- Email: [email protected]
AIDS-associated Cryptococcus infection before and after the highly active antiretroviral therapy era: emerging management problems
International Journal of Antimicrobial Agents 22 (2003) 449 /452 www.ischemo.org
AIDS-associated Cryptococcus infection before and after the highly active antiretroviral therapy era: emerging management problems Roberto Manfredi *, Leonardo Calza, Francesco Chiodo Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Bologna, S. Orsola Hospital, Via Massarenti 11, I40138 Bologna, Italy Received 31 October 2002; accepted 28 January 2003
Abstract The frequency, the microbiology and clinical features of AIDS-related primary episodes and relapses of cryptococcosis, before and after the introduction of highly active antiretroviral therapy (HAART), were compared. The study covered 58 cases diagnosed before the introduction of HAART, and eight episodes since 1997. Because of negative cultures, we sought a sensitive laboratory assay such as detection of polysaccharide antigen. Despite later diagnosis, there was reduced disease mortality. Clinical suspicion for HIV-associated cryptococcosis should be maintained in immunocompromised subjects. The introduction of HAART has led to significant clinical and laboratory changes of HIV-related cryptococcosis. # 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Cryptococcosis; Culture; Polysaccharide antigen search; HIV infection; Highly active antiretroviral therapy
1. Introduction Cryptococcus neoformans disease is characterized by insidious clinical and diagnostic features due to its slowly progressive and often atypical presentation. A specific effort should be made to exclude this fungal disease in all patients with a severe T-cell immunodeficiency (such as subjects with advanced HIV disease), and suspicious signs and symptoms. Lumbar puncture with direct cerebrospinal fluid (CSF) microscopy, culture of CSF, blood or other clinical specimens, or search of the specific capsular polysaccharide antigen in different pathological samples, contrast-enhanced brain CT scan or cerebral MRI and eventually histopathologic studies allow recognition of cryptococcosis in all immunocompromised hosts including HIV-infected patients, as well as in the infrequent cases of cryptococcosis occurring in non-immunocompromised subjects [1,2]. The cryptococcal antigen assay is the most sensitive test (positive in /97% of cases), followed by
* Corresponding author. Tel.: /39-051-63-63-355; fax: /39-05134-35-00. E-mail address: [email protected] (R. Manfredi).
CSF and blood cultures (81 and 44% rate) according to a recently published study reporting on a period immediately preceding the highly active antiretroviral therapy (HAART) era [1]. HAART introduction in late 1996 led to a sharp drop of frequency, relapses and mortality rate of all opportunistic diseases including cryptococcosis [3]. However, the rapid immune recovery following HAART may be responsible for varied presentations of AIDS-related opportunism [4 /6], making diagnosis and treatment more difficult. The aim of our study was to compare the frequency and the microbiological and clinical features of AIDSrelated primary episodes and relapses of cryptococcosis, before and after the introduction of HAART as the standard care of HIV infection. 1.1. Patients and methods All episodes of HIV-associated cryptococcosis diagnosed by direct CSF microscopy examination, positive CSF and/or blood culture, polysaccharide antigen search and/or histopathological studies were assessed. The introduction in 1992 of specific antigen testing as a screening procedure of all HIV-infected patients with an unexplained headache and/or fever identified episodes
0924-8579/03/$30 # 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/S0924-8579(03)00113-4
450
R. Manfredi et al. / International Journal of Antimicrobial Agents 22 (2003) 449 /452
