Antinori, Spinello

Fasan, Marco

Galimberti, Laura

Magni, Carlo

Parravicini, Carlo

Radice, Anna

PubMed

S. Antinori

RADICE, ANNA

L. Galimberti

C. Magni

M. Fasan

C. Parravicini

AIR Universita degli studi di Milano

JOURNAL OF CLINICAL MICROBIOLOGY, Nov. 2005, p. 5828–5829 Vol. 43, No. 110095-1137/05/$08.000 doi:10.1128/JCM.43.11.5828–5829.2005Copyright © 2005, American Society for Microbiology. All Rights Reserved.Letters to the EditorThe Role of Cryptococcal Antigen Assay in Diagnosis and Monitoringof Cryptococcal MeningitisIn a recent paper evaluating the significance of cryptococcalantigen test results for 29 Chinese human immunodeficiencyvirus (HIV)-negative patients affected by cryptococcal menin-gitis, Lu and colleagues (8) showed in all patients a decrease ofantigen titer from the baseline following antifungal therapyand suggested that a decrease can be used to monitor antifun-gal therapy efficacy but cannot be used as an index of cure. Wehave reviewed our experience with 66 HIV-positive patientsout of 118 with cryptococcal meningitis for whom at least threeserial determinations (at baseline, day 7, and day 14) of cryp-tococcal antigen tests on cerebrospinal fluid (CSF) were avail-able (1). A total of 440 determinations (range, 3 to 28 antigendeterminations; median, 5 antigen determinations) were avail-able, and for 55 patients the last determination was considered(median, 13 weeks; range, 2 to 84 weeks). In Fig. 1 is depictedthe kinetics of CSF cryptococcal antigen together with theresults of CSF culture. Overall, 53 patients (80%) showed adecrease of CSF antigen titer from the baseline (7 of whomhad negative results), as follows: 27 cases of 1 to 3 dilutions, 16cases of 4 to 6 dilutions, and 10 cases of 7 or more dilutions.However, 13 out of 15 of these patients for whom postmortemexamination was available, despite evidence of several intravi-tam negative CSF cultures, still had cryptococcal meningitis ordisseminated disease at autopsy (demonstrated by histopathol-ogy). Eight patients had an increase in the CSF antigen titer(four of 1 to 3 dilutions and four of 4 to 8 dilutions), and fiveshowed stable (i.e., the same value) results throughout thefollow-up. All the patients but two with an increase of CSFantigen titer had persistent positive CSF culture and died; fourunderwent autopsy showing disseminated cryptococcosis.Our experience regarding the role of cryptococcal antigen tomonitor antifungal therapy in AIDS patients is in keeping withthat previously reported by Powderly et al. (11), who showedthe lack of any correlation of changes of CSF or serum cryp-tococcal antigen and the outcome of cryptococcal meningitis.However, a high CSF antigen level has been identified as a signFIG. 1. Change over time of CSF cryptococcal antigen titers andcorrelation with CSF cryptococcal cultures in 66 HIV-positive patients.Data of CSF antigen are median values. Data regarding CSF culturesrefers to the total number of patients (n  66), whereas those of CSFantigen titer are the number of patients for whom it was available.TABLE 1. Efficiency of different techniques in the diagnosis of cryptococcal meningitis in different hostsaReference Country No. ofpatients Host conditionNo. positive byCSF Ag (%)No. positive byCSF culture(%)No. positive byIndia ink (%)No. positive byserum Ag (%)12 Brazil 65 AIDS 3/3 (100) 65/65 (100) 61/65 (93.8) NR4 United States 89 AIDS 80/88 (90.9) 89/89 (100) 64/87 (73.5) 70/71 (98.6)3 Australia 128 AIDS 112/128 (87.5) 111/128 (86.7) 93/128 (72.6) NR1 Italy 119 AIDS 112/114 (98.2) 115/118 (97.5) 84/95 (88.4) 111/112 (99.1)Total 401 307/333 (92.2) 380/401 (94.7) 302/375 (80.5) 181/183 (98.9)12 Brazil 44 Immunocompetent 5/6 (83.3) 26/30 (86.7) 34/44 (77.2) NR9 Australia 31 Immunocompetent 27/31 (87.1) 26/31 (83.5) 19/31 (61.3) NR3 Australia 41 Immunocompetent 40/41 (97.6) 39/41 (95.1) 36/41 (87.8) NRTotal 116 72/78 (92.3) 91/102 (89.2) 89/116 (76.7) 181/183 (98.9)12 Brazil 19 HIV negative, immunocompromised NR 17/18 (94.4) 14/18 (77.8) NR6 United States 5 Cancer patients 5/5 (100) 5/5 (100) 5/5 (100) NR10 United States 157 HIV negative, immunocompromised 144/149 (96.6) 132/149 (89) 68/133 (51) 91/105 (87)5 United Statesb 122 Organ transplant recipients 37/37 (100) 76/82 (93) 38/47 (77) 18/21 (86)13 United States 28 Organ transplant recipients 28/28 (100) 21/28 (77) 14/28 (50) 20/22 (90.9)Total 331 214/219 (97.7) 251/282 (89) 139/231 (60.2) 129/148 (87.2)Overall total 848 593/630 (94.1) 722/785 (92) 430/722 (59.6) 310/331 (93.6)a Ag, antigen; NR, not reported.b Review of published reports.5828of poor prognosis in patients with AIDS (1, 7); interestingly,more recently Thay cohorts of HIV-positive patients with cryp-tococcal meningitis showed a significant positive correlationbetween CSF cryptococcal colony-forming units (CFU) andCSF cryptococcal