Abstract

Aim: To describe the main characteristics and the treatment of cryptococcosis in patients with sarcoidosis.

Design: Multicenter study including all patients notified at the French National Reference Center for Invasive Mycoses and Antifungals.

Methods: Retrospective chart review. Each case was compared with two controls without opportunistic infections.

Results: Eighteen cases of cryptococcosis complicating sarcoidosis were analyzed (13 men and 5 women). With 2749 cases of cryptococcosis registered in France during the inclusion period of this study, sarcoidosis accounted for 0.6% of all the cryptococcosis patients and for 2.9% of the cryptococcosis HIV-seronegative patients. Cryptococcosis and sarcoidosis were diagnosed concomitantly in four cases; while sarcoidosis was previously known in 14/18 patients, including 12 patients (67%) treated with steroids. The median rate of CD4 T cells was 145 per mm3 (range: 55–1300) and not related to steroid treatment. Thirteen patients had cryptococcal meningitis (72%), three osteoarticular (17%) and four disseminated infections (22%). Sixteen patients (89%) presented a complete response to antifungal therapy. After a mean follow-up of 6 years, no death was attributable to cryptococcosis. Extra-thoracic sarcoidosis and steroids were independent risk factors of cryptococcosis in a logistic regression model adjusted with the sex of the patients.

Conclusions: Cryptococcosis is a significant opportunistic infection during extra-thoracic sarcoidosis, which occurs in one-third of the cases in patients without any treatment; it is not associated to severe CD4 lymphocytopenia and has a good prognosis.

Introduction

Cryptococcosis is a devastating opportunistic infection caused by an encapsulated yeast, Cryptococcus neoformans that typically occurs in severely immunosuppressed patients.1,Cryptococcus gattii, first described in tropical and subtropical areas, also causes diseases more commonly in non-human immunodeficiency virus (HIV) patients and has gained its importance recently as the causative agent of the cryptococcosis outbreak in British Columbia and North-Western USA.2 T-cell-mediated immunity is the predominant pathway for preventing cryptococcal infections. Th1-Th2 balance influenced host defense against infections with C. neoformans,3 with a central role of TNFα, IL 12 and IFNγ. IL 23 complemented the more dominant role of IL 12 in protection against the fungal infection by an enhanced inflammatory cell response and distinct cytokine regulation (IL 17A and IL 22).4 Currently, acquired immunodeficiency syndrome (AIDS) is the predisposing factor in 70% of cryptococcal infections in the Western world,5,6 but other immunocompromised states,7 such as malignancy diseases, organ transplant,8 sarcoidosis, idiopathic CD4 lymphopenia,9 diabetes mellitus, autoimmune diseases and chronic renal failure have also been described. The incidence of cryptococcosis associated with these diseases and without HIV infection is estimated at 0.8 per 100 000 inhabitants.10

Cell-mediated immunodeficiency and chronic corticosteroid therapy are risk factors for the onset of opportunistic infections in patients with sarcoidosis.11 The most reported infection is chronic pulmonary aspergillosis which occurs, according to the series, in 1–10% of the patients, through the development of parenchymal cysts (radiographic stage IV sarcoidosis).11,12

Three studies have been undertaken to analyze the presentation and risk for developing opportunistic infections in sarcoidosis patients. Two were retrospective: Baughman and Lower13 reported seven fungal infections in 753 patients (0.9%) seen at their institution including three cases of cryptococcosis; Rubinstein et al.14 did not report any cryptococcosis case of 197 sarcoidosis with 36% who were treated with corticosteroids. In their prospective study of 122 patients with sarcoidosis, Winterbauer and Kraemer15 reported three patients with pulmonary aspergilloma, one case of pulmonary tuberculosis and one patient with disseminated herpes zoster requiring hospitalization. Girard et al. performed a literature review on the risk of opportunistic infections in sarcoidosis in 2004.16 They documented 85 cases reports of sarcoidosis complicated by opportunistic infections between 1966 and 2004. Cryptococcosis was the most commonly reported infection with 41 observations (48.2%). Most cases existed as single or double case reports and only 11 of the 30 documented cases of cryptococcal infection were receiving corticosteroids.

To our knowledge, no case control study has ever compared characteristics of patients with cryptococcal disease associated with sarcoidosis with those of sarcoidosis patients without opportunistic infections. Given these data, we conducted the nation-based retrospective multicenter study of sarcoidosis and cryptococcal infection. The aims of the study were (i) to describe the clinical features of sarcoidosis patients with cryptococcal infection, (ii) to describe the clinical presentation, treatments and outcome of cryptococcosis during sarcoidosis and (iii) to determine whether this opportunistic infection is associated with a particular clinical phenotype of sarcoidosis in comparison with patients without any opportunistic infections.

Patients and methods

We undertook a retrospective study of patients presenting a cryptococcal infection in association with sarcoidosis. Written informed consent had been obtained in accordance with the French Ethical Committee Recommendations. The study received the institutional review board approval. Patients with C. neoformans infection notified from 1985 to 2010 at the National Reference Center for Invasive Mycoses and Antifungals (NRCMA), Institut Pasteur, Paris, were reviewed. Furthermore, the design of this study was presented at the annual meeting of the Societé Nationale Française de Médecine Interne (SNFMI) in June 2011 and at that of the Groupe Sarcoïdose Francophone (GSF) in December 2010. Eighteen cases were identified from 14 centers in France and compared with a control group.

Identification and validation of cases

The patients were included in this study if they met the following five criteria. Three of these criteria are those used for the diagnosis of sarcoidosis according to the statement on sarcoidosis17: (i) clinical and paraclinical features consistent with sarcoidosis, (ii) a histopathological analysis revealing non-caseating granuloma (except for patients presenting Löfgren’s syndrome for whom the diagnosis of sarcoidosis was made without requiring histological evidence), (iii) the exclusion of other possible causes, including other granulomatous disorders, (iv) proven cryptococcosis infection required that the encapsulated yeast was detected by histological analysis of a tissue specimen: detection of capsular antigen, a positive result of an India ink preparation of cerebrospinal fluid (CSF) or any positive culture result18 and (v) exclusion of any risk factor of cryptococcosis as progressive neoplasia and presence of anti-HIV antibodies.

Disseminated cryptococcosis was defined as an infection involving at least two non-contiguous sites.

Identification and validation of controls

The patients with cryptococcosis associated with sarcoidosis were compared with controls subjects who had sarcoidosis but no active or past cryptococcal infection. The patients of the control group were selected among 298 incident cases of histologically proven sarcoidosis hospitalized in the Lyon University Hospital between 2002 and 2006. Each patient with a cryptococcal infection was matched with two controls according to their radiological stage of sarcoidosis (Scadding stage method).19

Collected data

Clinical and laboratory data were collected and analyzed by the same investigator (CB) using a standardized form validated by two of us (PS and OL). Data on their medical history, present illness, physical examination, data on the nature of the department where they were admitted and the sites of the tissue biopsies were recorded. Laboratory analyses including C-reactive protein (CRP), a blood lymphocytes count, liver tests, calcemia and the serum angiotensin-converting enzyme (ACE) level were gathered at the time of diagnosis of sarcoidosis and during the follow-up. The organ site involved by sarcoidosis was classified as pulmonary and extra-pulmonary with cardiac, ophthalmological, skin, musculoskeletal and neurological involvement. The criteria proposed by Zajicek et al.20 were used in the patients with isolated central nervous system (CNS) involvement. Chest radiographs were rated according to the Scadding stage method19: normal radiography (stage 0), mediastinal adenopathy (stage I), parenchymal involvement associated with mediastinal adenopathy (stage II), infiltrating lung disease without mediastinal adenopathy (stage III) and pulmonary fibrosis (stage IV). The patients described the level of activity causing shortness of breath which was ascribed a grade of dyspnea from 0 to 4. The results of other imaging findings including chest computed tomography (CT), pulmonary function tests, bronchoscopies with broncho-alveolar lavage (BAL), cardiac investigations and detailed medical treatments were also recorded, when available.