characterized (at least initially) by an isolated positive antigen test on either CSF, blood or other clinical specimens, in the absence of positive cultures. The present study considered patients who underwent the same diagnostic procedures in the 58 episodes diagnosed in the period 1992/1996 (pre-HAART era) versus the eight episodes occurred during the years 1997 /2001 (HAART period). Special attention was paid to laboratory testing for cryptococcosis and time to mycological diagnosis. Cryptococcal polysaccharide antigen search was performed by a latex agglutination assay (CryptoLA, International Biological Labs, Cranbury, NJ). All available data were assessed using Student’s t-test, Mantel-Haenszel Chi-square test and Fisher exact test, where appropriate. 1.2. Results When considering our cohort of approximately 1000 HIV-infected patients followed per year, during the HAART period (1997 /2001), only eight patients suffered from cryptococcosis, seven cases were newly diagnosed case and one was a relapse compared with 32 new cases and 26 recurrences observed in the period immediately preceding HAART introduction (1992 / 1996; Table 1). Between the two study periods, the newly diagnosed episodes declined from 6.4 and 5.2 cases per 1000 patients-year to 1.4 and 0.2 cases per 1000 patients-year, for new diagnoses and relapses, respectively (P B/0.0001). Of eight episodes diagnosed since 1997, C. neoformans meningoencephalitis was the first AIDS-defining disease in seven cases, while the remaining patient suffered from a focal recurrence, involving subcutaneous tissue and related lymph nodes only. Notwithstanding suggestive clinical and neurological features,
six of seven patients suffering from their first episode of neurocryptococcosis had repeatedly negative direct CSF microscopy, and CSF and blood cultures over 3/10 weeks. Only one ‘classical’ neurocryptococcosis characterized by early positive CSF microscopy, culture and antigen assay was observed in the years 1997 /2001, compared with 52 of 58 patients in the pre-HAART period (P B/0.0001). In the HAART era, among seven patients with delayed recognition, in six cases the diagnosis was indicated by an isolated positive antigen assay on either CSF and/or blood (obtained after 3 /16 weeks of repeated microbiological attempts), while the last patient had a history of cryptococcal meningoencephalitis 4 years before and experienced an abnormal disease relapse. This consisted of multiple, subcutaneous and lymph node exudative abscesses in the absence of neurological involvement, a positive histopathological biopsy study associated with a late, slight positive serum antigen test (16 weeks after the first appearance of the disease), confirming the diagnosis, in the absence of positive cultures on both blood and drainage material. When compared with the years 1992 /1996, an isolated positive CSF antigen test, accompanied by persistingly negative cultures during 5/19 weeks, led to a diagnosis in only five patients of 32 with primary disease (15.6%; P B/0.0001 versus patients followed during the HAART period), and in one more patient with a relapse out of 26 (3.8%; P B/0.0001 versus subjects diagnosed after 1996). In particular, the episodes of HIV-related cryptococcosis characterized by persistingly negative cultures rose from 10.3% of years 1992/1996 to 87.5% after 1997, and among 13 culture-negative patients, the time to diagnosis of cryptococcosis (based on positive antigen and/ or histopathological studies) proved significantly longer
Table 1 Changing epidemiological, diagnostic and clinical features of AIDS-related cryptococcosis between the pre-HAART and the HAART era in our population of around 1000 HIV-infected patients followed from 1992 until September 30, 2001 Disease features
Number of cases of newly diagnosed cryptococcosis Number of cases of relapses of cryptococcosis Number of cases with positive CSF microscopy and/or positive CSF or blood culture, and/or positive CSF or serum antigen assay during the first week of disease Number of cases with persistently negative cultures Time to mycological diagnosis in these last patients (weeks9/S.D. (range)) Mean CD4/ lymphocyte count at the occurrence of episodes (cells/ml9/S.D. (range)) Number of cases occurring in patients who took antifungal agents in the month preceding disease onset Number of episodes of cryptococcosis with a lethal outcome
Years 1992 /1996 (pre-HAART Years 1997 /2001 (HAART period) (58 episodes) period) (eight episodes) 32 26 52 (89.7%)
7 1 1 (12.5%)
6 (10.3%) 6.79/2.3 (5 /19) 29.69/26.5 (2 /51)
7 (87.5%) 9.59/2.0 (3 /16) 127.99/36.2 (32 /328)
42 (72.4%)
3 (37.5%)
39 (67.2%)
1 (12.5%)
58 episodes diagnosed during years 1992 /1996 are compared with those detected from 1997 to 2001.
