Original articles
Design of A Case Control Etiologic Study of Sarcoidosis (ACCESS),☆☆

https://doi.org/10.1016/S0895-4356(99)00142-0Get rights and content

Abstract

Sarcoidosis is a chronic granulomatous disorder of unknown cause, characterized by activation of T-lymphocytes and macrophages. A Case Control Etiologic Study of Sarcoidosis (ACCESS) is a multicenter study designed to determine the etiology of sarcoidosis. The study organization includes 10 Clinical Centers, a Clinical Coordinating Center, specialized Core Laboratories, a Central Specimen Repository, and a Project Office at the National Heart, Lung, and Blood Institute. In addition to etiology, ACCESS will examine the socioeconomic status and clinical course of patients with sarcoidosis. We propose to enroll 720 newly diagnosed cases of sarcoidosis and compare them to 720 age, sex, and race matched controls and follow the first 240 cases for two years.

Leads to the etiology of sarcoidosis have come from diverse sources: in clinical laboratory investigations, alveolitis has been found to precede granulomatous inflammation; in case control studies, familial aggregation has been identified; and in case reports, recurrence of granulomatous inflammation has been observed after lung transplantation. We describe the rationale for the study design based on genetic, environmental, infectious, and immune dysregulation hypotheses and the methods used for selecting controls.

The cause may not prove to be a single, known exposure. Interactions of exposures with genetic predispositions would have important implications for our understanding of immune responses as well as the pathogenesis of sarcoidosis.

Introduction

Sarcoidosis is a chronic granulomatous disorder of unknown cause that is characterized by activation of T-lymphocytes and macrophages 1, 2, 3. For many years, sarcoidosis was presumed to be an atypical manifestation of tuberculosis because of the similarity between the inflammatory responses of the two diseases. However, as culture techniques became more widely employed to diagnose tuberculosis and tuberculosis became less common, it became clear that sarcoidosis was not simply a variation of tuberculosis.

When the diagnosis of sarcoidosis became more specific, studies were performed to determine the incidence and prognosis of the disease 4, 5, 6. These studies provided more information on sarcoidosis, but they provided a biased view. Studies of the age, race, and residence of Americans with sarcoidosis emphasized the predominance of this disease in African-Americans over Caucasians in the United States. These studies also suggested that a rural background was quite common in this disease. A sarcoid belt was defined in the Central-Atlantic states. However, many of these observations were based on a selected population, United States veterans admitted to the Veterans Administration hospitals. These were men who had previously been healthy enough to serve in the military. International epidemiologic studies have focused on the differences among countries in the incidence and manifestations of sarcoidosis 7, 8.

The definitive diagnosis of sarcoidosis requires tissue confirmation of granuloma, with no evidence of mycobacterial or fungal infections 9, 10, but many epidemiologic studies did not require tissue diagnosis. Instead they relied on chest roentgenograms which are not specific. Studies based on autopsy may not be representative of patients with sarcoidosis, since the disease may totally resolve and the percentage of patients dying of sarcoidosis is less than 5%. [11]. Also, the data obtained from autopsy studies are limited since work and social histories are usually not available. Complete and valid case ascertainment as well as accurate medical, occupational, and social histories are important in the search for specific etiologies.

A Case Control Etiologic Study of Sarcoidosis (ACCESS) is a multicenter study designed to determine the etiology of sarcoidosis. The study organization includes ten Clinical Centers, a Clinical Coordinating Center, specialized Core Laboratories, a Central Specimen Repository, and a Project Office at the National Heart, Lung, and Blood Institute. In addition to etiology, ACCESS will examine the socioeconomic status and clinical course of patients with sarcoidosis. ACCESS proposes to enroll 720 newly diagnosed cases of sarcoidosis and compare them to 720 age, sex, and race matched controls and follow the clinical course of 240 cases for two years. This report describes the rationale for the study design, the methods used for selecting controls, and four major categories of etiologic hypotheses—genetic, environmental, infectious, and immune dysregulation.

Section snippets

Case and Control Selection

A case control study is the most appropriate design to assess possible etiologic factors of a relatively low incidence disease such as sarcoidosis [12]. In ACCESS, incident cases and matched controls will be compared on the prevalence of various exposures prior to the date of diagnosis of sarcoidosis. Information on exposures will be obtained through interview.

Some earlier case control studies had a large proportion of cases that may have had sarcoidosis for years prior to enrollment which

Genetic Aspects of Sarcoidosis

Genetic susceptibility to sarcoidosis is suggested by ethnic variation, a greater concordance of disease in monozygotic than dizygotic twins and by reports of familial aggregation 2, 17, 18. Over four hundred kindreds with more than one member affected with sarcoidosis have been reported [19]. Moreover, one study found that 19% of African-American patients and 6% of Caucasians report a positive family history of sarcoidosis [20].

In the context of a case control study design, three aspects of

Conclusion

Sarcoidosis has been well characterized pathologically, and the most interesting research results in recent years have addressed the cellular mechanisms of disease activity. Conclusions about etiologic factors which would be of use in treatment or primary prevention of sarcoidosis have been difficult to reach. Previous studies of the etiology and clinical course of sarcoidosis in the United States, especially in black patients in the United States, have been limited to relatively small numbers

Acknowledgements

This research is supported by contracts NO1-HR-56065 through NO1-HR-56075 from the National Heart, Lung, and Blood Institute.

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    Members of the ACCESS Research Group are listed in Appendix 1.

    ☆☆

    The content of this article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

    *

    Principal Investigator(s) for ACCESS Research Group.

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