The organ sites infected by cryptococcosis were classified as CNS [cryptococcal meningoencephalitis (CME)], lung, skin, soft tissue and bone or joint involvements and/or any other site. In addition to the immunosuppressive therapy at the time of the fungal infection, the treatment and clinical responses of the patients with C. neoformans infection were recorded. Induction therapy was defined as initial therapy administered for at least three consecutive days during the acute phase of the cryptococcosis. A consolidation therapy followed a successful response to induction therapy during 2–6 weeks.7,21 The maintenance therapy was defined as the therapy given in the absence of any disease activity to prevent the disease relapse after 8–10 weeks of consolidation therapy. The status of the cryptococcosis was recorded as: ‘clinical cure’ (complete response to therapy) or ‘failure’ (persistence or progression demonstrated through clinical, laboratory, radiographic or mycologic evidence of the disease despite an antifungal therapy). ‘Relapse’ was defined as a new positive fungal culture with clinical and/or radiographical evidence of recrudescence after discontinuation of antifungal therapy. Mortality was judged to be due to cryptococcosis when it happened before 30 days after the diagnosis.

Statistical analysis

The data were described as number and percentage for the qualitative variables or median range from minimum to maximum for the quantitative variables. To limit risk alpha consumption, cases and controls were compared for only few variables selected a priori. A chi-square test or an exact Fisher test was used to compare the qualitative variables. The quantitative variables were compared with an unpaired t-test or a Mann–Whitney rank test.

Adjusted analyses were performed fitting logistic regression of the cryptococcosis probability. To avoid optimism and overfitting, the number of variables tested in the model was limited. The treatment with corticosteroids and extra-pulmonary phenotype of sarcoidosis were introduced and tested, first without adjustment, then adjusted on sex, the male sex being already known to increase the risk of cryptococcosis.

All the comparison tests were two-sided and limited a priori for the calculation of a risk-adjusted α, hence P-values were considered significant when P < 0.2. Statistical analyses were performed with IBM SPSS Statistics 17.0 (IBM Corporation, Somers, USA).

Results

Eighteen patients presenting cryptococcosis complicating sarcoidosis were identified from the NRCMA. With 2749 cases of cryptococcosis registered in France at the inclusion period of this study (from 1985 to 2010) including 614 HIV-negative patients, sarcoidosis accounted for 2.9% (18/614) of HIV-negative cryptococcosis patients. Five of these cases were not included in our analysis, due to the lack of histological evidence (n = 1) and insufficient data (n = 3). Moreover, we excluded one patient (n = 1) with a medical history of recurrent infections and severe combined hypogammaglobulinemia which was in fact related to a common variable immunodeficiency.22 We identified four supplementary patients from the SNFMI group and one from the GSF. Overall, the total number of presented patients is 18.

Case report

To illustrate the diagnostic difficulties, we have reported here one case (patient 10): A 27-year-old-man was diagnosed as having mediastinal and pulmonary stage II sarcoidosis in 1991. The histological proof was found through a bronchial biopsy performed in 2000 because of an increase of the size of mediastinal nodes. He had a past history of Graves’ disease. He was given a steroid therapy as prednisone 0.5 mg/kg daily which resulted in a decrease of the lymph nodes. In 2000, while the patient received 15 mg/day of prednisone, he was admitted for an acute history of headache with fever. Physical examination revealed meningeal symptoms. The CSF analysis disclosed the following: white blood cell count, 44 per mm3; protein level, 2.2 g/l and glucose level, 0.2 mmol/l. The Gram and the India ink stainings, CSF bacterial and mycobacterial cultures were negative. Other investigations including gadolinium-enhanced magnetic resonance imaging (MRI) were normal. An empirical 6-month course of anti-tuberculosis treatment was not successful. The clinical failure was neurological with worse results of the lumbar puncture and with the occurrence of a cardiac involvement. A diagnosis of probable neurosarcoidosis (on Zajicek20 criteria) and cardiac sarcoidosis was made. The treatment was intensified with a high dose of methylprednisolone (three pulses of 500 mg) which resulted in the resolution of the cardiac sarcoidosis manifestations, even if the CSF abnormalities persisted. A monthly intravenous pulse of cyclophosphamide (CPM) was introduced in 07/2001 as the cardiac involvement reappeared with a contractile deficit of the ventricular septal on the echography. On the lumbar puncture of 07/2001, CSF culture grew C. neoformans after 3 weeks. The patient showed, at this time, no clinical worsening but a CD4 lymphopenia at 96 per mm3 on peripheral blood samples. Immunosuppressive treatments were continued and an anti-fungal therapy by fluconazole 600 mg/day was initiated for 3 months. CME was successfully treated, and then fluconazole 200 mg/day was used as a maintenance therapy. At 1 year of follow-up, while his cardiac echography and CSF were normal, he developed a corticosteroid induced osteoporosis with a vertebral fracture of lumbar vertebrae 2. At 3 years of follow-up, sarcoidosis evolved on the breathing pattern with fibrotic lesions while he was treated with prednisone 10 mg/day.

Description of the cases

Demographic characteristics of patients

On the whole, 18 patients were included for the analysis (Table 1). Cases 9, 15, 16 and 17 have been published partially elsewhere.16,23–25 As indicated in Table 2, there were 13 men (72%) and 5 women (28%) aged 18–55 at the time of sarcoidosis (median age: 28 years and mean age: 32 years). Nine of the 18 patients were of Caucasian origin (50%), 3 originated from Maghreb (17%) and 3 from Black Africa (17%); data were not available in 3 cases.

Table 1

Demographic, clinical and biological features in patients with cryptococcosis complicating sarcoidosis

Cases (age at cryptococcal diagnosis, sex) Corticosteroids at the onset of cryptococcosis (mg equivalent of prednisone/day) LT CD4 (cell/mm3Time for diagnosis (days) Site of C. neoformans infection Serum antigen C. neoformans Localization of sarcoidosis Stage of sarcoidosis Outcome 
1 (M/39) No 90 CME Mediastino-pulmonary II 
2 (M/27) No 160 CME Heart + skin + ophthalmological + parotidis + pulmonary + adenopathy + arthritis II 
3 (F/28) No 144 CME − Pulmonary + adenopathy II 
4 (M/49) No 129 CME (ventriculitis) − Ophthalmological + mediastino- pulmonary + skin + parotidis + adenopathy II Death 
5 (F/28) No 436 33 CME − Pulmonary II 
6 (M/27) No 228 295 CME + disseminated Pulmonary + adenopathy + parotidis II 
7 (M/36) 20 74 1704 Skin − Neurosarcoidosis + pulmonary + adenopathy II 
8 (F/35) 7.5 270 700 Skin Neurosarcoidosis (hypothalamic) with angiitis of the CNS + pulmonary + arthritis 
9 (M/30) 35 63 84 CME Pulmonary + liver II 
10 (M/37) 50 96 3683 CME − Neurosarcoidosis + heart + mediastino-pulmonary II 
11 (F/67) 50 146 4505 CME Pulmonary + adenopathy III Death 
12 (M/46) 1309 CME Pulmonary + skin + arthritis II 
13 (M/18) 20 55 240 CME + disseminated Pulmonary + adenopathy II 
14 (M/34) 5 + CPM 83 5113 CME + disseminated (cholangitis, skin, pulmonary, bone and arthritis, bone marrow) Neurosarcoidosis + pulmonary + adenopathy + skin II 
15 (M/33) 30 795 2295 CME + skin + arthritis (disseminated) Kidney 
16 (M/47) 10 + IFX + MTX 719 2022 Fongemia + arthritis − Neurosarcoidosis + heart + mediastinal 
17 (M/37) 14 1300 5876 Pyomyositis Ophthalmological + mediastino-pulmonary II 
18 (F/31) 16 2136 Liver abscesses and cholangitis Pulmonary + adenopathy II 
Cases (age at cryptococcal diagnosis, sex) Corticosteroids at the onset of cryptococcosis (mg equivalent of prednisone/day) LT CD4 (cell/mm3Time for diagnosis (days) Site of C. neoformans infection Serum antigen C. neoformans Localization of sarcoidosis Stage of sarcoidosis Outcome 
1 (M/39) No 90 CME Mediastino-pulmonary II 
2 (M/27) No 160 CME Heart + skin + ophthalmological + parotidis + pulmonary + adenopathy + arthritis II 
3 (F/28) No 144 CME − Pulmonary + adenopathy II 
4 (M/49) No 129 CME (ventriculitis) − Ophthalmological + mediastino- pulmonary + skin + parotidis + adenopathy II Death 
5 (F/28) No 436 33 CME − Pulmonary II 
6 (M/27) No 228 295 CME + disseminated Pulmonary + adenopathy + parotidis II 
7 (M/36) 20 74 1704 Skin − Neurosarcoidosis + pulmonary + adenopathy II 
8 (F/35) 7.5 270 700 Skin Neurosarcoidosis (hypothalamic) with angiitis of the CNS + pulmonary + arthritis 
9 (M/30) 35 63 84 CME Pulmonary + liver II 
10 (M/37) 50 96 3683 CME − Neurosarcoidosis + heart + mediastino-pulmonary II 
11 (F/67) 50 146 4505 CME Pulmonary + adenopathy III Death 
12 (M/46) 1309 CME Pulmonary + skin + arthritis II 
13 (M/18) 20 55 240 CME + disseminated Pulmonary + adenopathy II 
14 (M/34) 5 + CPM 83 5113 CME + disseminated (cholangitis, skin, pulmonary, bone and arthritis, bone marrow) Neurosarcoidosis + pulmonary + adenopathy + skin II 
15 (M/33) 30 795 2295 CME + skin + arthritis (disseminated) Kidney 
16 (M/47) 10 + IFX + MTX 719 2022 Fongemia + arthritis − Neurosarcoidosis + heart + mediastinal 
17 (M/37) 14 1300 5876 Pyomyositis Ophthalmological + mediastino-pulmonary II 
18 (F/31) 16 2136 Liver abscesses and cholangitis Pulmonary + adenopathy II 

