Cryptococcal meningitis in a patient with sarcoidosis Traci N. Adams, MD, and Maeghan Gibson, MD

Sarcoidosis is a multisystem granulomatous disease characterized by the presence of noncaseating granulomas. Case reports have previously described an association between sarcoidosis and cryptococcal infection, but many of these patients were receiving immunosuppression at the time of diagnosis or had limited cutaneous disease. We report a case of cryptococcal meningitis in a 65-year-old man with a new presentation of sarcoidosis who was not receiving immunosuppressive medications.


arcoidosis has been described as an “immune paradox” in which patients demonstrate both exaggerated inflammation and peripheral anergy as demonstrated by reduced delayed-type hypersensitivity to tuberculin skin testing and increased susceptibility to infection (1–3). We present a case that is unique in that it describes the development of cryptococcal meningitis in a patient with sarcoidosis who was not on immunosuppressive therapy and did not have extrathoracic manifestations of the disease. CASE PRESENTATION A previously healthy 65-year-old man presented with chronic cough. He had been in his usual state of health until 1 year earlier when he visited his primary care physician for a nonproductive cough. He denied any history of gastroesophageal reflux, nasal congestion, wheezing, coughing while eating, orthopnea, hemoptysis, or dyspnea on exertion. He also denied tobacco or drug use, recent travel, sick contacts, and bird or mold exposure. His only medications were acetaminophen and ibuprofen for back pain and simvastatin for hyperlipidemia. His chest radiograph was reportedly unremarkable, and he was treated with azithromycin and levofloxacin but did not improve. He was then evaluated at an outside hospital, where computed tomography (CT) of his chest revealed a spiculated left lower lobe nodule measuring 2.5 × 1.6 cm; left supraclavicular, mediastinal, and hilar adenopathy; and extensive peribronchovascular nodularity with a perihilar distribution (Figure 1). Bronchoscopy with bronchoalveolar lavage, bronchial brushings, transbronchial biopsies of the right upper lobe, and biopsies of the subcarinal lymph nodes were performed. Cytology of the bronchial brushing was negative for malignancy, and bronchoalveolar lavage fluid was negative for malignant cells and Proc (Bayl Univ Med Cent) 2016;29(2):207–208

cytomegalovirus. Transbronchial biopsies revealed focal chronic bronchiolitis, and lymph node biopsy was benign. One month later he presented to a neurologist with headache, dysarthria, and left hand numbness. His temperature was 98.5°F; heart rate, 89 beats per minute; blood pressure, 138/88 mm Hg; and oxygen saturation, 96% on room air. His jugular venous pulse was at 6 cm, crackles were heard in the bilateral lower lung fields, and lower extremities were not edematous. Neurologic examination revealed an intact mental status, normal cranial nerve function, normal strength and sensation throughout his arms and legs, 2+ reflexes, and intact finger-to-nose bilaterally. CT and magnetic resonance imaging of the brain were unremarkable. Lumbar puncture revealed an opening pressure of 20 cm of water, and cerebrospinal studies included a white blood cell count of 111/mm3, total protein of 166 g/dL, and glucose of 31 mg/dL. His cerebrospinal microbiologic studies revealed a cryptococcal antigen titer of 1:256 and were otherwise negative. Serum cryptococcal antigen was positive at 1:128. His serum HIV, QuantiFERON Gold, histoplasmosis serum antigen and serology, and viral hepatitis serologies were negative. He began treatment for cryptococcal meningitis with flucytosine and liposomal amphotericin, and his neurologic symptoms resolved. Following his recovery from cryptococcal meningitis, he underwent a CT-guided core biopsy of his left lower lobe mass, histologically containing noncaseating granulomas (Figure 2). Gomori methenamine silver and acid-fast stains as well as fungal and acid-fast cultures on the biopsy specimen were negative. His angiotensin-converting enzyme level was normal. Spirometry, total lung capacity, and diffuse capacity of carbon monoxide were within normal limits. His workup for extrapulmonary sarcoidosis including ophthalmology evaluation, 1,25-hydroxy vitamin D levels, electrocardiogram, and urine calcium-tocreatinine ratio were unremarkable. With normal pulmonary function tests and lack of extrapulmonary involvement, the From the Division of Pulmonary and Critical Care Medicine (Adams) and Department of Internal Medicine (Gibson), The University of Texas Southwestern Medical Center, Dallas, Texas. Corresponding author: Traci N. Adams, MD, Division of Pulmonary and Critical Care Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75219 (e-mail: [email protected]). 207




Figure 1. (a) Coronal and (b, c) axial CT images demonstrating a perilymphatic nodular pattern with extensive involvement of the peribronchovascular interstitium.

