifetime risk of acquiring ascertainable sarcoidosis in a screened Scandinavian population33 (an ethnicity with a notably high incidence). If, as suggested by Munro, the granulomatous character of a positive Kveim test result reflects an inefficient immunologic response, one would predict that individuals who failed to respond to antigens that elicit a lymphocyte-mediated response might exhibit positive Kveim responses. Hart et al,34 in a study comparing the Kveim responses of bacille Calmette-Guérin (BCG) nonconverters vs converters and persons not immunized because of a positive tuberculin test result, reported that "positive reactions to the Kveim test were found in a large proportion of clinically normal young adults who had failed to be ‘converted’ to tuberculin sensitivity following two BCG vaccinations." Nonconverters with histologically positive test results characteristically showed large nodules at 4 weeks in response to the Kveim test, which were not seen in BCG converters or in persons who were not immunized because of previous tuberculin sensitivity. Nonconverters also exhibited a marked reduction in their skin test response to Candida albicans but not to streptokinase-streptodornase as compared with converters and nonimmunized persons. None of the participants had evidence of current or remote sarcoidosis. Gomez et al35 ably summarized 12 reported instances of sarcoidosis coinciding with AIDS. In seven patients not receiving highly active antiretroviral therapy (HAART), the CD4 lymphocyte count was only modestly reduced. In five patients with sarcoidosis developing as a manifestation of immune reconstitution following HAART, the onset of sarcoidosis coincided with CD4 repletion to normal or near-normal levels. One possible interpretation of this data is that AIDS-induced CD4 depletion impaired normal cellular immune processing in a fashion similar to that seen in common variable immune deficiency; that, as a consequence, granulomatous responses to an undefined antigen(s) evolved as an immunologic fallback, which became evident in AIDS patients with only mild CD4 depletion, and in severely CD4- depleted individuals only following HAART- induced CD4 repletion.
  5. If the propensity to acquire sarcoidosis were dependent, in part, on the efficiency with which certain antigen classes are presented to or processed by CD4+ T lymphocytes, there would be an expected variance in incidence or course in persons possessing certain HLA II alleles. Berlin et al36 found both to be the case when the authors matched the HLA haplotypes of 122 Scandinavian patients with sarcoidosis against a healthy group of 250 control subjects: HLA-DR17 was twice as frequent in the former than the latter; and HLA-DR146 and HLA-DR152 were each associated with chronic disease. McGrath et al37 provided a current, thorough review of the association between the major histocompatibility complexes and both the incidence and course of sarcoidosis, in addition to infectious etiologic candidates.


   Conclusions
TOP
 Introduction
 Conclusions
References
 
The operational definition of sarcoidosis advanced by Scadding and Mitchell4 circumvents ambiguities that arise from the currently accepted descriptive definition. Subsumed within this definition is the concept that sarcoidosis is, most likely, etiologically heterogeneous.

It appears likely that the granulomas characterizing sarcoidosis are a response to an antecedent, inefficient, and uncharacterized abnormality in cell-mediated immunity. Its corollary—that suppression of this response with CST adversely affects the long-term course in some individuals with early sarcoidosis—is amply supported both by the outcomes in tertiary vs population-based settings and controlled trials.


   Footnotes
 
Abbreviations: BCG = bacille Calmette-Guérin; CST = corticosteroid therapy; HAART = highly active antiretroviral therapy; HLA = human leukocyte antigen; MMMF = man-made mineral fibers; NCG = noncaseating epithelioid granuloma

Received for publication March 18, 2002. Accepted for publication October 11, 2002.