*Patients living.

Table 2

Demographic and characteristics of 18 cases of cryptococcosis complicating sarcoidosis and their controls

 Cases, n (%)/ median (min–max) Controls, n (%) P-value 
Number of patients 18 36  
Age 28 (18–55) 42 (23–79) 0.0004 
Sex   0.145 
    Female 5 (28) 19 (53)  
    Male 13 (72) 17 (47)  
Ethnic background   0.751 
    Caucasian 9 (50) 24 (67)  
    North African 3 (17) 11 (31)  
    Black 3 (17) 1 (3)  
    Unknown 3 (17) 0 (0)  
Number of comorbidities   0.310 
    0 5 (28) 18 (50)  
    1 6 (33) 9 (25)  
    2 or more 7 (39) 9 (25)  
Smokers 1 (6) 3 (8)  
Auto-immune diseases 1 (6) 1 (3)  
Malignancy 0 (0) 1 (3)  
High blood pressure 3 (17) 4 (11)  
Diabetes mellitus 1 (6) 4 (11)  
 Cases, n (%)/ median (min–max) Controls, n (%) P-value 
Number of patients 18 36  
Age 28 (18–55) 42 (23–79) 0.0004 
Sex   0.145 
    Female 5 (28) 19 (53)  
    Male 13 (72) 17 (47)  
Ethnic background   0.751 
    Caucasian 9 (50) 24 (67)  
    North African 3 (17) 11 (31)  
    Black 3 (17) 1 (3)  
    Unknown 3 (17) 0 (0)  
Number of comorbidities   0.310 
    0 5 (28) 18 (50)  
    1 6 (33) 9 (25)  
    2 or more 7 (39) 9 (25)  
Smokers 1 (6) 3 (8)  
Auto-immune diseases 1 (6) 1 (3)  
Malignancy 0 (0) 1 (3)  
High blood pressure 3 (17) 4 (11)  
Diabetes mellitus 1 (6) 4 (11)  

Bold values are values with P < 0.2.

All the patients were found to have systemic clinical involvement allowing confirmation of the sarcoidosis diagnosis, including bilateral lymphadenopathy and/or pulmonary involvement in 17 patients (2 stages I, 14 stages II and 1 stage III).

The clinical features are shown in Table 3. The most frequent extra-pulmonary localizations were lymph nodes (n = 9), neurosarcoidosis (n = 5), the skin with specific lesions (n = 4) as specific sarcoid lesions (n = 4) and lupus pernio (n = 1), the salivary glands (n = 3), sinonasal (n = 1), arthritis (n = 1) and arthralgia (n = 2), ophthalmological with two uveitis and one scleritis and cardiac involvement (n = 3).

Table 3

Clinical manifestations in 18 sarcoidosis patients with cryptococcosis and their controls

 Cases, n (%) Controls, n (%) P-value 
Number of patients 18 36  
Extra-pulmonary involvement 15 (83) 20 (56) 0.069 
Cardiac involvement 3 (17) 0 (0) 0.033 
Neurosarcoidosisa 5 (28) 3 (8) 0.010 
Lymph nodes 9 (50) 4 (11)  
ENTb 3 (17) 0 (0) 0.033 
Bones/joints 3 (17) 4 (11) 0.674 
Kidneyc 1 (6) 0 (0)  
Skin 4 (22) 9 (25) 0.73 
    Specific skin lesionsd 4 (22) 6 (17)  
    Erythema nodosum 0 (0) 3 (8)  
Eyese 3 (17) 4 (11) 1.00 
    Uveitis 2 (11) 4 (11)  
General signsf 11 (61) 10 (28)  
Pulmonary involvement 17 (94) 34 (94) 1.00 
Löfgren syndrome 0 (0) 2 (6)  
 Cases, n (%) Controls, n (%) P-value 
Number of patients 18 36  
Extra-pulmonary involvement 15 (83) 20 (56) 0.069 
Cardiac involvement 3 (17) 0 (0) 0.033 
Neurosarcoidosisa 5 (28) 3 (8) 0.010 
Lymph nodes 9 (50) 4 (11)  
ENTb 3 (17) 0 (0) 0.033 
Bones/joints 3 (17) 4 (11) 0.674 
Kidneyc 1 (6) 0 (0)  
Skin 4 (22) 9 (25) 0.73 
    Specific skin lesionsd 4 (22) 6 (17)  
    Erythema nodosum 0 (0) 3 (8)  
Eyese 3 (17) 4 (11) 1.00 
    Uveitis 2 (11) 4 (11)  
General signsf 11 (61) 10 (28)  
Pulmonary involvement 17 (94) 34 (94) 1.00 
Löfgren syndrome 0 (0) 2 (6)  

aNeurosarcoidosis = CNS involvement or/and peripheral nervous system involvement.

bENT involvement = naso-sinusal and/or parotid involvement.

cKidney involvement = nephrocalcinosis or glomerular nephropathy.

dSpecific skin lesions = sarcoids and lupus pernio.

eEyes involvement = uveitis and/or other ophthalmological signs (sclerit, keratitis, choroiditis or conjonctive nodules).

fGeneral signs = fever >38°C and/or weight loss >5 kg.

Bold values are values with P < 0.2.

The paraclinical features are described in Table 4. A spirometry was performed in 16 patients and showed normal lung function in nine cases. In six patients, BAL further disclosed a mean ratio CD4/CD8 of 4.65.

