Clinical Neurology and Neurosurgery 131 (2015) 59–63
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Cryptococcal meningitis in Chinese patients with systemic lupus erythematosus Yuhua Zhong a , Min Li a , Jia Liu a , Weixi Zhang b,∗ , Fuhua Peng a,∗ a Multiple Sclerosis Center, Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong 510630, China b Department of Neurology, The First Affiliated Hospital Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China
a r t i c l e
i n f o
Article history: Received 22 April 2014 Received in revised form 8 January 2015 Accepted 23 January 2015 Available online 2 February 2015 Keywords: Cryptococcal meningitis Systemic lupus erythematosus Chinese
a b s t r a c t Objective: Systemic lupus erythematosus (SLE) is a chronic immunologic disorder that can affect multiple organ systems and makes the patient susceptible to infection. Cryptococcal meningitis (CM) is a rare but often fatal complication of SLE. Design: In this study, 6 patients with CM were identified among 631 patients with SLE. The demographic, clinical, laboratory profiles, serological features and outcomes of these 6 SLE patients with CM were retrospectively analyzed. Results: The mean age of these patients was 24.1 years (range 12–42) at the time of SLE diagnosis, and 27.1 years (range 14–42) at the time of Cryptococcus neoformans infection, with mean disease duration of 37 months (range 3–72). Four patients had active SLE. All patients were receiving glucocorticoids therapy (mean prednisone dose of 20.5 (5.0–36.0) mg/day) at the onset of infection. Five patients had received other immunosuppressive drugs. The most common presentations of CM were headache and fever and 4 of the 6 patients were normal on physical examination. The cerebrospinal fluid (CSF) indices (protein and glucose) were normal in 4 cases, whereas they were mildly abnormal in the other 2 patients. White counts in the CSF ranged from 8 to 240 cells/mm. C. neoformans were isolated from CSF of 4 patients. The isolation of crytococci from extraneural sites, including blood and lungs, was found in 2 patients. Results of the head computed tomography scan were unremarkable in 5 of the patients. The infection was completely resolved in 5 patients, and it was resolved with serious sequelae in one patient. Conclusions: In conclusion, the key to a rapid diagnosis of CM in patients with SLE is to maintain a high degree of awareness which will help avoid delays in treatment. This is mainly due to the fact that the clinical presentation and laboratory results from routine hematological, biochemical and CSF analyses of CM in patients with SLE are mostly non-specific. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Cryptococcus neoformans, as one of the most common pathogenic species worldwide, can cause infection disease in humans [1]. The central nervous system (CNS) is a common site for cryptococcal infection which usually presents cryptococcal meningitis (CM) [2]. Systemic lupus erythematosus (SLE) is an autoimmune disease with myriad of presentations and is characterized by the immune dysregulation in its pathogenesis [3]. Therefore, SLE patients are susceptible to infection because of their disease-related immunological defect or concomitant immunosuppressive therapies [4]. The CNS, which is an uncommon site, constitutes only about 3%of the infections in SLE patients.
CM is the most common cause of CNS infection with a high mortality rate in patients with SLE [5]. The clinical features of CM may be non-specific which may lead to a missed diagnosis or delayed treatment, especially in patients receiving immunosuppressive therapy [6]. However, neuropsychiatric systemic lupus erythematosus (NPSLE) encompasses highly diverse clinical manifestations and may occur at any time in SLE [7]. Therefore, CM in patients with SLE can be misdiagnosed as NPLSE or an activation of SLE. In this retrospective study, we described the demographic characteristics, clinical histories, laboratory profiles, serological features and outcomes of 6 SLE patients with CM. 2. Patients and methods 2.1. Definitions
∗ Corresponding authors. Tel.: +86 18922102909. E-mail address: [email protected] (F. Peng). http://dx.doi.org/10.1016/j.clineuro.2015.01.023 0303-8467/© 2015 Elsevier B.V. All rights reserved.
We retrospectively reviewed the inpatients medical records of patients with SLE from January 2008 to June 2013 admitted to the
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Table 1 Clinical and serological features of SLE. Patient Parameter Gender Age at SLE diagnosis (years) Age at onset of CM (years) Interval between diagnosis of SLE and CM (months) SLEDAI when suffering from Cryptococcus infection Active renal disease Medications before the diagnosis of CM Glucocorticoids dose at the time of infection diagnosis (mg/day) Clinical features of SLE
1 Female 24
2 Female 26
3 Female 42
4 Female 24
5 Female 17
6 Female 12
31
32
42
24
20
14
84
72
3
3
36
25
8
8
28
12
2
1
No P, HCQ, AZA
Yes P, AZA
Yes IVMP
Yes IVMP, CTX, HCQ
No P, MTX, AZA, HCQ
No IVMP, AZA, MTX
Prednisolone 5
Prednisolone 15
Methylprednisolone 25
Methylprednisolone 45
Prednisolone 15
Methylprednisolone 40
Arthritis, malar rash
Vasculitis, cerebral hemorrhage, nephritis
Fever, fatigue
Arthritis, malar rash
Fever, dropsy
Serologic feature of SLE
AnuA 24 U/ml, AHA 36 U/ml, ANA1:1000, anti-RNP+, anti-Sm+
ANA1:100, CCP 9 U/ml, anti-SSA+, anti-SSB+
Fever, arthritis, malar rash, baldness, oral ulcer, nephritis, altered mental status ANA1:160, anti-RNP+, anti-Sm+, anti-SSA+, anti-SSB+
ANA1:100
ANA1:100, anti-SSA+
ANA1:3200, anti-dsDNA1:320, AnuA115 U/ml, AHA131 U/ml
Abbreviations: SLE: systemic lupus erythematosus; CM: cryptococcal meningitis; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; P: prednisolone; IVMP: methylprednisolone; HCQ: hydroxychloroquine; AZA: azathioprine; CTX: cyclophosphamide; MTX: methotrexate.