   References
TOP
 Introduction
 Conclusions
 References
 

  1. Wheat, LJ, French, ML, Wass, JL (1989) Sarcoidlike manifestations of histoplasmosis. Arch Intern Med 149,2421-2426[CrossRef][ISI][Medline]
  2. Reich, JM Deciphering histoplasmosis, systemic noncaseating granuloma, and sarcoidosis in the literature [letter]. Chest 1998;113,1143[Free Full Text]
  3. Hunninghake, GW, Costabel, U, Ando, M, et al ATS, ERS, WASOG statement on sarcoidosis. American Thoracic Society, European Respiratory Society, World Association of Sarcoidosis and other Granulomatous Disorders. Am J Respir Crit Care Med 1999;160,736-755[Free Full Text]
  4. Scadding, JG, Mitchell, DN Definition. Sarcoidosis 1985,36-42 Chapman and Hall. London, UK:
  5. Scadding, JG Mycobacterium tuberculosis in the aetiology of sarcoidosis. BMJ 1960;2,1617-1623
  6. Thomas, PD, Hunninghake, GW State of the art: current concepts of the pathogenesis of sarcoidosis. Am Rev Respir Dis 1987;135,747-760[ISI][Medline]
  7. Reich, JM, Mullooly, JP, Johnson, RE Linkage analysis of malignancy-associated sarcoidosis. Chest 1995;107,605-613[Abstract/Free Full Text]
  8. James, DG, Thompson, DG The Kveim test in sarcoidosis. Q J Med 1995;24,49-60
  9. Douglas, SD, Siltzbach, LE Electron microscopy of Kveim biopsies in sarcoidosis. Iwai, K Hosoda, K eds. Sixth international conference on sarcoidosis 1974,54-56 University Press. Tokyo, Japan:
  10. Mitchell, DN, Scadding, JG, Heard, BE, et al Sarcoidosis: histopathological definition and clinical diagnosis. J Clin Pathol 1977;30,395-408[Abstract/Free Full Text]
  11. Mishra, BB, Poulter, LW, Janossy, G, et al The distribution of lymphoid and macrophage like cell subsets of sarcoid and Kveim granulomata: possible mechanism of negative PPD reaction in sarcoidosis. Clin Exp Immunol 1983;54,705-715[ISI][Medline]
  12. Martin, AG, Kleinherz, ME, Elmets, CA Immunohistologic identification of antigen-presenting cells in cutaneous sarcoidosis. J Invest Dermatol 1986;86,625-628[CrossRef][ISI][Medline]
  13. Munro, CS, Campbell, DA, du Bois, RM, et al Dendritic cells in cutaneous, pulmonary and lymph node lesions of sarcoidosis. Scand J Immunol 1987;25,461-467[CrossRef][ISI][Medline]
  14. Munro, CS The Kveim response: still useful, still a puzzle [editorial]. Thorax 1987;42,321-331[Free Full Text]
  15. 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
  16. Munro, CS, Mitchell, DN, Poulter, LW, et al Early cellular responses to intradermal injection of Kveim suspension in normal subjects and those with sarcoidosis. J Clin Pathol 1986;39,176-182[Abstract/Free Full Text]
  17. Meyer, KC Beryllium and lung disease. Chest 1994;106,942-946[Free Full Text]
  18. Drent, M, Bomans, PHH, Van Suylen, RJ, et al Association of man-made mineral fiber exposure and sarcoidlike granulomas. Respir Med 2000;94,815-820[CrossRef][ISI][Medline]
  19. Hughes, JM, Jones, RN, Glindemeyer, HW, et al Follow up study of workers exposed to man made mineral fibres. Br J Ind Med 1993;50,658-667[ISI][Medline]
  20. Ward, K, O’Connor, C, Odlum, C, et al Prognostic value of bronchoalveolar lavage in sarcoidosis: the critical influence of disease presentation. Thorax 1989;44,6-12[Abstract/Free Full Text]
  21. Valeyre, D, Saumon, G, Georges, R, et al The relationship between disease duration and noninvasive pulmonary explorations in sarcoidosis with erythema nodosum. Am Rev Respir Dis 1984;129,938-943[ISI][Medline]
  22. Foley, NM, Coral, AP, Tung, K, et al Bronchoalveolar lavage cell counts as a predictor of short term outcome in pulmonary sarcoidosis. Thorax 1989;44,732-738[Abstract/Free Full Text]