Table 4

Paraclinical features in 18 sarcoidosis patients with cryptococcosis and their controls

 Cases, n (%) Controls, n (%) 
Number of patients 18 36 
Chest radiography stage   
    Stage 0 
    Stage I 
    Stage II 14 28 
    Stage III 
Pulmonary function testsa   
    Normal 9/16 (56) 13/29 (45) 
    Obstructive syndromeb 4/16 (25) 3/29 (10) 
    Restrictive syndromec 4/16 (25) 11/29 (38) 
    Alteration of diffusion capacityd 3/16 (19) 7/29 (24) 
BAL   
    Hypercellularitye 8/12 (67) 15/29 (52) 
    Lymphocytosisf 8/12 (67) 20/29 (69) 
ACE ≥50 UI/l 12/14 (86) 19/24 (79) 
CRP >5 mg/l 7/12 (58) 14/20 (70) 
Creatinin ≥100 µmol/l 1/13 (0.08) 7/29 (24) 
Hypercalcemiag 0/13 (0) 3/27 (11) 
 Cases, n (%) Controls, n (%) 
Number of patients 18 36 
Chest radiography stage   
    Stage 0 
    Stage I 
    Stage II 14 28 
    Stage III 
Pulmonary function testsa   
    Normal 9/16 (56) 13/29 (45) 
    Obstructive syndromeb 4/16 (25) 3/29 (10) 
    Restrictive syndromec 4/16 (25) 11/29 (38) 
    Alteration of diffusion capacityd 3/16 (19) 7/29 (24) 
BAL   
    Hypercellularitye 8/12 (67) 15/29 (52) 
    Lymphocytosisf 8/12 (67) 20/29 (69) 
ACE ≥50 UI/l 12/14 (86) 19/24 (79) 
CRP >5 mg/l 7/12 (58) 14/20 (70) 
Creatinin ≥100 µmol/l 1/13 (0.08) 7/29 (24) 
Hypercalcemiag 0/13 (0) 3/27 (11) 

aPulmonary function test contains spirometry and diffusion capacity.

bObstructive syndrome = forced expiratory volume in 1 s/forced vital capacity <70%.

cRestrictive syndrome = forced vital capacity <80%.

dDiffusion capacity = lung of carbon monoxide (DLCO)/alveolar volume <70%.

eHypercellularity >150 × 103 cells.

fLymphocytosis means lymphocytes count >15% of total of white cells.

gHypercalcemia = calcemia ≥2.5 mmol/l.

Histology of sarcoidosis

All the patients had a biopsy evidencing non-caseous granulomatous lesions in bronchi (n = 9), peripheral (n = 6) and mediastinal lymph nodes (n = 3), minor salivary glands (n = 2), skin (n = 3), kidney (n = 1), liver (n = 1) or bone marrow (n = 1). According to Zajicek et al.20 criteria, five of the cases with CNS involvement were classified as probable.

Sarcoidosis treatment and outcome

Thirteen patients were treated with an initial dosage of 1 mg/kg/day equivalent prednisone for at least 1 month, and steroid therapy was then tapered according to the response. In addition, two patients received higher doses (>1.5 mg/kg/day) of methylprednisolone intravenously.

Three patients with neurosarcoidosis received immunosuppressive agents. Patient 10 received methylprednisolone pulses then CPM through a relapse, concomitantly with the occurring of CME. Methotrexate (MTX) was initiated for patient 16, as a rescue therapy because of a lack of response to corticosteroids alone. Because of progressive intracranial hypertension, he received CPM, then thalidomide, then infliximab which was changed for etanercept when cryptococcosis occurred. We should underline that the treatment of patient 16 is not a consensus approach at this time; first, thalidomide is usually used only for lupus pernio26; second, etanercept has no proved efficacity in sarcoidosis27,28 and could be responsible of paradoxical cases of proven sarcoidosis.29 Patient 14 received azathioprine for 3 years which was replaced by CPM after higher doses of methylprednisolone intravenously because of severe cardiac and CNS involvement.

The mean follow-up duration from the diagnosis of sarcoidosis was 6 years (range from 1 to 20 years). One patient was lost of follow-up. One patient died in a bedridden setting while he was hospitalized because of the occurrence of a vertebral fracture due to corticosteroids. Another died of liver-kidney syndrome due to an alcohol-induced cirrhosis 6 years later. Recovery, defined as disappearance of all the sarcoidosis symptoms and absence of recurrence with no treatment for at least 1 year, occurred in three patients (17%), while three patients received corticosteroids at low dose (3–7 mg/day) with significative clinical improvement. For five patients, disease was stable without possibility to taper treatment. Finally, the disease worsened for six patients.

Chronological relationship between cryptococcosis and sarcoidosis

At the cryptococcosis diagnosis, sarcoidosis had already been diagnosed in 14 of the 18 patients (77%), with a median time of 1005 days (0–5876 days) from the onset of the disease. All but 2 of the 14 patients with a previously known sarcoidosis had been treated with corticosteroids at the time of cryptococcosis (67% of all patients). The median duration and dose of steroids at the occurrence of cryptococcosis were 137 days (range from 0 to 5695 days) and 18 mg/day of equivalent of prednisone (0–55 mg/day). Moreover, two patients were receiving immunosuppressive agents, at the time of cryptococcosis, including CPM for one, and MTX plus infliximab for the other. In the remaining four patients (22%), cryptococcosis and sarcoidosis were diagnosed concomitantly. In front of the diagnosis of cryptococcosis or of granuloma, a search for cellular immunizing deficit T was realized and allowed to diagnose sarcoidosis concomitantly with cryptococcosis. The median level of CD4 lymphocytes at the time of cryptococcosis (available in 16 patients) was 145 per mm3 (range from 55 to 1300 per mm3) and appeared to be independent of the existence of the corticosteroid treatment (P = 0.792) (Table 5).

Table 5

Cryptococcosis occurring on treated sarcoidosis vs. de novo cryptococcosis or occurring on untreated sarcoidosis (group ‘untreated’ n = 6)

 Treated, n (%) Untreated, n (%) P-value 
Number of patients 12  
Sex    
    Male 9 (75) 4 (67) 
Neurosarcoidosis 5 (42) 0 (0) 0.114 
Cardiac disease 2 (17) 1 (17) 
LTCD4 rate per mm3 121 152 0.792 
 Treated, n (%) Untreated, n (%) P-value 
Number of patients 12  
Sex    
    Male 9 (75) 4 (67) 
Neurosarcoidosis 5 (42) 0 (0) 0.114 
Cardiac disease 2 (17) 1 (17) 
LTCD4 rate per mm3 121 152 0.792 

Cryptococcosis

Signs and symptoms

Among the 18 patients, 13 (72%) had a CNS fungal involvement, 4 (22%) had skin or soft tissue, 3 (17%) had bone or joint, 2 (11%) had hepatic and 1 (6%) had pulmonary cryptococcal infection. Four patients (22%) had disseminated cryptococcosis defined as two non-contiguous body sites infected. Four patients had localized infection, as skin (n = 2), liver (n = 1) and myositis (n = 1) (Table 6).

Table 6

Description of characteristics of cryptococcosis for 18 patients with sarcoidosis

 Yes, n (%) No, n (%) 
Clinics   
    Sudden onset 6 (33) 12 (67) 
    Fever >38°C 12 (67) 6 (33) 
Samples   
    Fungemia (available for 11) 3 (27) 8 (73) 
    Serum C. neoformans antigen 12 (676 (33) 
    Muscular abscess 1 (6) 17 (94) 
    Skin biopsy 2 (11) 16 (89) 
    Myelogram 1 (6) 17 (94) 
Cryptococcal localization   
    Extra-meningeal 8 (44) 10 (55) 
    CNS disease 13 (72) 5 (28) 
    Disseminateda 4 (2214 (78) 
Treatment of cryptococcosis   
    Intensive care hospitalization 3 (17) 15 (83) 
    Clinical cure at week 2 9 (50) 9 (50) 
 Yes, n (%) No, n (%) 
Clinics   
    Sudden onset 6 (33) 12 (67) 
    Fever >38°C 12 (67) 6 (33) 
Samples   
    Fungemia (available for 11) 3 (27) 8 (73) 
    Serum C. neoformans antigen 12 (676 (33) 
    Muscular abscess 1 (6) 17 (94) 
    Skin biopsy 2 (11) 16 (89) 
    Myelogram 1 (6) 17 (94) 
Cryptococcal localization   
    Extra-meningeal 8 (44) 10 (55) 
    CNS disease 13 (72) 5 (28) 
    Disseminateda 4 (2214 (78) 
Treatment of cryptococcosis   
    Intensive care hospitalization 3 (17) 15 (83) 
    Clinical cure at week 2 9 (50) 9 (50) 

aDisseminated infection = infection of two non-contiguous sites.

Bold values are values with P < 0.2.