antigen titers at baseline (P  0.0001), butthe rapid rate of decline in CSF CFU was not correlated withthat in CSF cryptococcal antigen titers (2).As shown in Table 1, regardless of the different hosts inwhom cryptococcal meningitis is diagnosed, among all meth-ods employed the cryptococcal CSF antigen had the best over-all sensitivity (94.1%) followed by the serum antigen (93.6%).However, some differences were observed in the different cat-egories of hosts, with lower sensitivity in AIDS and immuno-competent patients (92%) and higher sensitivity among theother immunocompromised hosts without HIV infection. Per-sistently elevated CSF cryptococcal antigen in HIV-infectedpatients carries a poor prognosis and indicates ongoing pro-duction of viable Cryptococcus neoformans in tissue. In conclu-sion, CSF cryptococcal antigen seems to be the best test fordiagnosis of cryptococcal meningitis in terms of sensitivity, butit is an unreliable tool, at least among HIV-positive patients, todrive therapeutic monitoring, particularly in assessing thepoint of discontinuation of antifungal therapy in HIV-infectedpatients.REFERENCES1. Antinori, S., L. Galimberti, C. Magni, A. Casella, L. Vago, F. Mainini, M.Piazza, N. Nebuloni, M. Fasan, C. Bonaccorso, G. M. Vigevani, A. Cargnel,M. Moroni, and A. L. Ridolfo. 2001. Cryptococcus neoformans infection in acohort of Italian AIDS patients: natural history, early prognostic parameters,and autopsy findings. Eur. J. Clin. Microbiol. Infect. Dis. 20:711–717.2. Brouwer, A. E., P. Teparrukkul, S. Pinpraphapora, R. A. Larsen, W. Chi-erakul, S. Peacock, N. Duy, N. J. White, and T. S. Harrison. 2005. Baselinecorrelation and comparative kinetics of cerebrospinal fluid colony-formingunit counts and antigen titers in cryptococcal meningitis. J. Infect. Dis.192:681–684.3. Chen, S., T. Sorrell, G. Nimmo, B. Speed, B. Currie, D. Ellis, D. Marriott, T.Pfeiffer, D. Parr, K. Byth, and the Australasian Cryptococcal Study Group.2000. Epidemiology and host- and variety-dependent characteristics of in-fection due to Cryptococcus neoformans in Australia and New Zealand. Clin.Infect. Dis. 31:499–508.4. Chuck, S. L., and M. A. Sande. 1989. Infections with Cryptococcus neofor-mans in the acquired immunodeficiency syndrome. N. Engl. J. Med. 321:794–799.5. Husain, S., M. M. Wagener, and N. Singh. 2001. Cryptococcus neoformansinfection in organ transplant recipients: variables influencing clinical char-acteristics and outcome. Emerg. Infect. Dis. 7:375–381.6. Kontoyiannis, D. P., W. K. Peitsch, B. T. Reddy, E. E. Whimbey, X. Y. Han,G. P. Bodey, and K. V. I. Rolston. 2001. Cryptococcosis in patients withcancer. Clin. Infect. Dis. 32:e145–150.7. Larsen R. A., M. A. E. Leal, and L. S. Chan. 1990. Fluconazole comparedwith amphotericin B plus flucytosine for cryptococcal meningitis in AIDS: arandomized trial. Ann. Intern. Med. 113:183–187.8. Lu, H., Y. Zhou, Y. Yin, X. Pan, and X. Weng. 2005. Cryptococcal antigen testrevisited: significance for cryptococcal meningitis therapy monitoring in atertiary Chinese hospital. J. Clin. Microbiol. 43:2989–2990.9. Mitchell, D. H., T. C. Sorrell, A. M. Allworth, C. H. Heath, A. R. McGregor,K. Papanaoum, M. J. Richards, and T. Gottlieb. 1995. Cryptococcal diseaseof the CNS in immunocompetent hosts: influence of cryptococcal variety onclinical manifestations and outcome. Clin. Infect. Dis. 20:611–616.10. Pappas, P. G., J. R. Perfect, G. A. Cloud, R. A. Larsen, G. A. Pankey, D. J.Lancaster, H. Henderson, C. A. Kaufmann, D. W. Hass, M. Saccente, R. J.Hamill, M. S. Holloway, R. M. Warren, and W. E. Dismukes. 2001. Crypto-coccosis in human immunodeficiency virus-negative patients in the era ofeffective azole therapy. Clin. Infect. Dis. 33:690–699.11. Powderly, W. G., G. A. Cloud, W. E. Dismukes, and M. S. Saag. 1994.Measurement of cryptococcal antigen in serum and cerebrospinal fluid:value in the management of AIDS-associated cryptococcal meningitis. Clin.Infect. Dis. 18:789–792.12. Rozenbaum, R., and A. J. R. Goncalves. 1994. Clinical epidemiological studyof 171 cases of cryptococcosis. Clin. Infect. Dis. 18:369–380.13. Wu, G., R. A. Vilchez, B. Eidelman, J. Fung, R. Kormos, and S. Kusne. 2002.Cryptococcal meningitis: an analysis among 5521 consecutive organ trans-plant recipients. Transplant Infect. Dis. 4:183–188.Spinello Antinori*Anna RadiceLaura GalimbertiDepartment of Clinical Sciences L. SaccoUniversity of MilanVia GB Grassi 74, 20157 Milan, ItalyCarlo MagniI Division of Infectious DiseasesL. Sacco HospitalMilan, ItalyMarco FasanII Division of Infectious DiseasesL. Sacco HospitalMilan, ItalyCarlo ParraviciniPathology UnitL. Sacco HospitalVia GB Grassi 74, 20157 Milan, Italy*Phone: 390239042668Fax: 390250319758E-mail: spinello.antinori@unimi.itVOL. 43, 2005 LETTERS TO THE EDITOR 5829

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