Third Affiliated Hospital of Sun Yat-Sen University in Guangzhou, China. Of these patients, 6 patients with CM were identified. All patients fulfilled the 1982 American College of Rheumatology (ACR) classification criteria for SLE [8]. Cryptococcal antigen test was not available at the Third Affiliated Hospital of Sun Yat-Sen University, so CM was defined as clinical features of meningitis along with isolation of C. neoformans in CSF cultures or a positive CSF India ink stain. A standardized case collection form was used to record gender, age at SLE diagnosis and at the time of CM diagnosis, interval between SLE diagnosis and CM diagnosis, lupus clinical and serological manifestations prior or at cryptococcal infection onset, CM clinical manifestations, disease activity, glucocorticoids and immunosuppressors administered prior to and at infection diagnosis, prednisolone dose, at the time of infection, cytotoxic agents, prior to infection, active renal disease, HIV testing, laboratory data, 24-h urine total protein, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum complement levels (C3 and C4), initial cerebrospinal fluid findings, extra-CNS involvement, antifungal agents used, and outcomes. Disease activity was calculated using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and considered active if scores were ≥4. The time from the initial observation of symptoms to the time of definite diagnosis was considered as the symptom duration. The interval from positive CSF India ink for the first time to negative CSF India ink for the third time were considered as the time to sterile CSF. This study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University (200733) and in compliance with the Helsinki Declaration. All subjects provided informed consents to participate in this study. 2.2. Statistical analysis Descriptive statistical data are presented as mean (range) values for continuous variables and as frequencies and percentages
for categorical variables. Analyses were performed using the SPSS software version 13.0. 3. Results From January 2008 to June 2013, 631 patients with SLE were identified. Of these 631 patients, six patients developed cryptococcal infection. All of these 6 patients were female, with mean age of 24.1 years (range 12–42) at SLE diagnosis, and 27.1 years (range 14–42) at the time of C. neoformans infection, with mean disease duration of 37 months (range 3–72). Four patients (patients 1–4) had active SLE (SLEDAI score ≥ 4) at the time when CM was diagnosed. All patients were tested negative for anti-HIV antibodies. All but 1 patient (patient 3) had no underlying diseases and had not used antibiotics use prior to cryptococcal infection. Patient 3 had hypertension and received a short course of cefminox sodium (3–4 days) prior to cryptococcal infection. All of these patients were receiving glucocorticoids therapy (mean prednisone dose of 20.5 (5.0–36.0) mg/day) at the onset of infection before the onset of CM. There was concomitant use of other immunosuppressants in 5 patients, including hydroxychloroquine (patient 1), azathioprine (patients 1, 2, 5, and 6), cyclophosphamide (patient 4), methotrexate (patients 5 and 6). Characteristics of patients with cryptococcal meningitis are shown in Table 1. Headache and fever were the most common symptoms of CM, displayed by all of the patients, followed by vomiting (n = 3). Other initial presentations included altered mental status and seizure. On neurological examination, 4 of the 6 patients displayed normal characteristics, including papilloedema and meningeal irritation. The average time from the appearance of initial symptoms to diagnosis was 25 days (range 4–103) (Table 2). There was no record of hemolytic anemia in any of the patients. However, lymphopenia (6 mg/L) was observed in 2 patients but platelets and leukocytes
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Table 2 Presenting clinical symptoms and laboratory data of SLE patients with cryptococcal meningitis. Patient Parameter Initial symptoms of C. neoformans infection
1 Headache, fever
3 Headache, fever, altered mental status
4 Headache, fever
5 Headache, fever, vomiting
6 Fever, headache, vomiting
Normal
2 Seizure, headache, fever, vomiting, altered mental status Neck rigidity, Kernig’s+
Neurological examination Duration of initial symptoms to diagnosis (day)
Normal
Kernig’s±
Normal
Normal
4
13
103
12
10
10
Blood Lymphocytes*103 /mm3 Serum C3 levels (g/L) Serum C4 levels (g/L) CRP (mg/L) ESR (mm/H) 24 h urine total protein (g/day)
0.88 1.13 0.29 3 13 0
0.76 1.17 0.15 22.9 115 0.05
0.87 0.41 0.1 3.5 116 0.6
0.65 0.92 0.09 0 30 0.03
0.82 0.94 0.37 5 70 0
0.49 1.96 0.83 99.3 37 0.8
10 0.41 2.49 None
42 1.21 1.12 C. neoformans
8 0.4 2.71 None
14 0.18 2.93 C. neoformans
20 0.25 1.5 C. neoformans
240 1.11 3.24 C. neoformans
CSF WBC (UL) Proteins (g/L) Glucose (mmol/L) Isolated microorganisms Other site involvement of C. neoformans Openpressure, mmH2 O
Lungs
None
None
Blood
None
None
125
350
>300
100
>360
130
Brain images (CT or MRI) CT
Normal
NP
Normal
Normal
Density lesion
Meningeal enhancement (bilateral cerebral hemisphere)
Meningeal enhancement (bilateral cerebral hemisphere, tentorium cerebelli), cerebral Hemorrhage (right basal ganglia region), arteritis
Cerebral arteriosclerosis, local ischemic Meningeal enhancement (right cerebral hemisphere), hydrocephalus (third ventricle)
Normal
NP
Abscess (head of caudate nucleus on the left side)
MRI (location)
Abbreviations: CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; CSF: cerebrospinal fluid; CT: computed tomography; MRI: magnetic resonance imaging; NP: not performed.
were normal or even slightly increased in these patients. ESR, another important marker of SLE activity, was elevated in 5 patients (Table 2). CSF examination showed mean WBC of 55 (8–240) cells/mm3 , mean protein level of 0.59 (0.18–1.21) g/L and mean glucose level of 2.29 (1.12–3.24) mmol/L. India-ink staining of CSF for cryptococcal organisms was positive for all patients. The CSF culture was positive for C. neoformans in 4 of the 6 patients. Lungs and blood cultures revealed C. neoformans in patients 1 and 4 (Table 2). Brain computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed on 5 patients. CT scan was normal in 3 patients (patients 1, 4 and 5). The results of CT scan showed cerebral arteriosclerosis and local ischemic in patient 3 and density lesion in patient 6. The MRI indicated meningeal enhancement in 3 patients (patients 1–3) and cerebral abscess in patient 6 (Fig. 1). Patient 4 had a normal CNS imaging in both MRI and CT. Antifungal therapy was initiated as soon as diagnosis was microbiologically confirmed. Four patients (patients 1, 3, 4, and 6) were initially treated with fluconazole (0.4 g/day) whereas two of the patients were switched to intravenous amphotericin B. Lipid amphotericin B and amphotericin B were initially administrated for patients 2 and 5, respectively. Amphotericin B was initially used with 1 mg daily, in increasing doses up the total cumulative amount of 3 g. There was concomitant use of flucytosine in all of the patients. Oral fluconazole (200 mg/day) was continued indefinitely as maintenance therapy for all patients (Table 3). All of the patients but one (patient 3) recovered completely from CM without any sequel.