Table 7

Characteristics of 13 CME in sarcoidosis

 Yes, n (%)/ median (min–max) No, n (%) 
Clinics   
    Fever 10 (77) 3 (23) 
    Altered mental statusa 6 (46) 7 (54) 
    Meningitis 10 (77) 3 (23) 
    Focal neurological signs 2 (15) 11 (85) 
Samples (n = 12)   
    Median leukocytes CSF (cell/mm394 (11–498)  
    CSF glucose <1 mmol/l 3 (25) 9 (75) 
    Median CSF glucose (mmol/l) 1.8 (0.10–2.70)  
    CSF protein >50 mg/dl 12 (100) 0 (0) 
    Median CSF protein (mg/dl) 115 (73–853)  
    India ink CSF 7 (64) 4 (36) 
    Antigen C. neoformans CSF 12 (100) 0 (0) 
    Culture C. neoformans CSF 11 (92) 1 (8) 
    Antigen C. neoformans serum 9 (69) 4 (31) 
Treatment of CME   
    CSF sterilization at week 2 8/9 (89) 1 (11) 
    Clinical cure at week 2 7 (54) 6 (46) 
 Yes, n (%)/ median (min–max) No, n (%) 
Clinics   
    Fever 10 (77) 3 (23) 
    Altered mental statusa 6 (46) 7 (54) 
    Meningitis 10 (77) 3 (23) 
    Focal neurological signs 2 (15) 11 (85) 
Samples (n = 12)   
    Median leukocytes CSF (cell/mm394 (11–498)  
    CSF glucose <1 mmol/l 3 (25) 9 (75) 
    Median CSF glucose (mmol/l) 1.8 (0.10–2.70)  
    CSF protein >50 mg/dl 12 (100) 0 (0) 
    Median CSF protein (mg/dl) 115 (73–853)  
    India ink CSF 7 (64) 4 (36) 
    Antigen C. neoformans CSF 12 (100) 0 (0) 
    Culture C. neoformans CSF 11 (92) 1 (8) 
    Antigen C. neoformans serum 9 (69) 4 (31) 
Treatment of CME   
    CSF sterilization at week 2 8/9 (89) 1 (11) 
    Clinical cure at week 2 7 (54) 6 (46) 

aAltered mental status = disturbance of consciousness or behavior.

Neurological signs and symptoms occurred in 11 of the 13 patients (85%) who presented a CME as meningitis in 10 patients (77%) and altered mental status (disturbance of consciousness and behavior) in 6 patients (46%). Two of the 13 patients (15%) with CME presented focal neurologic symptoms including pyramidal lesions and these 2 patients had a negative serum cryptococcal antigen. Fever was most common among the patients with CME (77%). A cerebral MRI or CT scan was performed in 12 patients and showed abnormalities in three, consisting in a meningeal contrast uptake, peri-radicular infiltrations or nodular lesions.

Cryptococcal antigen results

The baseline serum cryptococcal antigen assay was positive for 12 patients (67%) out of the 18 including 9 of the 13 patients with CME (69%) and 4 (100%) patients with disseminated cryptococcosis.

All the patients with CME had one of the three test positive (India ink preparation, CSF culture and/or CSF antigen) except one patient who presented a disseminated cryptococcosis with meningoencephalitis but the lumbar puncture was not performed because of a disseminated intravascular coagulopathy and the patient improved while receiving antifungal therapy (Table 7).

Among the 12 patients who underwent a lumbar puncture, the CSF culture was positive for 11 (92%), whereas India ink was positive for 7 (64%). One patient had an India ink positive without positive culture. For all the patients with a positive CSF culture, CSF cryptococcal antigen was detected locally.

A discrepancy in antigen C. neoformans detection between serum and CSF (negative in serum and positive in CSF) was seen in 4 cases of the 12 available (33%).

Antifungal therapy and outcome

Among the 13 patients with CME, 11 patients (85%) were successfully treated. The two others presented a slow clinical improvement, classified as ‘failure’, but no relapse was noted.

Only five (38%) of them were treated according to the guidelines with an induction therapy consisting of amphotericin B and 5-fluocytosine (5-FC) during 4 weeks, they had a consolidation therapy with fluconazole 400 mg/day during 8 weeks, then a maintenance therapy by fluconazole 200 mg/day during 6–12 months or even longer. Induction therapy involved administration of amphotericin B plus 5-FC in seven patients (54%), amphotericin B alone in two patients (15%), amphotericin B plus fluconazole in one patient (8%), fluconazole alone in two patients (15%) and 5-FC plus fluconazole in one patient (8%). The median duration of the induction therapy was 24 days (ranging from 5 to 85 days). The consolidation therapy with fluconazole 400 mg was given to six patients (46%) for a median duration of 63 days.

Four of five remaining patients were treated with fluconazole alone. Amphotericin B plus 5-FC followed by voriconazole had been given to one patient who presented fungemia.

Among the 18 patients, clinical cure after 2 weeks was obtained for nine patients (50%), seven of them having CME at baseline. At week 2, the negativity of antigen C. neoformans in CSF was obtained for eight of the nine patients who underwent a subsequent CSF analysis. No relapse was identified.

In this study, two patients died after 30 days and none of the deaths were attributed to cryptococcosis or any related complication. Two deaths were attributed to other diseases, one to multicomplicated liver cirrhosis and one to bedridden complication.

Comparison between patients with cryptococcosis plus sarcoidosis and controls

The results are summarized in Tables 2–4. The two groups were statistically similar in terms of ethnic distribution, smoking habits, number and type of comorbidities, clinical outcome, pulmonary function tests and biological features.

The patients presenting cryptococcosis were mostly men (72 vs. 47%) and significantly younger than patients without opportunistic infections (median of 28 vs. 42 years, P = 0.0004).

The clinical features were significantly different between the two groups at the time of the diagnosis of sarcoidosis, concerning the frequency of extra-pulmonary localizations (83 vs. 56%, P = 0.069), neurological (28 vs. 8%, P = 0.010), heart (17 vs. 0%, P = 0.033), and ear nose throat (ENT) with naso-sinusal and parotid (17 vs. 0%, P = 0.033) involvements which were more frequent in the cryptococcosis group.

The proportion of patients receiving a systemic treatment was similar in the two groups. Concerning the proportion of patients receiving oral corticosteroids (13 patients in cryptococcosis group and 21 patients in the control group), or immunosuppressants as an initial treatment, there was no difference between the two groups.

The mean follow-up duration was 6 years (ranging from 1 to 20 years) in the cryptococcosis group and 5.5 years in the control group. There was no difference on the mortality rate between the two groups: two patients in each group died.

We assessed factors with potential impact on cryptococcosis occurrence by means of adjusted and non-adjusted analyses (Table 8). In the adjusted model for all the patients, the factors significantly associated with cryptococcosis were extra-thoracic sarcoidosis (P = 0.055) and a treatment with corticosteroids (P = 0.123) with a mean duration of 137 days (from 8 to 1591 days). Moreover, these results persisted when they were correlated with the male sex, a confounding factor of cryptococcosis.

Table 8

Adjusted analyses and logistic regression of cryptococcosis probability

 Univariate regression
 
Multivariate regression
 
 OR 80% IC P-value OR 80% IC P-value 
Sex       
    Male     
    Female 0.34 0.13–0.90 0.081 0.30 0.13–0.71 0.075 
Systemic corticosteroids       
    No     
    Yes 3.57 1.18–11.96 0.066 3.23 1.22–8.57 0.123 
Extra-pulmonary sarcoidosis       
    No     
    Yes 4.00 1.32–13.34 0.043 4.31 1.62–11.42 0.055 
Diabetes       
    No      
    Yes 0.47 0.38–2.89 0.515    
 Univariate regression
 
Multivariate regression
 
 OR 80% IC P-value OR 80% IC P-value 
Sex       
    Male     
    Female 0.34 0.13–0.90 0.081 0.30 0.13–0.71 0.075 
Systemic corticosteroids       
    No     
    Yes 3.57 1.18–11.96 0.066 3.23 1.22–8.57 0.123 
Extra-pulmonary sarcoidosis       
    No     
    Yes 4.00 1.32–13.34 0.043 4.31 1.62–11.42 0.055 
Diabetes       
    No      
    Yes 0.47 0.38–2.89 0.515    

Bold values are values with P < 0.2.

Discussion

To our knowledge, this study is the first case control series comparing sarcoidosis patients with cryptococcal infection, to sarcoidosis without any opportunistic infections. The results suggested that a cryptococcal infection happened in two-thirds of the cases on underlying sarcoidosis treated with corticosteroids and in one-third of the cases without any treatment with four cryptococcosis revealing sarcoidosis. The risk factors of cryptococcosis were corticosteroids treatments and also extra-thoracic sarcoidosis. The prognosis after an appropriate treatment of fungal infection was good with no relapse and no patient died from cryptococcosis or any related complication.

