Elsevier

Autoimmunity Reviews

Volume 14, Issue 1, January 2015, Pages 64-74
Autoimmunity Reviews

Review
The spectrum of opportunistic diseases complicating sarcoidosis

https://doi.org/10.1016/j.autrev.2014.10.006Get rights and content

Abstract

Sarcoidosis is an inflammatory disease marked by a paradoxical immune status. The anergic state, which results from various immune defects, contrasts with the inflammatory formation of granulomas. Sarcoidosis patients may be at risk for opportunistic infections (OIs) and a substantial number of cases have been reported, even in untreated sarcoidosis. It is not clear how OIs in patients with sarcoidosis are different from other groups at risk. In this review, we discuss the most common OIs: mycobacterial infection (including tuberculosis), cryptococcosis, progressive multifocal leukoencephalopathy, and aspergillosis. Unlike peripheral lymphocytopenia, corticosteroids are a major risk factor for OIs but the occurrence of Ols in untreated patients suggests more complex predisposing mechanisms. Opportunistic infections presenting with extrapulmonary features are often misdiagnosed as new localizations of sarcoidosis. Aspergillomas mostly develop on fibrocystic lungs. Overall, physicians should be aware of the possible occurrence of OIs during sarcoidosis, even in untreated patients.

Introduction

Sarcoidosis is a systemic disease of unknown cause that is characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system [1], [2]. The persistence of an as-yet unidentified poorly degradable antigen in genetically susceptible hosts is thought to trigger the typical Th1 cellular immune response, leading to formation of granulomas. Sarcoidosis is characterized by a paradoxical immune status. Indeed, the exaggerated immune response within granulomas contrasts with various immune defects that manifest by anergy to tuberculin test and by the possible occurrence of opportunistic infections (OIs).

Several situations can be observed. First, OIs may occur in untreated patients or reveal sarcoidosis. This is mainly described for cryptococcosis and progressive multifocal leukoencephalopathy (PML). Second, corticosteroid (CS) therapy [3], [4], [5] and the use of immunosuppressive agents or anti-tumor necrosis factor (TNF)-α [6] in severe or refractory sarcoidosis may, like in other systemic diseases, predispose patients to OIs. Third, OIs in sarcoidosis patients may only depend on epidemiologic or geographic factors. This is mostly true for tuberculosis and histoplasmosis. Finally, anatomic changes, such as parenchymal fibrocystic lesions in advanced pulmonary sarcoidosis, can predispose to aspergillosis.

Seven studies have focused on the risk of OI in the setting of sarcoidosis and have reported an incidence of 0–10% (Table 1) [4], [7], [8], [9], [10], [11], [12]. These studies were heterogeneous in terms of purpose, studied populations, sarcoidosis definition, and follow-up periods. Thus, it is not possible to conclude in an increased risk of OI during sarcoidosis.

Although the medical literature contains a substantial number of reports of OIs during sarcoidosis, only one focused review has been published in French, ten years ago [13]. Girard et al. reported on 65 cases of OIs complicating sarcoidosis, between 1966 and 2004. Cryptococcosis was the most frequently reported infection (59%) followed by mycobacterial infections (13%), nocardiosis (11%), histoplasmosis, pneumocystosis (9% each), and aspergillosis (7%). However, no newer reviews have been undertaken despite several new case series and case reports becoming increasingly available. Notably, two recent studies of our group have reported on several cases of cryptococcosis or PML complicating sarcoidosis [14], [15]. Mycobacterial infections are also increasingly reported. Given these data, we performed an exhaustive literature review with the aim of determining how sarcoidosis predisposes to OIs.

Section snippets

Search strategy

Searches were conducted in PubMed database (including Medline, National Library of Medicine, and PubMed Central), for the time period between January, 1974 and March, 2014, using strategies recommended by the Cochrane handbook [16]. The review strategies consisted of a exhaustive search using the terms “sarcoidosis”, “opportunistic infection”, “tuberculosis”, “mycobacteria”, “aspergillosis”, “cryptococcosis”, “nocardiosis”, “toxoplasmosis”, “mucormycosis”, “zygomycosis”, “histoplasmosis”,