3.1. Patient 3 This patient was a 42-year-old woman and was initially referred to the Department of Rheumatology with headache, fever, and altered mental status (Table 3). Results of her physical examination, including papilloedema and meningeal irritation, were not remarkable. The head CT scan showed cerebral arteriosclerosis and local ischemic. She had been diagnosed with NPSLE and was treated initially with prednisone (50 mg/day) for 5 days and was then switched to intravenous methylprednisolone (80 mg/day) for 1 week with concomitant use of cyclophosphamide (0.8 g/day). However, these symptoms had not improved and had worsened. The clinician started to suspect that these symptoms were manifestations of CNS infection. A lumbar puncture was performed 14 days after admission. It took 103 days to diagnose this patient from the onset of the initial symptoms. This diagnosis was significantly delayed compared to the other 5 patients whose mean duration from initial symptoms to diagnosis was 9 days (range 4–13). In patient 3, the India ink preparation showed the presence of encapsulated veast cells and anti-fungal therapy with fluconazole was initiated that day. Patient 3 presented neurologic sequelae, including headache, seizure, and blurred vision. 4. Discussion Infection is estimated to be responsible for 20–55% of the cases of morbidity and mortality in patients with SLE [9]. It has been reported that SLE ranked four as underlying diseases among
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Fig. 1. Brain magnetic resonance imaging of patient 6. (A) Axial T2-weighted fast spin-echo image shows circular focal lesions (arrows) with high signal intensity in left side of the head of the caudate nucleus of patient 6. (B) Sagittal T2-weigthed fast spin-echo image demonstrates the vertical extension of the lesion (arrow). (C) Image on axial T2-weighted MRI after 12 months of antifungal therapy. (D) Image on sagittal T2-weigthed MRI after 12 months of antifungal therapy.
patients with cryptococcosis in Yuchong et al.’s study [10]. CM is rare but a fatal complication in those patients [9]. However, it is difficult to differentiate infectious meningitis and neuropsychiatric systemic lupus erythematosus (NPSLE) [11]. A previous study of cases of SLE-associated CM reported a mortality rate of 42% [12]. The main findings of this study are related to the frequency of infection (0.95%), which was significantly higher than that reported in previous studies [13,14], and the clinical characteristics of patients with SLE-associated CM. As reported in Kim et al.’s study [14], CM was observed in 0.35% of Korean patients with SLE. In Hung et al.’s study [13], of the 3165 patients with SLE over a 20-year review period, there were 10 patients (0.31%) with confirmed cases of CM. The following reasons may explain this phenomenon. The frequency of C. neoformans infection varies depending on geographical areas. In addition, this may be caused by selection bias, since this study was not multi-centered compared with previous studies. SLE patients’ predisposition to infection is varied, and disease activities are highly associated with infection [15]. It has been reported that an SLEDAI score of 4 or higher in outpatients and greater than 8 in hospitalized patients, is a significant prognostic factor for the development of infection [16]. Successful host resistance to C. neoformans depends primarily on cell-mediated immunity [17]. All patients in this study had low lymphocyte counts and received corticosteroids prior to C. neoformans infection onset. However, some data indicate that corticosteroids can suppress cellmediated immunity in humans [18,19]. Moreover, corticosteroids suppress recruitment of neutrophils and monocytes/macrophages to the sites of inflammation [20]. Chen et al. [21] suggested that different corticosteroid doses prescribed at various times had a different impact on the incidence of fungal infection and its associated mortality. The immune function of patients with SLE is constitutively impaired as a result of the intrinsic immunological
defects associated with the disease [22]. Masami et al. [23] indicated that intrinsic immunological abnormality related to SLE predisposed to opportunistic infection. Moreover, several studies demonstrate that humoral immunity may also play a role in cryptococcal infections [24,25]. A defect in lymphocyte responsiveness to C. neoformans and low serum complement levels in patients with SLE may also contribute to its predisposition to infection [26]. In addition, Gonzalez et al.’s study stressed the importance of broadspectrum antibiotic use prior to fungal infection. Nonetheless, only patient 3 in this study had received a short course of cefminox sodium (3–4 days). In this context, the most common symptoms of CM were fever and headache. However, headache was also the most frequent characteristic of NPSLE. Patients with SLE usually experience fever when their disease is active [27]. Careful physical assessment revealed no infectious focus in 4 of the 6 patients. The CSF cell counts in 6 patients ranged from 8/mm3 to 240/mm3 . Only two patients (patients 2 and 6) showed a high total protein level in their CSF of 1.21 g/L and 1.11 g/L, respectively. The initial head CT scan results were unremarkable in 5 patients. These data suggest that the diagnosis of CM in patients with SLE cannot be based solely on clinical features. In the present study, the levels of C-reactive protein (CRP) in 4 of the 6 patients were normal though some previous investigators have proposed levels of CRP as a marker of infection [28]. Depressed inflammatory responses resulting from impaired immune function in patients with SLE may explain this phenomenon. Brain MRI was performed in 5 patients and results showed meningeal enhancement in 3 patients and abscess in 1 patient, whereas a CT brain scan showed no intracranial space-occupying lesions or abnormal meningeal enhancement in any of the patients. India-ink stain results for cryptococcal organisms were positive
Table 3 Treatment and outcomes of SLE patients with cryptococcal meningitis. Patient Parameter Treatment at the onset of CM
1 Fluconazole, flucytosine
Outcomes Residual neurological deficit Time of clinical improvements, days Duration of diagnosis to sterile CSF
S None
2 Lipid amphotericin B, amphotericin B, flucytosine, fluconazole S None
3 Fluconazole, flucytosine
4 Fluconazole, flucytosine, amphotericin B
5 Amphotericin B flucytosine, fluconazole
6 Fluconazole, flucytosine, amphotericin B
S None
S None
S None
39
Un S Headache, seizure, blurred vision 128
18
26
31
60
36
13
205
130
22
270
Abbreviations: CM: cryptococcal meningitis; S: satisfactory; Un S: unsatisfactory; CSF: cerebrospinal fluid.
