The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–3, 2014 Copyright Ó 2014 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter


of the absence of neurological involvement. As shown in Table 2, in about 50% of HIV-positive patients with cryptococcal meningitis, white blood cells are totally absent from CSF as a consequence of the markedly blunted immune response to infection observed in this setting. However, absence of white blood cells is also observed in about 22% of patients with SLE affected by cryptococcal meningitis. A possible clue to cryptococcal meningitis is the low glucose level found in the CSF. This is generally observed in both HIV-positive and SLE patients (Table 2). A clear CSF with low glucose levels, when observed in immunocompromised patients, should promptly raise suspicion for cryptococcal or tubercular meningitis. The former diagnosis may be easily confirmed (or discarded) by the use of highly sensitive and specific tests (e.g., India ink microscopic examination, cryptococcal antigen detection, and culture). Among patients with acquired immune deficiency syndrome (AIDS), cryptococcal antigen detection in both serum and CSF display high sensitivity and specificity for the diagnosis of cryptococcal meningitis. Generally, the cryptococcal antigen titers are higher than those observed in HIV-negative patients, reflecting very high fungal burdens (15). In our review of published cases of SLE and cryptococcal meningitis, we have not found any mention of the use of cryptococcal antigen detection in serum; we advocate its implementation also among patients with SLE presenting with fever and headache (or any other neurological sign) prior to performing lumbar puncture (16–23). It is worth noting that 64% of SLE patients with a diagnosis of cryptococcal meningitis had a positive blood culture for C. neoformans. This percentage is even higher than that seen in subjects with AIDS, indicating disseminated disease; thus, it is likely that the serum cryptococcal antigen test will perform similarly well when used in patients with SLE. HIV-positive patients are at increased risk of developing cryptococcosis in the late stages of the infection, typically when the CD4 T-cell lymphocyte counts are below 50/mL. The immunological abnormality that is responsible for the development of cryptococcal meningitis in SLE patients is less well defined, but it is generally attributed to the immunosuppressive therapy, in particular, prolonged, high-dose steroid and cyclophosphamide use.

, To the Editor: We read with interest the case report by Sivalingam and coworkers on “Covert cryptococcal meningitis in a patient with systemic lupus erythematosus ” (1). The authors are to be congratulated for their early diagnosis of a life-threatening infection and for raising awareness of an opportunistic infection that is frequently overlooked in patients who are not concomitantly infected with the human immunodeficiency virus (HIV) (1). We would also like to make some comments and suggestions about the diagnosis and treatment of cryptococcal meningitis in systemic lupus erythematosus (SLE) patients. It is well known that HIV infection is the main risk factor for the development of cryptococcal meningitis, having been identified in European epidemiological survey studies in 77–94% of cases (2,3). This is also reflected by the high burden of cryptococcal disease in sub-Saharan Africa, where over 720,000 cases per year are estimated to occur among HIV-positive patients and where Cryptococcus neoformans is now the leading cause of meningitis (4). Conversely, non-HIV-infected individuals with underlying rheumatologic or immunologic disorders account for 7–27% of patients in whom a diagnosis of cryptococcosis is made (Table 1) (5–13). As Sivalingam et al. correctly point out, “the clinical presentation can be non-specific with a subacute onset of symptoms,” but this is the rule, not the exception, in the majority of cases (1). Furthermore, classic meningeal signs and symptoms are seldom encountered in cryptococcal meningitis: neck stiffness is observed in only about one-third of HIV-positive patients, and apparently in only 5.4% of 37 patients with SLE who are described in the literature (Table 2) (14). On the contrary, in the high percentage of patients with SLE presenting with altered consciousness, it might be a consequence of delayed diagnosis and advanced disease. Moreover, in patients with cryptococcal meningitis, central nervous system imaging rarely reveals meningeal enhancement, and the cerebrospinal fluid (CSF) is often normal, with low or absent cellularity. This may give the clinician the erroneous impression, when both examinations are negative, 1

258 (28.9) 114 (12.8) 59 (6.9) 91 (10.2) 143 (16.7) 109 (12.2) 15 (43) 5 (14.3) 5 (14.3) 4 (11.4)‡ 3 (9) 5 (15.2) 11 (33.3) 18 (54.4) 9 (27.3)

4 (11.1) 2 (6.1) 12 (36.4) 7 (21.2)

9 (16.9) 3 (5.7) 19 (35.8) -

11 (20.7) 12 (22.6)

16 (40) 6 (16) 5 (14) 15 (41) 6 (16)†

2 (5) 10 (25)

72 (8.4) 81 (9.4) 45 (5.2) 69 (7.7) 155 (17.4)

n (%) n (%) n (%) n (%)

Table 2. Comparison of Clinical Presentation, CSF Parameters, and Outcome of Cryptococcal Meningitis Affecting HIV-positive Patients and Patients with Systemic Lupus Erythematosus (SLE)

1 (2.9) 5 (14.3)

Sex, male Age, median (range) Fever Headache Neck stiffness Altered consciousness Seizure Cranial nerve palsy Peripheral CD4+ cells/mL CSF WBC/mL, median % with 0 cells Glucose, mg/dL, median Protein, mg/dL Positive culture Cryptococcal antigen, median (range) Positive India ink Blood culture positive Outcome: death