Cryptococcosis in the face of sarcoidosis is a rare association and very few cases can be found. Excluding the cases of our study, between 1950 and 2011, 71 cases have been published in which 65 had available data (Table 9). In our study, we identified 18 cases over 25 years period from the NRCMA database. Sarcoidosis accounted for 0.6% of all cryptococcosis and for 2.9% of the HIV-negative patients. On the other hand, no study has prospectively assessed the prevalence of cryptococcosis in a cohort of sarcoidosis patients. Thanks to its existing database, we assessed cryptococcosis prevalence in the referral department of pneumology of the Avicenne Hospital taking part in this study (DV). Among 3000 cases recruited in this tertiary center during a period of 21 years, only one cryptococcosis case was identified.

Table 9

Literature review

Year Article Patient Infection site HIV Diagnostic delay Sarcoidosis stadification CD4 rate Corticotherapy Outcome 
1984 Adams and McDonald57 57 Acromio-clavicular arthritis NA NA NA NA Yes NA 
1989 Ahmad and Sharma58 W 55 CME NA 2 months Stage III NA 2 months Favorable 
1961 Allcock59 1 NA Pulmonary NA Simultaneous Stage III NA No NA 
1988 Allen et al.60 1 NA Pulmonary abscess NA NA NA NA NA NA 
1988 Allen 1 NA Pulmonary NA NA NA NA NA NA 
2005 Baughman and Lower13 1 NA CME NA NA NA NA Yes + MTX NA 
2005 Baughman 1 NA Pulmonary NA 6 months NA Leucopenia Yes + MTX NA 
2005 Baughman 1 NA Pulmonary NA NA NA NA Yes NA 
1975 Belcher et al.30 W 49 Bone NA 60 months Stage II + skin NA No NA 
1975 Belcher W 48 Pulmonary NA 96 months Stage II + skin NA 96 months NA 
1960 Bernard and Owens61 1 NA Pulmonary NA 36 months Stage I NA No NA 
1979 Blanchon et al.62 M 31 Skin + adenopathy NA 36 months Stage II NA No NA 
1996 Bohne et al.63 W 62 Infiltrative skin lesion NA NA Stage II NA Yes Favorable 
1999 Botha and Wessels64 W 49 CME Neg Simultaneous Stage III + liver NA No Death 
2007 Boyton et al.48 M 29 Pulmonary Neg Simultaneous Stage II NA No Favorable 
1959 Brandt and Sturup65 1 NA CME NA NA NA NA NA NA 
1972 Brock and Grieco66 M 56 Prostatic NA 24 months Stage II NA No NA 
2008 Cancelli et al.40 M 38 CME Neg 72 months Stage I 410 per mm3 No Death 
2006 Deb et al.42 M 65 CME + dementia NA 108 months Stage II NA Yes Favorable 
1950 Fisher67 M 20 Disseminated NA 6 months Stage II NA No NA 
1950 Gandy68 1 NA Skin NA 60 months Stage II NA No NA 
2009 Geller et al.56 M 38 Sterno-clavicular arthritis Neg NA Uveitis + bone marrow 270 per mm3 No Favorable 
2006 Gibold et al.69 M 48 Disseminated Neg 132 months Neurosarcoidosis 69% Ly Yes Favorable 
1999 Giner et al.70 W 30 CME NA Simultaneous Stage II NA No NA 
1999 Hajjeh et al.10 1 NA Cryptococcosis NA NA NA NA NA NA 
1999 Hajjeh 1 NA Cryptococcosis NA NA NA NA NA NA 
1999 Hajjeh 1 NA Cryptococcosis NA NA NA NA NA NA 
1999 Hajjeh 1 NA Cryptococcosis NA NA NA NA NA NA 
1999 Hajjeh 1 NA Cryptococcosis NA NA NA NA NA NA 
1965 Harris et al.71 1 NA Pulmonary NA 34 months Stage I NA No NA 
1957 Heller et al.72 M 22 Disseminated NA 14 months Stage II NA 14 months NA 
2001 Italiano et al.73 37 Arthritis of the knee NA NA NA NA Yes NA 
2007 Kanaly et al.74 M 58 Cryptococcoma + CME Neg 4 months Stage III 85 per mm3 No Favorable 
1968 Kuaity and Lewis75 1 NA Bone NA 96 months Stage I NA No NA 
2004 Hamilton et al.45 M 40 Disseminated Neg Simultaneous Stage II NA Yes Death 
1999 Kariniemi et al.76 M 42 Skin NA 48 months Stage III NA 12 months NA 
1957 Leithold et al.77 M 27 Adenopathy NA Simultaneous Stage III NA No NA 
1957 Lepow et al.78 1 NA CME NA Simultaneous Stage II NA No NA 
1985 Levine et al.79 W 35 Bone NA 84 months Stage I NA No NA 
1974 Levinson et al.80 W 38 Bone (knee) NA Simultaneous Stage IV NA No Favorable 
1998 Liu54 9 NA Osteomyelitis NA NA NA NA NA NA 
1974 Lord81 1 NA Cryptococcosis NA NA NA NA NA Coccidioidomycosis 
1958 McCullough82 M 23 Pulmonary NA 5 months Stage II NA 5 months NA 
2002 Mehrany et al.44 M 48 Disseminated Neg 24 months Stage I + neurosarcoidosis Lymphopenia 13 months Favorable 
2010 Nfoussi et al.83 1 NA Spondylodiscitis Neg NA NA NA NA Paraplegia 
1973 Nottebart et al.55 M 30 Disseminated NA 42 months Stage II NA 9 months NA 
1957 Plummer et al.84 M 33 Disseminated NA 2 months Stage III NA 2 months Death 
2004 Ramos-Barbosa et al.85 W 46 Mastitis NA NA Stage IV NA Yes NA 
2004 Riha and Allen86 1 NA Pulmonary NA NA NA NA Yes Favorable 
2004 Riha 1 NA Pulmonary NA NA NA NA Yes Abscess (nocardia) 
2004 Riha 1 NA Pulmonary NA NA NA NA Yes Favorable 
2004 Riha 1 NA Skin NA NA NA NA No Favorable 
2004 Riha 1 NA Skin NA NA NA NA Yes Favorable 
2002 Ross and Katz43 W 28 CME NA Simultaneous Stage I NA No NA 
1969 Scadding46 M 30 CME NA 9 months Stage III + extra-pulmonary NA 1 month + plaquenil Death 
2011 Scheer et al.87 M 20 Bone (temporal) Neg 24 months Stage II/III 170 per mm3 No Favorable 
1982 Shaff et al.88 1 NA Bone NA NA NA NA NA Tuberculosis 
1959 Shields89 W 42 Disseminated NA Simultaneous Stage I NA No NA 
1995 Shijubo et al.90 W 36 Pulmonary NA 4 months Stage I NA No Favorable 
1969 Sokolowski et al.91 W 32 Disseminated NA 1 month Stage I NA 1 month NA 
1957 Spivack et al.92 1 NA Kidney NA 36 months NA NA No NA 
1988 Tanaka et al.93 1 NA Cryptococcosis NA NA NA NA NA NA 
2005 Wildstein et al.94 M 20 Spondylodiscitis + epiduritis NA 36 months Stage I NA Yes Favorable 
Year Article Patient Infection site HIV Diagnostic delay Sarcoidosis stadification CD4 rate Corticotherapy Outcome 
1984 Adams and McDonald57 57 Acromio-clavicular arthritis NA NA NA NA Yes NA 
1989 Ahmad and Sharma58 W 55 CME NA 2 months Stage III NA 2 months Favorable 
1961 Allcock59 1 NA Pulmonary NA Simultaneous Stage III NA No NA 
1988 Allen et al.60 1 NA Pulmonary abscess NA NA NA NA NA NA 
1988 Allen 1 NA Pulmonary NA NA NA NA NA NA 
2005 Baughman and Lower13 1 NA CME NA NA NA NA Yes + MTX NA 
2005 Baughman 1 NA Pulmonary NA 6 months NA Leucopenia Yes + MTX NA 
2005 Baughman 1 NA Pulmonary NA NA NA NA Yes NA 
1975 Belcher et al.30 W 49 Bone NA 60 months Stage II + skin NA No NA 
1975 Belcher W 48 Pulmonary NA 96 months Stage II + skin NA 96 months NA 
1960 Bernard and Owens61 1 NA Pulmonary NA 36 months Stage I NA No NA 
1979 Blanchon et al.62 M 31 Skin + adenopathy NA 36 months Stage II NA No NA 
1996 Bohne et al.63 W 62 Infiltrative skin lesion NA NA Stage II NA Yes Favorable 
1999 Botha and Wessels64 W 49 CME Neg Simultaneous Stage III + liver NA No Death 
2007 Boyton et al.48 M 29 Pulmonary Neg Simultaneous Stage II NA No Favorable 
1959 Brandt and Sturup65 1 NA CME NA NA NA NA NA NA 
1972 Brock and Grieco66 M 56 Prostatic NA 24 months Stage II NA No NA 
2008 Cancelli et al.40 M 38 CME Neg 72 months Stage I 410 per mm3 No Death 
2006 Deb et al.42 M 65 CME + dementia NA 108 months Stage II NA Yes Favorable 
1950 Fisher67 M 20 Disseminated NA 6 months Stage II NA No NA 
1950 Gandy68 1 NA Skin NA 60 months Stage II NA No NA 
2009 Geller et al.56 M 38 Sterno-clavicular arthritis Neg NA Uveitis + bone marrow 270 per mm3 No Favorable 
2006 Gibold et al.69 M 48 Disseminated Neg 132 months Neurosarcoidosis 69% Ly Yes Favorable 
1999 Giner et al.70 W 30 CME NA Simultaneous Stage II NA No NA 
1999 Hajjeh et al.10 1 NA Cryptococcosis NA NA NA NA NA NA 
1999 Hajjeh 1 NA Cryptococcosis NA NA NA NA NA NA 
1999 Hajjeh 1 NA Cryptococcosis NA NA NA NA NA NA 
1999 Hajjeh 1 NA Cryptococcosis NA NA NA NA NA NA 
1999 Hajjeh 1 NA Cryptococcosis NA NA NA NA NA NA 
1965 Harris et al.71 1 NA Pulmonary NA 34 months Stage I NA No NA 
1957 Heller et al.72 M 22 Disseminated NA 14 months Stage II NA 14 months NA 
2001 Italiano et al.73 37 Arthritis of the knee NA NA NA NA Yes NA 
2007 Kanaly et al.74 M 58 Cryptococcoma + CME Neg 4 months Stage III 85 per mm3 No Favorable 
1968 Kuaity and Lewis75 1 NA Bone NA 96 months Stage I NA No NA 
2004 Hamilton et al.45 M 40 Disseminated Neg Simultaneous Stage II NA Yes Death 
1999 Kariniemi et al.76 M 42 Skin NA 48 months Stage III NA 12 months NA 
1957 Leithold et al.77 M 27 Adenopathy NA Simultaneous Stage III NA No NA 
1957 Lepow et al.78 1 NA CME NA Simultaneous Stage II NA No NA 
1985 Levine et al.79 W 35 Bone NA 84 months Stage I NA No NA 
1974 Levinson et al.80 W 38 Bone (knee) NA Simultaneous Stage IV NA No Favorable 
1998 Liu54 9 NA Osteomyelitis NA NA NA NA NA NA 
1974 Lord81 1 NA Cryptococcosis NA NA NA NA NA Coccidioidomycosis 
1958 McCullough82 M 23 Pulmonary NA 5 months Stage II NA 5 months NA 
2002 Mehrany et al.44 M 48 Disseminated Neg 24 months Stage I + neurosarcoidosis Lymphopenia 13 months Favorable 
2010 Nfoussi et al.83 1 NA Spondylodiscitis Neg NA NA NA NA Paraplegia 
1973 Nottebart et al.55 M 30 Disseminated NA 42 months Stage II NA 9 months NA 
1957 Plummer et al.84 M 33 Disseminated NA 2 months Stage III NA 2 months Death 
2004 Ramos-Barbosa et al.85 W 46 Mastitis NA NA Stage IV NA Yes NA 
2004 Riha and Allen86 1 NA Pulmonary NA NA NA NA Yes Favorable 
2004 Riha 1 NA Pulmonary NA NA NA NA Yes Abscess (nocardia) 
2004 Riha 1 NA Pulmonary NA NA NA NA Yes Favorable 
2004 Riha 1 NA Skin NA NA NA NA No Favorable 
2004 Riha 1 NA Skin NA NA NA NA Yes Favorable 
2002 Ross and Katz43 W 28 CME NA Simultaneous Stage I NA No NA 
1969 Scadding46 M 30 CME NA 9 months Stage III + extra-pulmonary NA 1 month + plaquenil Death 
2011 Scheer et al.87 M 20 Bone (temporal) Neg 24 months Stage II/III 170 per mm3 No Favorable 
1982 Shaff et al.88 1 NA Bone NA NA NA NA NA Tuberculosis 
1959 Shields89 W 42 Disseminated NA Simultaneous Stage I NA No NA 
1995 Shijubo et al.90 W 36 Pulmonary NA 4 months Stage I NA No Favorable 
1969 Sokolowski et al.91 W 32 Disseminated NA 1 month Stage I NA 1 month NA 
1957 Spivack et al.92 1 NA Kidney NA 36 months NA NA No NA 
1988 Tanaka et al.93 1 NA Cryptococcosis NA NA NA NA NA NA 
2005 Wildstein et al.94 M 20 Spondylodiscitis + epiduritis NA 36 months Stage I NA Yes Favorable 