Y. Zhong et al. / Clinical Neurology and Neurosurgery 131 (2015) 59–63
for all patients. CSF cultures tested positive for C. neoformans in 4 patients. These results suggest that India-ink stain of the CSF and brain MRI analysis have favorable diagnostic value for CM. Five of the 6 patients had a favorable response to induction therapy of amphotericin B or fluconazole combined with flucytosine, followed by long-term consolidation therapy with fluconazole. This was consistent with recommended treatments in previous studies [29,30]. In the present study, none of the patients had suffered relapse of CM while receiving long-term consolidation fluconazole therapy combined with glucocorticoids and immunosuppressive agents. Hence, we recommend the use of long-term therapy with fluconazole in SLE patients due to the immune abnormalities that put the SLE patients with CM at high risk for relapse. After the course of treatment, patient 3 was left with neurologic sequelae, including headache, seizure, and blurred vision, which were mainly due to her delayed diagnosis. Prasad et al.’s study [31] indicated that delayed diagnosis was considered an important prognostic factor in cases of non-HIV-related CM. This implies that cryptococcal infection in patients with SLE will have satisfactory outcomes as long as an accurate diagnosis is made timely and early appropriate therapy is rendered. Otherwise, this complication is reported to be associated with significant rates of mortality [13,32]. In summary, clinical presentations and findings from routine hematological, biochemical and CSF analyses of CM in patients with SLE are mostly nonspecific and often confused with a CNS manifestation of SLE or activation of disease. Physicians should remember that the possible presence of CNS infections, such as CM must be examined when SLE patients show neurological symptoms. The CSF should be centrifuged and an India ink preparation should always be carried out. Conflict of interest The authors declare that they have no competing interests. References [1] Liao CH, Chi CY, Wang YJ, Tseng SW, Chou CH, Ho CM, et al. Different presentations and outcomes between HIV-infected and HIV-uninfected patients with Cryptococcal meningitis. J Microbiol Immunol Infect 2012;45:296–304. [2] Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Giller TM. Estimation of the current global burden of cryptococcal meningitis persons living with HIV/AIDS. AIDS 2009;23:525–30. [3] Petri M, Magder L. Classification criteria for systemic lupus erythematosus: a review. Lupus 2004;13:839–49. [4] Caza T, Oaks Z, Perl A. Interplay of infections, autoimmunity, and immunosuppression in systemic lupus erythematosus. Int Rev Immunol 2014;33:330–63. [5] Sivalingam SK, Saligram P, Natanasabapathy S, Paez AS. Covert cryptococcal meningitis in a patient with systemic lupus erythematosus. J Emerg Med 2012;42:e101–4. [6] Zimmermann III B, Spiegel M, Lally EV. Cryptococcal meningitis in systemic lupus erythematosus. Semin Arthritis Rheum 1992;22:18–24. [7] Efthimiou P, Blanco M. Pathogenesis of neuropsychiatric systemic lupus erythematosus and potential biomarkers. Mod Rheumatol 2009;19:457–68.
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[8] Font J, Cervera R. 1982 revised criteria for the classification of systemic lupus erythematosus. Lupus 1993;2:339–41. [9] Fessler BJ. Infectious diseases in systemic lupus erythematosus: risk factors, management and prophylaxis. Best Pract Res Clin Rheumatol 2002;16:281–91. [10] Yuchong C, Fubin C, Jianghan C, Fenglian W, Nan X, Minghui Y, et al. Cryptococcosis in China (1985–2010): review of cases from Chinese database. Mycopathologia 2012;173:329–35. [11] Chen J, Feng X, Wang H, Hua B, Ding C, Liu B, et al. Discriminating infectious meningitis versus neuropsychiatric involvement in patients with systemic lupus erythematosus: a single-center experience. Clin Rheumatol 2014 (in press). [12] Antinori S, Corbellino M, Galimberti L, Ridolfo A, Milazzo L. Cryptococcal meningitis and systemic lupus erythematosus. J Emerg Med 2014;47:323–5. [13] Hung JJ, Ou LS, Lee WI, Huang JL. Central nervous system infections in patients with systemic lupus erythematosus. J Rheumatol 2005;32:40–3. [14] Kim JM, Kim KJ, Yoon HS, Kwok SK, Ju JH, Park KS, et al. Meningitis in Korean patients with systemic lupus erythematosus: analysis of demographics, clinical features and outcomes; experience from affiliated hospitals of the Catholic University of Korea. Lupus 2011;20:531–6. [15] Duffy KNW, Duffy CM, Gladman DD. Infection and disease activity in systemic lupus erythematosus: a review of hospitalized patients. J Rheumatol 1991;18:1180–4. [16] Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992;35:630–40. [17] Gottfredsson M, Perfect JR. Fungal meningitis. Semin Neurol 1992;20:307–22. [18] Cell-mediated immunity and resistance to infection: report of a WHO scientific group. World Health Organ Tech Rep Ser 1973;519:1–64. [19] Howard DH, Otto V, Gupta RK. Lymphocyte-mediated cellular immunity in histoplasmosis. Infect Immun 1971;4:605–10. [20] Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. Prevention of corticosteroidinduced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun 1993;61:4870–7. [21] Chen HS, Tsai WP, Leu HS, Ho HH, Liou LB. Invasive fungal infection in systemic lupus erythematosus: an analysis of 15 cases and a literature review. Rheumatology (Oxf) 2007;46:539–44. [22] Liou J, Chiu C, Tseng C, Chi C, Fu L. Cryptococcal meningitis in pediatric systemic lupus erythematosus. Mycoses 2003;46:153–6. [23] Matsumura M, Kawamura R, Inoue R, Yamada K, Kawano M, Yamagishi M. Concurrent presentation of cryptococcal meningoencephalitis and systemic lupus erythematosus. Mod Rheumatol 2011;21(3):305–8. [24] Coelho C, Bocca AL, Casadevall A. The intracellular