Correspondence
Sarcoidosis
N Engl J Med 2008; 358:1402-1405March 27, 2008
- Article
To the Editor:
We respectfully challenge the notion of Iannuzzi and colleagues (Nov. 22 issue)1 that in all cases (other than cases of Löfgren's syndrome) “a biopsy specimen should be obtained from the involved organ that is most easily accessed.” We believe that not all patients with sarcoidosis require a tissue biopsy. Physicians can be confident of a diagnosis of sarcoidosis in some patients after clinical, radiographic, and epidemiologic considerations, much in the same way that idiopathic pulmonary fibrosis can be diagnosed with high specificity in patients with typical clinical and high-resolution computed tomographic (CT) findings.2,3 Asymptomatic patients with hilar adenopathy, especially with erythema nodosum, should be informed of the small but real chance of an alternative diagnosis, as well as the equally small but real chance of a complication of a biopsy. This is an area ripe for a prospective evaluation.
3 ReferencesJames A. Murray, D.O.
Jason L. Lyons, M.D.
Unity Pulmonary Medicine, Rochester, NY 146261
Iannuzzi MC ,Rybicki BA ,Teirstein AS . Sarcoidosis. N Engl J Med 2007;357:2153-2165
Full Text | Web of Science | Medline2
Hiraga Y, Hosoda Y. Acceptability of epidemiological diagnostic criteria for sarcoidosis without histological confirmation. In: Mikami R, Hosoda Y, eds. Sarcoidosis. Tokyo: University of Tokyo Press, 1981:373-7.
3
Raghu G ,Mageto YN ,Lockhart D ,Schmidt RA ,Wood DE ,Godwin JD . The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study. Chest 1999;116:1168-1174
CrossRef | Web of Science | Medline
To the Editor:
As Iannuzzi et al. rightly point out, sarcoidosis occurs in all racial and ethnic groups. However, the diagnosis of sarcoidosis in regions of the world where tuberculosis is endemic poses a great challenge. Despite invasive diagnostic evaluation, it is often difficult to rule out categorically a diagnostic possibility of tuberculosis. A clinician would often be tempted to diagnose Löfgren's syndrome in a patient presenting with fever, erythema nodosum, bilateral ankle arthritis, and hilar lymphadenopathy. However, none of the features conventionally cited, such as necrosis on imaging or histologic assessment, acid-fast bacilli in tissue specimens, or mycobacterial cultures, when negative, have a sensitivity that is sufficient to bring the post-test probability below the treatment threshold for tuberculosis, since the pretest probability is very high in such settings.1 In other words, as it is often said, the absence of evidence of tuberculosis is not evidence of its absence. A tuberculin skin test, if positive, weighs strongly against a diagnosis of sarcoidosis in such clinical situations.2
2 ReferencesSurendra K. Sharma, M.D., Ph.D.
Tamilarasu Kadhiravan, M.D.
All India Institute of Medical Sciences, New Delhi 110608, India
sksharma@aiims.ac. in 1
Kopelman RI ,Wong JB ,Pauker SG . A little math helps the medicine go down. N Engl J Med 1999;341:435-439
Full Text | Web of Science | Medline2
Smith-Rohrberg D ,Sharma SK . Tuberculin skin test among pulmonary sarcoidosis patients with and without tuberculosis: its utility for the screening of the two conditions in tuberculosis-endemic regions. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:130-134
Web of Science | Medline
To the Editor:
Iannuzzi et al. outline the potential environmental causes of sarcoidosis. However, there is no mention of chronic beryllium disease, a granulomatous disease primarily affecting the lungs and due to beryllium sensitization.1-3
Chronic beryllium disease, which has been diagnosed in 6% of a cohort of patients with sarcoidosis, strongly resembles this condition.2 Associated with occupational exposure and inhalation of beryllium compounds, chronic beryllium disease may lead to the development of noncaseating granulomas in sensitized persons.
Microscopically, the histopathological features of sarcoidosis are otherwise indistinguishable from those of chronic beryllium disease.2,3 A useful blood test, the beryllium lymphocyte proliferation test, may differentiate these two conditions.2-4
Chronic beryllium disease should be considered as an important entity in the differential diagnosis of sarcoidosis.
4 ReferencesGianpaolo Guzzi, D.D.S.
Italian Association for Metals and Biocompatibility Research, 20122 Milan, Italy
gianpaolo_guzzi@fastwebnet.it Gianluca Severi, Ph.D.
Cancer Council Victoria, Melbourne, VIC 3053, Australia1
Newman LS ,Rose CS ,Maier LA . Sarcoidosis. N Engl J Med 1997;336:1224-1234[Erratum, N Engl J Med 1997;337:139.]
Full Text | Web of Science | Medline2
Infante PF ,Newman LS . Beryllium exposure and chronic beryllium disease. Lancet 2004;363:415-416
CrossRef | Web of Science | Medline3
Beckett WS . Occupational respiratory diseases. N Engl J Med 2000;342:406-413
Full Text | Web of Science | Medline4
Middleton DC . Chronic beryllium disease: uncommon disease, less common diagnosis. Environ Health Perspect 1998;106:765-767
CrossRef | Web of Science | Medline
To the Editor:
In their review of sarcoidosis, Iannuzzi et al. emphasize that the development of noncaseating epithelioid-cell granulomas is the hallmark of sarcoidosis in the absence of organisms or particles. We want to outline the importance of analyzing serum levels of IgG, IgA, and IgM in the initial evaluation of patients with suspected sarcoidosis. Most patients with sarcoidosis have a polyclonal hypergammaglobulinemia. A noncaseating granulomatous disease mimicking typical sarcoidosis occurs in approximately 10% of patients with common variable immunodeficiency.1-4 Moreover, granulomatous disease may be the first manifestation of common variable immunodeficiency. Clinicians should analyze the immune globulin levels in all patients with a granulomatous disease, since in cases of hypogammaglobulinemia, the patient could be considered to have common variable immunodeficiency with granulomatous complications rather than sarcoidosis with hypogammaglobulinemia.
4 ReferencesEmilie Catherinot, M.D.
Elisabeth Rivaud, M.D.
Louis-Jean Couderc, M.D.
Hôpital Foch, 92150 Suresnes, France
e.catherinot@hopital-foch. org 1
Fasano MB ,Sullivan KE ,Sarpong SB , et al. Sarcoidosis and common variable immunodeficiency: report of 8 cases and review of the literature. Medicine (Baltimore) 1996;75:251-261
CrossRef | Web of Science | Medline2
Mechanic LJ ,Dikman S ,Cunningham-Rundles C . Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997;127:613-617
Web of Science | Medline3
Bates CA ,Ellison MC ,Lynch DA ,Cool CD ,Brown KK ,Routes JM . Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004;114:415-421
CrossRef | Web of Science | Medline4
Couderc LJ ,Catherinot E . Granulomatose non sarcoidienne. Rev Mal Respir 2006;23:5S59-5S67
Medline
To the Editor:
Iannuzzi et al. describe the critical role of the CD4+-cell–dependent type 1 helper T (Th1) response in sarcoidosis. The lack of an animal model of sarcoidosis has limited our understanding of its pathogenesis. Mass chest radiographic screening has shown that subclinical sarcoidosis is not uncommon.1 In some cases, clinically symptomatic sarcoidosis may reflect augmentation of sarcoid-related Th1 immune response and granuloma formation by immune adjuvants. As such, sarcoidosis can complicate treatment with interferon alfa, presumably because of augmentation of interferon-γ expression. Treatment of patients who have human immunodeficiency virus (HIV)-infection with highly active antiretroviral therapy (HAART) is also associated with the development of sarcoidosis.2-4 This association illustrates the pivotal role of CD4+ T cells in both diseases and appears to reflect the immune reconstitution inflammatory syndrome, which is well described in HIV-related tuberculosis when HAART is initiated.2 The sarcoid response is proportional to the CD4+ cell count and is not seen at counts of less than 200 cells per cubic millimeter.4 These observations illustrate a unique experiment in nature that proves the dependence of sarcoidosis on CD4+ cells.
4 ReferencesAnthony W. O'Regan, M.D.
Catherine A. Fleming, M.D.
Galway University Hospital, Galway, Ireland
anthony.oregan@hse. ie 1
Poukkula A ,Huhti E ,Lilja M ,Saloheimo M . Incidence and clinical picture of sarcoidosis in a circumscribed geographical area. Br J Dis Chest 1986;80:138-147
CrossRef | Medline2
Almeida FA Jr ,Sager JS ,Eiger G . Coexistent sarcoidosis and HIV infection: an immunological paradox? J Infect 2006;52:195-201
CrossRef | Web of Science | Medline3
Foulon G ,Wislez M ,Naccache JM , et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004;38:418-425
CrossRef | Web of Science | Medline4
Morris DG ,Jasmer RM ,Huang L ,Gotway MB ,Nishimura S ,King TE Jr . Sarcoidosis following HIV infection: evidence for CD4+ lymphocyte dependence. Chest 2003;124:929-935
CrossRef | Web of Science | Medline
To the Editor:
Sarcoidosis has been associated with thyroid autoimmunity, predominantly in female patients, and some authors note that thyroid function should be included in the initial assessment of women with sarcoidosis.1 Recently, we saw a male patient who presented with constitutional symptoms, chest discomfort, and enlarged mediastinal lymph nodes in the CT scan of the chest. An initial diagnosis of Graves' disease was made, and this diagnosis led us to a diagnosis of sarcoidosis as the cause of the intrathoracic adenopathy.
1 ReferencesFrancisco José Fernández-Fernández, M.D.
Pascual Sesma, Ph.D.
Carmen Rodríguez-Rivas, M.D.
Hospital Arquitecto Marcide, 15405 Ferrol, Spain
fjf-fernandez@terra.es 1
Antonelli A ,Fazzi P ,Fallahi P ,Ferrari SM ,Ferrannini E . Prevalence of hypothyroidism and Graves disease in sarcoidosis. Chest 2006;130:526-532
CrossRef | Web of Science | Medline
To the Editor:
Iannuzzi et al. do not mention certain clinical and pathological features that can mislead clinicians. First, sarcoidlike granulomatous reactions in mediastinal lymph nodes have been observed in 1 to 3% of patients with lung cancer.1 An immunologic reaction to substances released by the tumor was suspected, especially in squamous-cell–subtype tumors. Second, there appears to be an association between sarcoidosis and tumors. An analysis of 6706 autopsies from Sweden showed that 43 patients (0.6%) had histologic sarcoidosis, of whom 22 (51%) had concomitant malignant conditions.2 An apparent excess of lung cancer and lymphoma-associated sarcoidosis was also reported in Danish and Swedish registry studies.3,4 These data are of particular relevance, since 18F-fluorodeoxyglucose positron-emission tomography (18FDG-PET) is described in the review as a means to identify sites for diagnostic biopsy, and it is widely used in the diagnosis and staging of lung cancer. Since overexpression of GLUT-1 receptors in the lymphoid follicle is associated with false positive 18FDG-PET results in lung cancer, alternative isotopic tracers have been proposed to distinguish cancer and sarcoidosis lesions.5
5 ReferencesEmmanuel Bergot, M.D.
Caen University Hospital, 14033 Caen CEDEX 05, FrancePhilippe Paparel, M.D.
Lyon-Sud University Hospital, 69495 Pierre-Bénite CEDEX, FranceGérard Zalcman, M.D., Ph.D.
Caen University Hospital, 14033 Caen CEDEX 05, France
zalcman-g@chu-caen.fr 1
Hunsaker AR ,Munden RF ,Pugatch RD ,Mentzer SJ . Sarcoidlike reaction in patients with malignancy. Radiology 1996;200:255-261
Web of Science | Medline2
Hagerstrand I ,Linell F . The prevalence of sarcoidosis in autopsy material from a Swedish town. Acta Med Scand Suppl 1964;425:171-174
Medline3
Brincker H ,Wilbek E . The incidence of malignant tumours in patients with respiratory sarcoidosis. Br J Cancer 1974;29:247-251
CrossRef | Web of Science | Medline4
Askling J ,Grunewald J ,Eklund A ,Hillerdal G ,Ekbom A . Increased risk for cancer following sarcoidosis. Am J Respir Crit Care Med 1999;160:1668-1672
Web of Science | Medline5
Chung JH ,Cho KJ ,Lee SS , et al. Overexpression of Glut1 in lymphoid follicles correlates with false-positive (18)F-FDG PET results in lung cancer staging. J Nucl Med 2004;45:999-1003
Web of Science | Medline
Author/Editor Response
With regard to the comments by Murray and Lyons, a diagnosis of sarcoidosis is reasonably certain without biopsy in patients who present with Löfgren's syndrome. In all others, the diagnosis of sarcoidosis is firm only when chest radiographic evidence is accompanied by compatible clinical features and noncaseating granulomas on biopsy, with all other causes of granulomas ruled out.
We agree with Sharma and Kadhiravan that a positive tuberculin skin test in regions where tuberculosis is endemic should evoke caution in diagnosing sarcoidosis, but we disagree that this test result weighs strongly against a diagnosis, since patients with sarcoidosis who have been exposed to tuberculosis may remain skin-test positive.
Guzzi and Severi emphasize that chronic beryllium disease should be considered in the differential diagnosis of sarcoidosis. Occupational exposure to beryllium may occur in the aerospace, automotive, electronic, telecommunications, and nuclear industries, in the recycling of computers, in the military, in metal shops, and during the manufacture of jewelry, bicycle frames, and dental appliances. Since chronic beryllium disease can take more than 30 years to develop,1 the occupational history taking should probe for all previous exposures.
The occurrence of noncaseating granulomatous lesions in patients with common variable immunodeficiency is well recognized. It is important to diagnose hypogammaglobulinemia, because an untreated antibody deficiency can lead to organ damage. Catherinot et al. recommend that clinicians analyze the immune globulin levels in all patients with a granulomatous disease. However, in their review of 30 patients with chronic beryllium disease and sarcoidosis, Fasano et al. (cited in the letter by Catherinot et al.) reported that a history of recurrent infections was frequently noted in those patients who presented initially with sarcoidosis alone, suggesting that an undiagnosed immune deficiency might have existed. The exact prevalence of granuloma among patients with common variable immunodeficiency is uncertain and ranges from 5.4 to 10.0%2; the prevalence of common variable immunodeficiency among patients with sarcoidosis is unknown. We believe that testing for common variable immunodeficiency should be directed by the history and physical examination instead of being performed routinely.
Initial reports that sarcoidosis improved as HIV infection worsened first called attention to an unusual experiment of nature. The appearance or worsening of sarcoidosis in the immune reconstitution inflammatory syndrome, after treatment with antiretroviral therapy, is well described and, as highlighted by O'Regan and Fleming, underscores the central pathogenic role of CD4+ cells in sarcoidosis.
Papadopoulos et al. reported that 15 of 89 patients with sarcoidosis (17%) had evidence of endocrine autoimmunity.2 Antonelli et al. (cited in the letter by Fernández-Fernández et al.) reported a significantly higher prevalence of subclinical and clinical hypothyroidism among patients with sarcoidosis, particularly women. Fernández-Fernández and colleagues add their experience to these reports. Complex immunologic and genetic mechanisms might explain the association of sarcoidosis with endocrine autoimmune diseases. The association of sarcoidosis with autoimmune disease and with cancer, as noted by Bergot and colleagues, could, however, represent an ascertainment bias. Further investigation of these associations is warranted, but it would be premature to recommend routine thyroid screening or the use of alternative isotopic tracers.
2 ReferencesMichael C. Iannuzzi, M.D.
Alvin S. Teirstein, M.D.
Mount Sinai School of Medicine, New York, NY 10029
michael.iannuzzi@mssm. edu 1
Kelleher PC ,Martyny JW ,Mroz MM , et al. Beryllium particulate exposure and disease relations in a beryllium machining plant. J Occup Environ Med 2001;43:238-249
CrossRef | Web of Science | Medline2
Papadopoulos KI ,Hornblad Y ,Liljebladh H ,Hallengren B . High frequency of endocrine autoimmunity in patients with sarcoidosis. Eur J Endocrinol 1996;134:331-336
CrossRef | Web of Science | Medline