decision was made to manage the sarcoidosis conservatively with serial pulmonary function testing. DISCUSSION An imbalance between effector and regulatory T cells may contribute to susceptibility to infection in patients with sarcoidosis (2, 4, 5). Regulatory CD4+CD25brightFoxP3+ T cells accumulate at the periphery of sarcoid granulomas, in bronchoalveolar lavage fluid, and in peripheral blood of sarcoidosis patients (2). These cells exhibit antiproliferative activity, which may contribute to anergy; however, because they are unable to completely inhibit the production of tumor necrosis factor–α, local inflammation and granuloma formation continue to occur (2). Immunosuppressive CD8+ T cells may also accumulate in peripheral blood and produce anergy (4). Further, a reduced number of CD4+ T cells and other effector T cells such as CD1drestricted natural killer cells and a decreased CD4+/CD8+ T cell ratio are found in the peripheral blood of sarcoidosis patients, which may inhibit their T cell–mediated immunity (5). These mechanisms of impaired T cell–mediated immunity in sarcoidosis contribute to increased susceptibility to cryptococcal infection, which has been demonstrated in both in vitro studies and case reports (6–11). Cryptococcus neoformans is an opportunistic mycosis, which begins as a primary respiratory tract

Figure 2. CT-guided core biopsy of the left lower lobe revealing granulomatous inflammation (hematoxylin and eosin, 100×). 208

infection and can disseminate hematogenously, with a propensity to localize to the central nervous system (6). It most frequently occurs in the setting of impaired T cell–mediated immunity, and the most common predisposing conditions include HIV, organ failure, and prolonged treatment with glucocorticoids (7–9). The largest clinical case series of C. neoformans infection revealed that sarcoidosis accounted for 0.6% of cryptococcal cases overall (8). Treatment with glucocorticoids and extrathoracic sarcoidosis are independent risk factors for cryptococcal infection in these patients (8, 11), and lung, bone, skin, and the central nervous system are the most common sites of infection (6, 9). 1.

Mathew S, Bauer KL, Fischoeder A, Bhardwaj N, Oliver SJ. The anergic state in sarcoidosis is associated with diminished dendritic cell function. J Immunol 2008;181(1):746–755. 2. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, Kambouchner M, Valeyre D, Chapelon-Abric C, Debré P, Piette JC, Gorochov G. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006;203(2):359–370. 3. Loke WS, Herbert C, Thomas PS. Sarcoidosis: immunopathogenesis and immunological markers. Int J Chronic Dis 2013;2013:928601. 4. Planck A, Katchar K, Eklund A, Gripenbäck S, Grunewald J. T-lymphocyte activity in HLA-DR17 positive patients with active and clinically recovered sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003;20(2):110–117. 5. Ho LP, Urban BC, Thickett DR, Davies RJ, McMichael AJ. Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet 2005;365(9464):1062–1072. 6. Botha RJ, Wessels E. Cryptococcal meningitis in an HIV negative patient with systemic sarcoidosis. J Clin Pathol 1999;52(12):928–930. 7. Pappas PG, Perfect JR, Cloud GA, Larsen RA, Pankey GA, Lancaster DJ, Henderson H, Kauffman CA, Haas DW, Saccente M, Hamill RJ, Holloway MS, Warren RM, Dismukes WE. Cryptococcosis in human immunodeficiency virus–negative patients in the era of effective azole therapy. Clin Infect Dis 2001;33(5):690–699. 8. Bernard C, Maucort-Boulch D, Varron L, Charlier C, Sitbon K, Freymond N, Bouhour D, Hot A, Masquelet AC, Valeyre D, Costedoat-Chalumeau N, Etienne M, Gueit I, Jouneau S, Delaval P, Mouthon L, Pouget J, Serratrice J, Brion JP, Vaylet F, Bremont C, Chennebault JM, Jaffuel S, Broussolle C, Lortholary O, Sève P; French Cryptococcosis Study Group. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases. QJM 2013;106(6):523–539. 9. Ross JJ, Katz JD. Cryptococcal meningitis and sarcoidosis. Scand J Infect Dis 2002;34(12):937–939. 10. Shih CC, Chen YC, Chang SC, Luh KT, Hsieh WC. Cryptococcal meningitis in non–HIV-infected patients. QJM 2000;93(4):245–251. 11. Jamilloux Y, Valeyre D, Lortholary O, Bernard C, Kerever S, Lelievre L, Neel A, Broussolle C, Seve P. The spectrum of opportunistic diseases complicating sarcoidosis. Autoimmun Rev 2015;14(1):64–74.

Baylor University Medical Center Proceedings

Volume 29, Number 2

Cryptococcal meningitis in a patient with sarcoidosis.

Sarcoidosis is a multisystem granulomatous disease characterized by the presence of noncaseating granulomas. Case reports have previously described an...
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