life of Cryptococcus neoformans. Annu Rev Pathol 2014;9:219–38. [25] Miller GP, Kohl S. Antibody-dependent leukocyte killing of Cryptococcus neoformans. J Immunol 1983;131:1455–9. [26] Mok CC, Lau CS, Yuen KY. Cryptococcal meningitis presenting concurrently with systemic lupus erythematosus. Clin Exp Rheumatol 1998;16:169–71. [27] Padovan M, Castellino G, Bortoluzzi A, Caniatti L, Trotta F, Govoni M. Factors and comorbidities associated with central nervous system involvement in systemic lupus erythematosus: a retrospective cross-sectional case-control study from a single center. Rheumatol Int 2012;32:129–35. [28] Vinicki JP, Catalan Pellet S, Pappalardo C, Cruzat VC, Spinetto MA, Dubinsky D, et al. Invasive fungal infections in Argentine patients with systemic lupus erythematosus. Lupus 2013;22:892–8. [29] Speller DC, Fakunle F, Cairns SA, Stephens M. Cryptococcal meningitis complicating systemic lupus erythematosus: two patients treated with flucytosine and amphotericin B. J Clin Pathol 1977;30:254–61. [30] Pappas PG, Perfect JR, Cloud GA, Larsen RA, Pankey GA, Lancaster DJ, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective a zoletherapy. Clin Infect Dis 2001;33:690–9. [31] Prasad KN, Agarwal J, Nag VL, Verma AK, Dixit AK, Ayyagari A. Cryptococcal infection in patients with clinically diagnosed meningitis in a tertiary care center. Neurol India 2003;51:364–6. [32] Vargas PJ, King G, Navarra SV. Central nervous system infections in Filipino patients with systemic lupus erythematosus. Int J Rheum Dis 2009;12:234–8.
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Cryptococcal meningitis in Chinese patients with systemic lupus erythematosus Yuhua Zhong a , Min Li a , Jia Liu a , Weixi Zhang b,∗ , Fuhua Peng a,∗ a Multiple Sclerosis Center, Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong 510630, China b Department of Neurology, The First Affiliated Hospital Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China
a r t i c l e
i n f o
Article history: Received 22 April 2014 Received in revised form 8 January 2015 Accepted 23 January 2015 Available online 2 February 2015 Keywords: Cryptococcal meningitis Systemic lupus erythematosus Chinese
a b s t r a c t Objective: Systemic lupus erythematosus (SLE) is a chronic immunologic disorder that can affect multiple organ systems and makes the patient susceptible to infection. Cryptococcal meningitis (CM) is a rare but often fatal complication of SLE. Design: In this study, 6 patients with CM were identified among 631 patients with SLE. The demographic, clinical, laboratory profiles, serological features and outcomes of these 6 SLE patients with CM were retrospectively analyzed. Results: The mean age of these patients was 24.1 years (range 12–42) at the time of SLE diagnosis, and 27.1 years (range 14–42) at the time of Cryptococcus neoformans infection, with mean disease duration of 37 months (range 3–72). Four patients had active SLE. All patients were receiving glucocorticoids therapy (mean prednisone dose of 20.5 (5.0–36.0) mg/day) at the onset of infection. Five patients had received other immunosuppressive drugs. The most common presentations of CM were headache and fever and 4 of the 6 patients were normal on physical examination. The cerebrospinal fluid (CSF) indices (protein and glucose) were normal in 4 cases, whereas they were mildly abnormal in the other 2 patients. White counts in the CSF ranged from 8 to 240 cells/mm. C. neoformans were isolated from CSF of 4 patients. The isolation of crytococci from extraneural sites, including blood and lungs, was found in 2 patients. Results of the head computed tomography scan were unremarkable in 5 of the patients. The infection was completely resolved in 5 patients, and it was resolved with serious sequelae in one patient. Conclusions: In conclusion, the key to a rapid diagnosis of CM in patients with SLE is to maintain a high degree of awareness which will help avoid delays in treatment. This is mainly due to the fact that the clinical presentation and laboratory results from routine hematological, biochemical and CSF analyses of CM in patients with SLE are mostly non-specific. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Cryptococcus neoformans, as one of the most common pathogenic species worldwide, can cause infection disease in humans [1]. The central nervous system (CNS) is a common site for cryptococcal infection which usually presents cryptococcal meningitis (CM) [2]. Systemic lupus erythematosus (SLE) is an autoimmune disease with myriad of presentations and is characterized by the immune dysregulation in its pathogenesis [3]. Therefore, SLE patients are susceptible to infection because of their disease-related immunological defect or concomitant immunosuppressive therapies [4]. The CNS, which is an uncommon site, constitutes only about 3%of the infections in SLE patients.
CM is the most common cause of CNS infection with a high mortality rate in patients with SLE [5]. The clinical features of CM may be non-specific which may lead to a missed diagnosis or delayed treatment, especially in patients receiving immunosuppressive therapy [6]. However, neuropsychiatric systemic lupus erythematosus (NPSLE) encompasses highly diverse clinical manifestations and may occur at any time in SLE [7]. Therefore, CM in patients with SLE can be misdiagnosed as NPLSE or an activation of SLE. In this retrospective study, we described the demographic characteristics, clinical histories, laboratory profiles, serological features and outcomes of 6 SLE patients with CM. 2. Patients and methods 2.1. Definitions
∗ Corresponding authors. Tel.: +86 18922102909. E-mail address: [email protected] (F. Peng). http://dx.doi.org/10.1016/j.clineuro.2015.01.023 0303-8467/© 2015 Elsevier B.V. All rights reserved.