NA, not available. Among the 71 cases reported in the literature between 1950 and 2011, data were available for 65 patients.

Cryptococcosis and sarcoidosis were diagnosed simultaneously in four of our cases, while two patients had a known sarcoidosis and were not on therapy. These data contrast with the results of the literature in which almost half the cases were free of treatment. Interestingly, none of these patients experienced other opportunistic infections. T-cell-mediated immunity known to be the predominant mechanism for combatting cryptococcal infection3 and it is recognized that patients with sarcoidosis have decreased reaction to cryptococcal antigen in vitro.30 Overall, these data suggested in some patient the existence of a rare and unexplained primary immunodeficiency which would favor both the occurrence of sarcoidosis and cryptococcosis.30

Contrary to the literature data, two-thirds of our patients received high dose and prolonged corticosteroids therapy. The use of corticosteroids is a well-recognized risk factor for cryptococcosis,7,10,31 almost its exacerbation and dissemination,32 and dosages >20 mg/day have been shown to place the patients at a higher risk for this opportunistic infection.33 Glucocorticoids cause both Th1/Th2 dysregulation of T helper cells by favoring Th2 predominant cytokines response and suppression of phagocyte effector cell functions and reducing chemotactic activity of CSF toward polymorphonuclear leukocytes, which leads to poor outcomes of fungal infection.34 Moreover, two of our patients were treated with immunosuppressive agents, at the time of cryptococcosis, including CPM, and MTX plus infliximab because of neurosarcoidosis or heart involvement. We should underline that the use of CPM as first or second or third line steroid sparing therapy is not a consensus approach to treating either cardiac or neurosarcoid manifestations and that CPM is usually used in severe involvements that are resistant to corticosteroids and other immunosuppressive drugs.35,36 These data suggested that, in the second group, the administration of immunosuppressive therapy or corticosteroids to patients with severe sarcoidosis may potentiate a relative susceptibility to cryptococcosis.