Sarcoidosis

Sarcoidosis affects people from all racial/ethnic origins and occurs at any time of life. Its incidence is estimated at between 4.7 and 64/100,000 and its prevalence varies from 1.0 to 35.5/100,000 per year, with a particular proclivity for young adults [1], [18], [19], [20]. Diagnosis is established when compatible clinico-radiological features are supported by histological evidence of a non-caseating epithelioid granuloma [21]. Histological confirmation should be obtained whenever possible,

Tuberculosis and other mycobacteria

The role of mycobacteria has been repeatedly investigated as an etiological agent for sarcoidosis but, so far, no study has given indisputable results [79], [80], [81]. A number of small trials using anti-tuberculous drugs to treat sarcoidosis have also been published with negative results [82]. It now seems clear that sarcoidosis-associated immunodepression is not a major risk factor for mycobacterial infection. Epidemiological factors and treatments, mainly CSs and immunosuppressants, are

Epidemiology

The annual incidence of invasive cryptococcosis in the USA has been estimated at 1700–6600/100,000 patients with AIDS and at 0.2–0.9/100,000 patients without HIV [91]. CS therapy is the main risk factor for non-HIV-associated cryptococcosis (28% of cases) [92]. Cryptococcosis is very rare in the setting of autoimmune diseases, except in patients taking CSs, but most series report that cryptococcosis occurs in up to 30% of cases with no discernible underlying condition [91].

Recently, we have

Epidemiology

While PML can occur in patients with minimal or occult immunodepression, it is more likely to occur in immunocompromised patients [106], [107]. In AIDS, the incidence of PML was estimated at 3.3/100,000 patients-years before the introduction of HAART whereas it is now estimated at 1.3/100,000 patients-years [108]. In a review of 61 patients with PML, ~ 80% had AIDS and the majority of patients who develop PML had a CD4 T-cell count of < 200/mm3 [109]. Progressive ML has also been associated with

Chronic pulmonary aspergillosis (CPA) and other Aspergillus-related disease

Sarcoidosis represents a risk factor in 7–17% of CPA cases [127], [128]. Conversely, CPA complicates around 2% (range 0–17%) of sarcoidosis, with geographic differences [4], [127], [128], [129], [130], [131], [132]. In > 90% of cases, it presents as aspergilloma simplex complicating fibrocystic lung cavities and is considered as a saprophytic colonization rather than OI. Overall, CPA mostly complicates advanced fibrocystic sarcoidosis [133], [134]. Long-term CS therapy is a major risk factor for

Limitations

As available data on OIs complicating sarcoidosis arise from case series it was not possible to determine their true frequency in sarcoidosis patients compared to other groups at risk. Therefore, it remains unclear if sarcoidosis is associated with a greater risk of OIs. A proper control group would have to be at the same risk in terms of immunosuppression and other risk factors (e.g. fibrocystic disease) to determine if sarcoidosis truly places the patients at higher risk. For example,

Conclusions

Opportunistic infections seem to be rare in the setting of sarcoidosis. Although, we have collected information on > 280 cases, large reference cohorts are needed to assess the exact risk for their occurrence during sarcoidosis. Sixty to 82% of sarcoidosis patients were receiving CS therapy, regardless of the OI. In contrast, the mean blood CD4 rate did not seem to influence the risk of OI.

A substantial number of OIs occurred while the patients were not receiving any treatment. Together, these

Disclosures

The authors declare that they have no conflict of interest and no source of funding for this review.

Take-home message

  • Although rare, opportunistic infections can occur during sarcoidosis, even in untreated patients.

References (150)

  • C. Cunningham-Rundles et al.

    Common variable immunodeficiency: clinical and immunological features of 248 patients

    Clin Immunol

    (1999)
  • E.S. Resnick et al.

    Morbidity and mortality in common variable immune deficiency over 4 decades

    Blood

    (2012)
  • H. Dussauze et al.

    Systemic corticosteroid treatment and risk of infectious diseases

    Rev Med Interne

    (2007)
  • D. Kovalovsky et al.

    Molecular mechanisms and Th1/Th2 pathways in corticosteroid regulation of cytokine production

    J Neuroimmunol

    (2000)
  • D. Valeyre et al.

    Sarcoïdose

    EMC Pneumol

    (2005)
  • A.M. Boerbooms et al.

    Infections during low-dose methotrexate treatment in rheumatoid arthritis

    Semin Arthritis Rheum

    (1995)
  • M.A. Antonelli et al.

    Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate

    Am J Med

    (1991)
  • G. Cunnane et al.

    Infections and biological therapy in rheumatoid arthritis

    Best Pract Res Clin Rheumatol

    (2003)
  • R. Caporali et al.

    DMARDS and infections in rheumatoid arthritis

    Autoimmun Rev

    (2008)
  • P. Termsarasab et al.

    Opportunistic infections in myasthenia gravis treated with mycophenolate mofetil

    J Neuroimmunol

    (2012)
  • B.H. Segal et al.

    Infectious complications of immunosuppressive therapy in patients with rheumatic diseases

    Rheum Dis Clin North Am

    (1997)
  • F. Lanternier et al.

    Incidence and risk factors of Legionella pneumophila pneumonia during anti-tumor necrosis factor therapy: a prospective French study

    Chest

    (2013)
  • R.S. Wallis

    Tumour necrosis factor antagonists: structure, function, and tuberculosis risks

    Lancet Infect Dis

    (2008)
  • C.F. Wong et al.

    A case of concomitant tuberculosis and sarcoidosis with mycobacterial DNA present in the sarcoid lesion

    Chest

    (1998)
  • E. Edelson

    Isoniazid in the treatment of sarcoidosis; a preliminary report

    J Invest Dermatol

    (1953)
  • A. Lalvani et al.

    Screening for tuberculosis infection prior to initiation of anti-TNF therapy

    Autoimmun Rev

    (2008)
  • P.Y.-F. Liu

    Cryptococcal osteomyelitis: case report and review

    Diagn Microbiol Infect Dis

    (1998)
  • A.E. Stuck et al.

    Risk of infectious complications in patients taking glucocorticosteroids

    Rev Infect Dis

    (1989)
  • R.P. Baughman et al.

    Fungal infections as a complication of therapy for sarcoidosis

    QJM

    (2005)
  • A.C. Ford et al.

    Opportunistic infections with anti-tumor necrosis factor-α therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials

    Am J Gastroenterol

    (2013)
  • R.H. Winterbauer et al.

    The infectious complications of sarcoidosis: a current perspective

    Arch Intern Med

    (1976)
  • I. Rubinstein et al.

    Fungal infections complicating pulmonary sarcoidosis

    J Infect Dis

    (1985)
  • S. Nagai et al.

    Clinical courses and prognoses of pulmonary sarcoidosis

    Curr Opin Pulm Med

    (1999)
  • A. Nardi et al.

    Stage IV sarcoidosis: comparison of survival with the general population and causes of death

    Eur Respir J

    (2011)
  • C. Bernard et al.

    Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases

    QJM

    (2013)
  • Y. Jamilloux et al.

    Progressive multifocal leukoencephalopathy in patients with sarcoidosis

    Neurology

    (2014)
  • Cochrane Collaboration

    Cochrane handbook for systematic reviews of interventions. Chichester, England

    (2008)
  • D.A. Stevens et al.

    Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America

    Clin Infect Dis

    (2000)
  • G. Hillerdal et al.

    Sarcoidosis: epidemiology and prognosis. A 15-year European study

    Am Rev Respir Dis

    (1984)
  • B.A. Rybicki et al.

    Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization

    Am J Epidemiol

    (1997)
  • M.C. Iannuzzi et al.

    Sarcoidosis

    N Engl J Med

    (2007)
  • U. Costabel et al.

    ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders

    Eur Respir J

    (1999)
  • M.C. Iannuzzi et al.

    Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics

    JAMA

    (2011)
  • R.P. Baughman et al.

    Treatment of sarcoidosis

    Clin Chest Med

    (2008)
  • R.P. Baughman et al.

    Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial

    Sarcoidosis Vasc Diffuse Lung Dis

    (2000)
  • R.P. Baughman et al.

    Leflunomide for chronic sarcoidosis

    Sarcoidosis Vasc Diffuse Lung Dis

    (2004)
  • G. Androdias et al.

    Mycophenolate mofetil may be effective in CNS sarcoidosis but not in sarcoid myopathy

    Neurology

    (2011)
  • C.A. Lazar et al.

    Treatment of sarcoidosis

    Semin Respir Crit Care Med

    (2010)
  • J.P. Cremers et al.

    Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide

    Curr Opin Pulm Med

    (2013)
  • R.P. Baughman et al.

    Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement

    Am J Respir Crit Care Med

    (2006)
  • Cited by (0)

    View full text