We retrospectively reviewed the inpatients medical records of patients with SLE from January 2008 to June 2013 admitted to the
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Y. Zhong et al. / Clinical Neurology and Neurosurgery 131 (2015) 59–63
Table 1 Clinical and serological features of SLE. Patient Parameter Gender Age at SLE diagnosis (years) Age at onset of CM (years) Interval between diagnosis of SLE and CM (months) SLEDAI when suffering from Cryptococcus infection Active renal disease Medications before the diagnosis of CM Glucocorticoids dose at the time of infection diagnosis (mg/day) Clinical features of SLE
1 Female 24
2 Female 26
3 Female 42
4 Female 24
5 Female 17
6 Female 12
31
32
42
24
20
14
84
72
3
3
36
25
8
8
28
12
2
1
No P, HCQ, AZA
Yes P, AZA
Yes IVMP
Yes IVMP, CTX, HCQ
No P, MTX, AZA, HCQ
No IVMP, AZA, MTX
Prednisolone 5
Prednisolone 15
Methylprednisolone 25
Methylprednisolone 45
Prednisolone 15
Methylprednisolone 40
Arthritis, malar rash
Vasculitis, cerebral hemorrhage, nephritis
Fever, fatigue
Arthritis, malar rash
Fever, dropsy
Serologic feature of SLE
AnuA 24 U/ml, AHA 36 U/ml, ANA1:1000, anti-RNP+, anti-Sm+
ANA1:100, CCP 9 U/ml, anti-SSA+, anti-SSB+
Fever, arthritis, malar rash, baldness, oral ulcer, nephritis, altered mental status ANA1:160, anti-RNP+, anti-Sm+, anti-SSA+, anti-SSB+
ANA1:100
ANA1:100, anti-SSA+
ANA1:3200, anti-dsDNA1:320, AnuA115 U/ml, AHA131 U/ml
Abbreviations: SLE: systemic lupus erythematosus; CM: cryptococcal meningitis; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; P: prednisolone; IVMP: methylprednisolone; HCQ: hydroxychloroquine; AZA: azathioprine; CTX: cyclophosphamide; MTX: methotrexate.
Third Affiliated Hospital of Sun Yat-Sen University in Guangzhou, China. Of these patients, 6 patients with CM were identified. All patients fulfilled the 1982 American College of Rheumatology (ACR) classification criteria for SLE [8]. Cryptococcal antigen test was not available at the Third Affiliated Hospital of Sun Yat-Sen University, so CM was defined as clinical features of meningitis along with isolation of C. neoformans in CSF cultures or a positive CSF India ink stain. A standardized case collection form was used to record gender, age at SLE diagnosis and at the time of CM diagnosis, interval between SLE diagnosis and CM diagnosis, lupus clinical and serological manifestations prior or at cryptococcal infection onset, CM clinical manifestations, disease activity, glucocorticoids and immunosuppressors administered prior to and at infection diagnosis, prednisolone dose, at the time of infection, cytotoxic agents, prior to infection, active renal disease, HIV testing, laboratory data, 24-h urine total protein, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum complement levels (C3 and C4), initial cerebrospinal fluid findings, extra-CNS involvement, antifungal agents used, and outcomes. Disease activity was calculated using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and considered active if scores were ≥4. The time from the initial observation of symptoms to the time of definite diagnosis was considered as the symptom duration. The interval from positive CSF India ink for the first time to negative CSF India ink for the third time were considered as the time to sterile CSF. This study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University (200733) and in compliance with the Helsinki Declaration. All subjects provided informed consents to participate in this study. 2.2. Statistical analysis Descriptive statistical data are presented as mean (range) values for continuous variables and as frequencies and percentages
for categorical variables. Analyses were performed using the SPSS software version 13.0. 3. Results From January 2008 to June 2013, 631 patients with SLE were identified. Of these 631 patients, six patients developed cryptococcal infection. All of these 6 patients were female, with mean age of 24.1 years (range 12–42) at SLE diagnosis, and 27.1 years (range 14–42) at the time of C. neoformans infection, with mean disease duration of 37 months (range 3–72). Four patients (patients 1–4) had active SLE (SLEDAI score ≥ 4) at the time when CM was diagnosed. All patients were tested negative for anti-HIV antibodies. All but 1 patient (patient 3) had no underlying diseases and had not used antibiotics use prior to cryptococcal infection. Patient 3 had hypertension and received a short course of cefminox sodium (3–4 days) prior to cryptococcal infection. All of these patients were receiving glucocorticoids therapy (mean prednisone dose of 20.5 (5.0–36.0) mg/day) at the onset of infection before the onset of CM. There was concomitant use of other immunosuppressants in 5 patients, including hydroxychloroquine (patient 1), azathioprine (patients 1, 2, 5, and 6), cyclophosphamide (patient 4), methotrexate (patients 5 and 6). Characteristics of patients with cryptococcal meningitis are shown in Table 1. Headache and fever were the most common symptoms of CM, displayed by all of the patients, followed by vomiting (n = 3). Other initial presentations included altered mental status and seizure. On neurological examination, 4 of the 6 patients displayed normal characteristics, including papilloedema and meningeal irritation. The average time from the appearance of initial symptoms to diagnosis was 25 days (range 4–103) (Table 2). There was no record of hemolytic anemia in any of the patients. However, lymphopenia (6 mg/L) was observed in 2 patients but platelets and leukocytes
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Table 2 Presenting clinical symptoms and laboratory data of SLE patients with cryptococcal meningitis. Patient Parameter Initial symptoms of C. neoformans infection
1 Headache, fever
3 Headache, fever, altered mental status
4 Headache, fever
5 Headache, fever, vomiting
6 Fever, headache, vomiting
Normal
2 Seizure, headache, fever, vomiting, altered mental status Neck rigidity, Kernig’s+
Neurological examination Duration of initial symptoms to diagnosis (day)
Normal
Kernig’s±
Normal
Normal
4
13
103
12
10
10
Blood Lymphocytes*103 /mm3 Serum C3 levels (g/L) Serum C4 levels (g/L) CRP (mg/L) ESR (mm/H) 24 h urine total protein (g/day)
0.88 1.13 0.29 3 13 0
0.76 1.17 0.15 22.9 115 0.05
0.87 0.41 0.1 3.5 116 0.6
0.65 0.92 0.09 0 30 0.03
0.82 0.94 0.37 5 70 0
0.49 1.96 0.83 99.3 37 0.8
10 0.41 2.49 None
42 1.21 1.12 C. neoformans
8 0.4 2.71 None
14 0.18 2.93 C. neoformans
20 0.25 1.5 C. neoformans
240 1.11 3.24 C. neoformans
CSF WBC (UL) Proteins (g/L) Glucose (mmol/L) Isolated microorganisms Other site involvement of C. neoformans Openpressure, mmH2 O
Lungs
None
None
Blood
None
None
125
350
>300
100
>360
130
Brain images (CT or MRI) CT
Normal
NP
Normal
Normal
Density lesion
Meningeal enhancement (bilateral cerebral hemisphere)
Meningeal enhancement (bilateral cerebral hemisphere, tentorium cerebelli), cerebral Hemorrhage (right basal ganglia region), arteritis
Cerebral arteriosclerosis, local ischemic Meningeal enhancement (right cerebral hemisphere), hydrocephalus (third ventricle)
Normal
NP
Abscess (head of caudate nucleus on the left side)
MRI (location)
Abbreviations: CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; CSF: cerebrospinal fluid; CT: computed tomography; MRI: magnetic resonance imaging; NP: not performed.