  23. Haslam, PL Clinical evaluation of different markers of inflammation in relation to disease activity and long-term outcome in pulmonary sarcoidosis. Sarcoidosis 1992;(Suppl 1),37-42
  24. Milburn, HJ, Poulter, LW, Dilmec, A, et al Corticosteroids restore the balance between locally produced Th1 and Th2 cytokines and immunoglobulin isotypes to normal in sarcoid lung. Clin Exp Immunol 1997;108,105-113[CrossRef][ISI][Medline]
  25. Reich, JM Mortality of intrathoracic sarcoidosis in referral vs population-based settings: influence of stage, ethnicity, and corticosteroid therapy. Chest 2002;121,32-39[Abstract/Free Full Text]
  26. Young, RL, Harkleroad, LE, Lordon, RE, et al Pulmonary sarcoidosis: a prospective evaluation of glucocorticoid therapy. Ann Intern Med 1970;73,207-212[ISI][Medline]
  27. Harkleroad, LE, Young, RL, Savage, PJ, et al Pulmonary sarcoidosis: long-term follow-up of the effects of steroid therapy. Chest 1982;82,84-87[Abstract/Free Full Text]
  28. Israel, HL, Fouts, DW, Beggs, RA A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis 1973;107,609-614[ISI][Medline]
  29. Eule, H, Weinecke, A, Roth, I The possible influence of corticosteroid therapy on the natural course of sarcoidosis. Ann N Y Acad Sci 1986;465,695-701[ISI][Medline]
  30. Selroos, O, Niemistö, M, Riska, N A follow-up study of treated and untreated early sarcoidosis. Iwai, K Hosoda, Y eds. Proceedings of the VI International Conference on Sarcoidosis, Tokyo 1972 1974,525-528 University of Tokyo Press. Tokyo, Japan:
  31. Viskum, K, Vestbo, J Vital prognosis in intrathoracic sarcoidosis with special reference to pulmonary function and radiographic stage. Eur Respir J 1993;6,349-353[Abstract]
  32. Fasano, MB, Sullivan, KE, Sarpong, SB, et al Sarcoidosis and common variable immunodeficiency: report of 8 cases and review of the literature. Medicine 1996;75,251-261[CrossRef][Medline]
  33. Hillerdal, G, Nou, E, Osterman, K, et al Sarcoidosis: epidemiology and prognosis: a 15-year European study. Am Rev Respir Dis 1984;130,29-32[ISI][Medline]
  34. Hart, DP, Mitchell, DN, Sutherland, I Associations between Kveim test results, previous BCG vaccination, and tuberculin sensitivity in healthy young adults. BMJ 1964;5386,795-804[ISI][Medline]
  35. Gomez, V, Smith, PR, Burack, J, et al Sarcoidosis after antiretroviral therapy in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2000;31,1278-1280[CrossRef][ISI][Medline]
  36. Berlin, M, Fogdell-Hahn, A, Olerup, O, et al HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 1997;156,1601-1605[Abstract/Free Full Text]
  37. McGrath, DS, Goh, N, Foley, PJ, et al Sarcoidosis: genes and microbes—soil or seed? Sarcoidosis Vasc Diffuse Lung Dis 2001;18,149-164[ISI][Medline]



This article has been cited by other articles:


Home page
 J. Clin. Pathol.Home page
A Brunner, J Kantner, and A Tzankov
Granulomatous reactions cause symptoms or clinically imitate treatment resistance in small lymphocytic lymphoma/chronic lymphocytic leukaemia more frequently than in other non-Hodgkin lymphomas
J. Clin. Pathol., August 1, 2005; 58(8): 815 - 819.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
D. M. Skillrud, G. L. Baum, and J. Reich
Sarcoidosis Cycle
Chest, March 1, 2004; 125(3): 1171 - 1172.
[Full Text] [PDF]

This Article
Right arrow Full Text (PDF) Free
Right arrow Erratum (v124,p1181)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Reich, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reich, J. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS