opinions/hypotheses What Is Sarcoidosis? Jerome M. Reich, MD, FCCP

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1 opinions/hypotheses What Is Sarcoidosis? Jerome M. Reich, MD, FCCP (CHEST 2003; 124: ) Key words: drug therapy; granuloma; histoplasmosis; Kveim; sarcoidosis; tuberculosis 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 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 histoplasmo- For editorial comment see page 6 sis 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 *Dr. Reich is in private practice in Portland, OR. Manuscript received March 18, 2002; revision accepted October 11, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: Jerome M. Reich, MD, FCCP, 5051 SW Barnes Rd, Portland, OR 97221; Reichje@dnamail.com 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 enigmatic 2 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 CHEST / 124 / 1/ JULY,

2 conclusive diagnosis of sarcoidosis in a doubtful case (such as the one presented). Scadding 5 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 Hunninghake 6 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 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 al 15 employed immunohistologic techniques 16 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 Hunninghake 6 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. Scadding 5 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 368 Opinions/Hypotheses

3 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 al 19 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 Haslam 23 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 al 24 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, 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 al 32 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 population 33 (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 lymphocytemediated 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 al 35 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 imwww.chestjournal.org CHEST / 124 / 1/ JULY,

4 mune 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 HAARTinduced 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 al 36 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-DR14 6 and HLA-DR15 2 were each associated with chronic disease. McGrath et al 37 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 The operational definition of sarcoidosis advanced by Scadding and Mitchell 4 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 cellmediated 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. References 1 Wheat LJ, French ML, Wass JL. 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