were normal or even slightly increased in these patients. ESR, another important marker of SLE activity, was elevated in 5 patients (Table 2). CSF examination showed mean WBC of 55 (8–240) cells/mm3 , mean protein level of 0.59 (0.18–1.21) g/L and mean glucose level of 2.29 (1.12–3.24) mmol/L. India-ink staining of CSF for cryptococcal organisms was positive for all patients. The CSF culture was positive for C. neoformans in 4 of the 6 patients. Lungs and blood cultures revealed C. neoformans in patients 1 and 4 (Table 2). Brain computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed on 5 patients. CT scan was normal in 3 patients (patients 1, 4 and 5). The results of CT scan showed cerebral arteriosclerosis and local ischemic in patient 3 and density lesion in patient 6. The MRI indicated meningeal enhancement in 3 patients (patients 1–3) and cerebral abscess in patient 6 (Fig. 1). Patient 4 had a normal CNS imaging in both MRI and CT. Antifungal therapy was initiated as soon as diagnosis was microbiologically confirmed. Four patients (patients 1, 3, 4, and 6) were initially treated with fluconazole (0.4 g/day) whereas two of the patients were switched to intravenous amphotericin B. Lipid amphotericin B and amphotericin B were initially administrated for patients 2 and 5, respectively. Amphotericin B was initially used with 1 mg daily, in increasing doses up the total cumulative amount of 3 g. There was concomitant use of flucytosine in all of the patients. Oral fluconazole (200 mg/day) was continued indefinitely as maintenance therapy for all patients (Table 3). All of the patients but one (patient 3) recovered completely from CM without any sequel.
3.1. Patient 3 This patient was a 42-year-old woman and was initially referred to the Department of Rheumatology with headache, fever, and altered mental status (Table 3). Results of her physical examination, including papilloedema and meningeal irritation, were not remarkable. The head CT scan showed cerebral arteriosclerosis and local ischemic. She had been diagnosed with NPSLE and was treated initially with prednisone (50 mg/day) for 5 days and was then switched to intravenous methylprednisolone (80 mg/day) for 1 week with concomitant use of cyclophosphamide (0.8 g/day). However, these symptoms had not improved and had worsened. The clinician started to suspect that these symptoms were manifestations of CNS infection. A lumbar puncture was performed 14 days after admission. It took 103 days to diagnose this patient from the onset of the initial symptoms. This diagnosis was significantly delayed compared to the other 5 patients whose mean duration from initial symptoms to diagnosis was 9 days (range 4–13). In patient 3, the India ink preparation showed the presence of encapsulated veast cells and anti-fungal therapy with fluconazole was initiated that day. Patient 3 presented neurologic sequelae, including headache, seizure, and blurred vision. 4. Discussion Infection is estimated to be responsible for 20–55% of the cases of morbidity and mortality in patients with SLE [9]. It has been reported that SLE ranked four as underlying diseases among
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Y. Zhong et al. / Clinical Neurology and Neurosurgery 131 (2015) 59–63
Fig. 1. Brain magnetic resonance imaging of patient 6. (A) Axial T2-weighted fast spin-echo image shows circular focal lesions (arrows) with high signal intensity in left side of the head of the caudate nucleus of patient 6. (B) Sagittal T2-weigthed fast spin-echo image demonstrates the vertical extension of the lesion (arrow). (C) Image on axial T2-weighted MRI after 12 months of antifungal therapy. (D) Image on sagittal T2-weigthed MRI after 12 months of antifungal therapy.