HIV-positive, n = 134*

SLE, n = 50†

117/134 (87.3%) 33 (21–60) 125 (93.3%) 92 (68.5%) 38 (28.5%) 28 (21.2%) 6 (4.3%) 12 (10.9%) 27/mL

9/50 (18%) 27 (8–67) 21/37 (56.8%) 24/37 (64.9%) 2/37 (5.4%) 21/37 (56.8%) 7/37 (18.9%) 5/37 (13.5%) 154/mL‡

4/mL 46% 37 mg/dL 64.5 mg/dL 129/134, 96.3% 1:1024 (1:4–1:512,000) 86% 54.5% 91% at 24 months§

29.5/mL 21.8% 23.5 mg/dL 120 mg/dL 45/45, 100% 1:256 (1:2–1:16,384) 21/28 (75%) 29/45, 64.4% 21/50, 42%

CSF = cerebrospinal fluid; HIV = human immunodeficiency virus; WBC = white blood cells. * Reference (14). † Based on references (16–23). ‡ Three patients. § This rate refers to the period preceding the introduction of highly active antiretroviral therapy.

HIV = human immunodeficiency virus. * Three patients with systemic lupus erythematosus (SLE). † All patients with SLE. ‡ All patients with SLE. § Coexistence of more than one underlying condition in several patients.

18 (15) 16 (13) 17 (14) 38 (12) 54 (18) 17 (6) 38 (12) 51 (17) 16 (12) 6 (4) 5 (4) 5 (4) 8 (6) 5 (7) 11 (15.5)

6 (6.4) 5 (5.3) 6 (6.4) 34 (36.2)

22 (18) 25 (20) 28 (23) 17 (14) 41 (30) 31 (23) 30 (22) 25 (18) 17 (13)

Underlying illness None reported Cancer Hematologic malignancy Diabetes mellitus Steroid therapy Rheumatologic or immunologic disease Lung disease Organ transplant Renal failure/dialysis Chronic liver disease Others

43 (60.5) 4 (5.6) 4 (5.6) 5 (7)*

52 (55.3) 6 (6.4) 11 (11.7) 8 (8.5) 10 (10.6)

66 (22) 29 (9) 29 (9) 85 (28) 41 (13)

n (%) n (%) n (%) n (%)

n (%)

n (%)

11 (France) n = 53 10 (Thailand) n = 40§ 9 (USA) n = 124§ 8 (USA) n = 306§ 7 (Taiwan) n = 94§ 6 (USA) n = 135§ 5 (Taiwan) n = 71 Reference (Country) n Patients

Table 1. Reported Underlying Conditions in Non-HIV-infected Persons with Cryptococcosis

Total n = 891 13 (Taiwan) n = 35

Letters to the Editor

12 (Taiwan) n = 33§


However, it is intriguing to note that in 5 patients, the diagnosis of cryptococcal meningitis was made concurrently with the diagnosis of SLE or prior to the administration of any immunosuppressive therapy (23). One of these patients had low CD4 cell counts (e.g., 33/mL), and 3 showed low levels of complement (C4). Matsumura and coworkers explain the latter finding, recalling the important contribution of complement in the opsonization of pathogens for their efficient phagocytic removal (23). Finally, the treatment of cryptococcal meningitis in SLE patients deserves some comment. The Infectious Diseases Society of America guidelines, which were updated and published in 2010, clearly indicate a low level of evidence (either BII or BIII) for the recommended induction therapy with amphotericin B deoxycholate (AmBd) or liposomal amphotericin B plus flucytosine in non-HIV-infected and nontransplant patients (24). Liposomal amphotericin B should be substituted for AmBd in patients with renal impairment. The use of AmBd and flucytosine is associated with better and faster CSF sterilization in comparison with other regimens, but it should be noted that patients with lupus nephritis or reduced creatinine clearance might not be able to tolerate

The Journal of Emergency Medicine

such drugs, even with the appropriate dosage adjustment. Fluconazole, a better-tolerated drug, is fungistatic and generally not recommended for primary therapy of cryptococcal meningitis, but it might be considered in such cases, although even for this drug, a dosage adjustment is necessary in patients with reduced renal function. In patients with AIDS and cryptococcosis, maintenance therapy with fluconazole is imperative until the CD4 cell counts are persistently above the cutoff level of 100/mL (e.g., for at least 6–12 months) and are a better predictive test with respect to a negative serum antigen result (25). The same is probably true for HIV-negative, immunosuppressed patients, and we suggest the use of peripheral CD4 cell counts even among SLE patients to guide the safe stopping of secondary prophylaxis. In the case reported by Sivalingam et al., no suppressive therapy was prescribed, and although they reported no disease relapse at 10-month follow-up, as infectious diseases specialists, we would have recommended it. Spinello Antinori, MD Mario Corbellino, MD Laura Galimberti, MD AnnaLisa Ridolfo, MD Laura Milazzo, MD Department of Biomedical and Clinical Sciences “L. Sacco” University of Milano Milano, Italy


7. 8. 9.

10. 11.

12. 13.



16. 17. 18. 19.

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Cryptococcal meningitis and systemic lupus erythematosus.

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