As shown in our illustrative case, it may be extremely difficult to differentiate CME from neurosarcoidosis; cranial nerve palsy, meningism and hydrocephalus may be present in both diseases,13,37 and vice versa the absence of fever and meningism does not exclude the diagnosis of CME.37 Brain CT and MRI may detect aspecific lesions or may be normal, in CME as in CNS sarcoidosis.38,39 The CSF profile may be misleading as well; a modest lymphocytic pleiocytosis and a slight increase in CSF protein content are common in both diseases. Even though a low CSF glucose could suggest a diagnosis of CME rather than CNS sarcoidosis, a normal CSF glucose does not exclude a diagnosis of cryptococcal meningitis.40 As shown in five of our cases, CSF analysis with India ink stain or cryptococcal cultures may be negative.37 Thus, repeated lumbar punctures with an adequate volume of CSF analyzed, including these three tests, are mandatory to perform an accurate diagnosis, as it was reported by Pappas et al. in a population of 157 patients with CME seronegative for HIV.7 Interestingly, only 67% of the 18 cryptococcosis had a positive cryptococcal antigen in serum. It has been previously shown that negative antigen detection in serum does not rule out dissemination especially among HIV-negative patients,6 what is different from HIV-positive patients, in which almost all with cryptococcosis have positive serum cryptococcal antigen titers.41

In patients with known systemic sarcoidosis, the risk is that any new neurological condition may be attributed to the systemic disease without any alternative diagnosis being made.39,40,42–44 In the literature, several patients were treated as neurosarcoidosis cases with a diagnosis of CME unfortunately done in post mortem.45,46

On the other hand, cryptococcosis is a prototype of a chronic granulomatous infection that is clinically able to mimic sarcoidosis. When cases of sarcoidosis and cryptococcal disease coincide, it could be difficult to be sure whether one condition has preceded the other and has predisposed to it and vice versa.47,48 All our patients had (i) a histologically proven granulomatous disease with clinical manifestation compatible with sarcoidosis, (ii) a clinically detectable deterioration which punctuated the onset of the infection and (iii) an improvement of these manifestations under antifungal therapy. For example, a pulmonary sarcoidosis stage II was discovered in patient 5, 1 month before developing CME. Sarcoidosis was diagnosed on: (i) clinical and paraclinical arguments (Chest X-ray, lung scan, hypercellularity and lymphocytosis at BAL,49 increase of ACE), a bronchic biopsy with granulomatous, (ii) no argument for a lung localization of cryptococcosis (search of C. neoformans in BAL negative), (iii) a past history of erythematous nodosum in 1990 treated with corticosteroids, an argument of great importance.

To diagnose a cryptococcal infection complicating sarcoidosis, when the duration of follow-up of sarcoidosis is no longer than 1 year, all the clinically detectable deteriorations which punctuate the onset of the infection should occur in organs different from those involved in sarcoidosis.15

Some demographic features and extra-pulmonary involvement make the difference between sarcoidosis with and without cryptococcosis. Unlike what is usually observed in sarcoidosis, in which the people affected are mainly middle aged (30–35 years), with a second peak of cases at about 50 years of age [mostly women (female/male ratio 1.8/1)],50 more than two-thirds of our sarcoidosis patients presenting cryptococcosis were male and were significantly younger than controls. We could explain the differences in the sex ratio by the demographic distribution of cryptococcosis with a ratio male/female in HIV-negative patients of 1.7/1.31,51

Among extra-thoracic localizations, we found a highly positive association with neurosarcoidosis and heart involvement, which were respectively presented in 28 and 17% of our cases. As previously discussed, we think that the high interaction between corticosteroids and severe extra-thoracic manifestations52 may explain the results.

The prognosis of cryptococcosis was favorable in this study without any death attributable to cryptococcosis, even when neurologic signs, such as altered mental status, abnormal imaging or disseminated cryptococcosis were present at the onset. This good prognosis contrasts with the 16% rate of mortality reported in the cryptococcosis HIV-negative patients7, and in the systemic lupus erythematosus patients with CME (mortality rate of 50%).53 These results also contrast with the mortality rate of 20% among the patients identified with cryptococcosis and sarcoidosis in the literature review (Table 9). No predictive factor of the outcome was found in our study, such as altered mental status, abnormal cerebral imagery, presence of fungemia, disseminated infection, hypoglycorachia or hyponatremia, because of the favorable outcomes. In contrast, other studies found worse prognosis in the HIV-negative patients who present with extra-neurological and extra-pulmonary sites of infection,7 or a worse survival probability at 3 months when their neurology or brain imagery was abnormal at baseline.6

The distribution of localizations in our study was similar to data reported in non-HIV patients for disseminated infection in four patients, similar to the 16% in HIV and non-HIV cryptococcosis patients.31 The pulmonary localization was rare for patients with sarcoidosis43 (one patient in our study) which contrasts with 29%10 to 36%7 of pulmonary cryptococcosis reported in others uninfected HIV patients. According to the literature review (Table 9), the cryptococcosis localizations were disseminated in 9 cases (14%); it involved the CNS in 11 cases (17%), the lungs in 14 cases (22%), the bones in 20 cases (31%) and other localizations in 15% of the cases. On the other hand, sarcoidosis has been reported in 25% of the patients with cryptococcal osteomyelitis,54–56 and is thought to be the most important risk for cryptococcal skeletal involvement regardless of HIV patients.31 We have not found this element in this study, as only three cases had osteoarticular localization. CME was frequent (72%) in this study which is close to the data reported in AIDS patients (81%), but higher than the rate reported in the HIV-negative patients with cryptococcosis (63%).31

CD4 lymphocytopenia was not an independent risk factor of cryptococcosis in this study, and all patients have not presented other opportunistic infections. Sarcoidosis presented an ‘immune paradox’11: despite an extensive local inflammation, anergy may develop, as indicated by the suppression of the immune response to tuberculin.95 In contrast with the accumulation of CD4 T-lymphocyte in active granulomas, peripheral blood CD4 lymphocytopenia occurs in 50% of the sarcoidosis active patients and is associated with chronic diseases.96 Several studies have shown that lymphopenia is correlated with the disease severity with no significant relationship between specific medical therapies and lymphocytes counts.97 The median result of 145 CD4 per mm3 in our study was comparable with the results reported in other reports (middle level of 230±124 cells/mm3).96 The T-lymphocyte population distribution during the course of sarcoidosis was variable, so we could not compare with level CD4 of the control group. It should be noted that, Pneumocystis jiroveci pneumonia is distinctly rare in patients treated for sarcoidosis, compared with others systemic diseases as granulomatous with polyangiitis (12%).98 Patients with HIV and cryptococcosis had a median CD4 count of 26 per mm3 (range 0–230), and 90% of the patients had a CD4 level under 100 per mm3.31 Cryptococcosis also occurred in idiopathic CD4 lymphocytopenia, with median CD4 count of 82 per mm3.99 Given these data, we considered that the CD4 levels in this study did not explain cryptococcosis in sarcoidosis.

Other studies should be designed to investigate about immunological factors that could explain the differences in susceptibility to cryptococcosis among sarcoidosis in regard to the other opportunistic infections and to understand the existence of a possible immune deficiency favoring the association of the two diseases.

To our knowledge, our study is the largest study of sarcoidosis patients with cryptococcosis, thanks to its multicenter design, it is also the first case control series which attempts to identify factors associated with the occurrence of cryptococcosis. All isolates were C. neoformans, and therefore we have no experience of C. gattii complicating sarcoidosis. We are aware that the retrospective nature and design of our study limited the power of the analysis. The small number of events precluded the possibility of making adjustments for more confounders in multivariate analysis. Second, the control cases, which have been referred to a teaching institution, were expected to be more severe on average than those expected to be encountered in a primary setting; that was why the selection has been done on the different stages of sarcoidosis. Thus, although our comparison group was not ideal, the direction bias was probably unfavorable to the association between the severity of sarcoidosis and our cases. Despite the several strategies used to identify all the cases in France, we could not exclude the possibility that we missed some cases and that our incidence rate might be underestimated.

In conclusion, our study reinforces the possibility of an unusual association between sarcoidosis and cryptococcosis. Clinicians should consider cryptococcal infection in patients with sarcoidosis if initial presentation is unusual, or in case of clinical deterioration (especially in case of acute neuro-meningeal symptoms with fever). Factors independently associated with the occurrence of cryptococcosis were corticosteroids treatment and extra-thoracic sarcoidosis. Nevertheless, cryptoccocosis can occur in one-third of cases in absence of immunosuppressive treatment. Cryptococcosis in the face of sarcoidosis is not associated to severe CD4 lymphocytopenia and has a good prognosis.

Acknowledgement

We thank Ms Marie-Agnès Charrier for her expert assistance in the preparation of the manuscript.

Conflict of interest: None declared.

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Author notes

*P. Sève and O. Lortholary contributed equally to this study.