patients with cryptococcosis in Yuchong et al.’s study [10]. CM is rare but a fatal complication in those patients [9]. However, it is difficult to differentiate infectious meningitis and neuropsychiatric systemic lupus erythematosus (NPSLE) [11]. A previous study of cases of SLE-associated CM reported a mortality rate of 42% [12]. The main findings of this study are related to the frequency of infection (0.95%), which was significantly higher than that reported in previous studies [13,14], and the clinical characteristics of patients with SLE-associated CM. As reported in Kim et al.’s study [14], CM was observed in 0.35% of Korean patients with SLE. In Hung et al.’s study [13], of the 3165 patients with SLE over a 20-year review period, there were 10 patients (0.31%) with confirmed cases of CM. The following reasons may explain this phenomenon. The frequency of C. neoformans infection varies depending on geographical areas. In addition, this may be caused by selection bias, since this study was not multi-centered compared with previous studies. SLE patients’ predisposition to infection is varied, and disease activities are highly associated with infection [15]. It has been reported that an SLEDAI score of 4 or higher in outpatients and greater than 8 in hospitalized patients, is a significant prognostic factor for the development of infection [16]. Successful host resistance to C. neoformans depends primarily on cell-mediated immunity [17]. All patients in this study had low lymphocyte counts and received corticosteroids prior to C. neoformans infection onset. However, some data indicate that corticosteroids can suppress cellmediated immunity in humans [18,19]. Moreover, corticosteroids suppress recruitment of neutrophils and monocytes/macrophages to the sites of inflammation [20]. Chen et al. [21] suggested that different corticosteroid doses prescribed at various times had a different impact on the incidence of fungal infection and its associated mortality. The immune function of patients with SLE is constitutively impaired as a result of the intrinsic immunological
defects associated with the disease [22]. Masami et al. [23] indicated that intrinsic immunological abnormality related to SLE predisposed to opportunistic infection. Moreover, several studies demonstrate that humoral immunity may also play a role in cryptococcal infections [24,25]. A defect in lymphocyte responsiveness to C. neoformans and low serum complement levels in patients with SLE may also contribute to its predisposition to infection [26]. In addition, Gonzalez et al.’s study stressed the importance of broadspectrum antibiotic use prior to fungal infection. Nonetheless, only patient 3 in this study had received a short course of cefminox sodium (3–4 days). In this context, the most common symptoms of CM were fever and headache. However, headache was also the most frequent characteristic of NPSLE. Patients with SLE usually experience fever when their disease is active [27]. Careful physical assessment revealed no infectious focus in 4 of the 6 patients. The CSF cell counts in 6 patients ranged from 8/mm3 to 240/mm3 . Only two patients (patients 2 and 6) showed a high total protein level in their CSF of 1.21 g/L and 1.11 g/L, respectively. The initial head CT scan results were unremarkable in 5 patients. These data suggest that the diagnosis of CM in patients with SLE cannot be based solely on clinical features. In the present study, the levels of C-reactive protein (CRP) in 4 of the 6 patients were normal though some previous investigators have proposed levels of CRP as a marker of infection [28]. Depressed inflammatory responses resulting from impaired immune function in patients with SLE may explain this phenomenon. Brain MRI was performed in 5 patients and results showed meningeal enhancement in 3 patients and abscess in 1 patient, whereas a CT brain scan showed no intracranial space-occupying lesions or abnormal meningeal enhancement in any of the patients. India-ink stain results for cryptococcal organisms were positive
Table 3 Treatment and outcomes of SLE patients with cryptococcal meningitis. Patient Parameter Treatment at the onset of CM
1 Fluconazole, flucytosine
Outcomes Residual neurological deficit Time of clinical improvements, days Duration of diagnosis to sterile CSF
S None
2 Lipid amphotericin B, amphotericin B, flucytosine, fluconazole S None
3 Fluconazole, flucytosine
4 Fluconazole, flucytosine, amphotericin B
5 Amphotericin B flucytosine, fluconazole
6 Fluconazole, flucytosine, amphotericin B
S None
S None
S None
39
Un S Headache, seizure, blurred vision 128
18
26
31
60
36
13
205
130
22
270
Abbreviations: CM: cryptococcal meningitis; S: satisfactory; Un S: unsatisfactory; CSF: cerebrospinal fluid.
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for all patients. CSF cultures tested positive for C. neoformans in 4 patients. These results suggest that India-ink stain of the CSF and brain MRI analysis have favorable diagnostic value for CM. Five of the 6 patients had a favorable response to induction therapy of amphotericin B or fluconazole combined with flucytosine, followed by long-term consolidation therapy with fluconazole. This was consistent with recommended treatments in previous studies [29,30]. In the present study, none of the patients had suffered relapse of CM while receiving long-term consolidation fluconazole therapy combined with glucocorticoids and immunosuppressive agents. Hence, we recommend the use of long-term therapy with fluconazole in SLE patients due to the immune abnormalities that put the SLE patients with CM at high risk for relapse. After the course of treatment, patient 3 was left with neurologic sequelae, including headache, seizure, and blurred vision, which were mainly due to her delayed diagnosis. Prasad et al.’s study [31] indicated that delayed diagnosis was considered an important prognostic factor in cases of non-HIV-related CM. This implies that cryptococcal infection in patients with SLE will have satisfactory outcomes as long as an accurate diagnosis is made timely and early appropriate therapy is rendered. Otherwise, this complication is reported to be associated with significant rates of mortality [13,32]. In summary, clinical presentations and findings from routine hematological, biochemical and CSF analyses of CM in patients with SLE are mostly nonspecific and often confused with a CNS manifestation of SLE or activation of disease. Physicians should remember that the possible presence of CNS infections, such as CM must be examined when SLE patients show neurological symptoms. The CSF should be centrifuged and an India ink preparation should always be carried out. Conflict of interest The authors declare that they have no competing interests. References [1] Liao CH, Chi CY, Wang YJ, Tseng SW, Chou CH, Ho CM, et al. Different presentations and outcomes between HIV-infected and HIV-uninfected patients with Cryptococcal meningitis. J Microbiol Immunol Infect 2012;45:296–304. [2] Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Giller TM. Estimation of the current global burden of cryptococcal meningitis persons living with HIV/AIDS. AIDS 2009;23:525–30. [3] Petri M, Magder L. Classification criteria for systemic lupus erythematosus: a review. Lupus 2004;13:839–49. [4] Caza T, Oaks Z, Perl A. Interplay of infections, autoimmunity, and immunosuppression in systemic lupus erythematosus. Int Rev Immunol 2014;33:330–63. [5] Sivalingam SK, Saligram P, Natanasabapathy S, Paez AS. Covert cryptococcal meningitis in a patient with systemic lupus erythematosus. J Emerg Med 2012;42:e101–4. [6] Zimmermann III B, Spiegel M, Lally EV. Cryptococcal meningitis in systemic lupus erythematosus. Semin Arthritis Rheum 1992;22:18–24. [7] Efthimiou P, Blanco M. Pathogenesis of neuropsychiatric systemic lupus erythematosus and potential biomarkers. Mod Rheumatol 2009;19:457–68.
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