R. Manfredi et al. / International Journal of Antimicrobial Agents 22 (2003) 449 /452
in HAART versus the pre-HAART period (P B/0.04; Table 1). All eight episodes of cryptococcosis observed after HAART introduction involved patients with a lesssevere immunodeficiency compared with the preHAART period, as expressed by their mean CD4/ lymphocyte count (P B/0.0001). The cases occurred in the absence of prior antifungal treatment performed in five cases of eight (compared with the 16 cases of 58 of the pre-HAART era (P B/0.05; Table 1). The patients diagnosed since 1997 took an effective HAART regimen for 4 /41 months (mean: 15.19/7.2), as expressed by a significant (]/2 log10) reduction of plasma HIV-RNA levels or a complete viral suppression (HIV-RNA B/50 copies/ml, using a branched-DNA ultrasensitive assay). This led to an immune recovery shown by an increase of CD4/ count of 40/170% over baseline levels. All episodes of cryptococcosis were promptly treated with systemic antifungals. In patients belonging to the HAART group, following diagnostic confirmation, a high-dose antimycotic treatment with liposomal amphotericin B or fluconazole was administered. These courses achieved a complete clinical and mycological cure in 4/ 11 weeks and no clinical and/or mycological relapses in 8 /43-month follow-up. Although antifungal regimens were not comparable between the pre-HAART and the HAART era, a reduced mortality was observed during recent years (one case only in the HAART era, compared with 39 episodes during years 1992 /1996; P B/0.007).
2. Discussion Until HAART introduction, cryptococcosis was a common AIDS-related opportunistic infection, but clinical and microbiological management proved effective, especially when the different available assays were combined [1,2,7]. After the sharp drop of both morbidity and mortality of cryptococcosis following HAART introduction [2,3], these epidemiological changes were associated with a change in pattern of disease. To our knowledge, only 10 cases of AIDS-related cryptococcosis have been described in detail in patients who received HAART, and the great majority of them showed abnormal clinical and/or laboratory findings [8 /11]. Our experience describing eight episodes of cryptococcosis occurred during HAART administration confirms the dramatic drop of incidence of primary and relapsing disease after the introduction of potent antiretroviral combinations [2,3] and an increasing importance of polysaccharide antigen test; a positive result was often delayed, up to 16 weeks in our series, compared with direct CSF microscopy, and CSF and blood cultures, which tested positive in only one case of eight treated with HAART. In the patient with an
451
abnormal clinical relapse, the diagnosis was obtained after histopathological studies and a late serum antigenpositive result. Repeatedly, negative cultures occurred in five of eight evaluable literature episodes [8,10,11], as well as in seven cases of eight in our series. The apparent absence of viable organisms might be explained by the increased immune response against a latent infection due to HAART use, the co-administration of suppressive antifungal therapy and the pro-inflammatory role played by cryptococcal antigen, even in the absence of active fungal replication. Until HAART introduction, histopathological data essentially came from necropsy surveys [1], while in vivo biopsy has become an essential diagnostic tool in recently diagnosed cases [9,11]. As a result, confirmation of a potentially severe HIV-associated disease and its specific treatment have been increasingly delayed during recent years thus leading to an increased crypticity of AIDS-related cryptococcosis. After the introduction of HAART, an atypical clinical presentation of primary or relapsing cryptococcosis was seen in six cases of 10 in the literature [8 /11]. Isolated lymph node localization was an emerging feature noticed in four patients of 10 described during HAART [10,11] and in one patient of ours. Cutaneous involvement reported by Michelet et al. [9] and characterizing our patient with relapsing disease while on HAART became more frequent. While disease dissemination was common during end-stage cryptococcosis occurring before HAART introduction, HIV-associated isolated focal disease without neurological involvement was exceedingly rare in the years preceding HAART use [1,3]. The immune restoration obtained by HAART achieved more evident benefit in patients suffering from or at the risk for opportunistic infections including cryptococcosis [1,2,12]. However, it remains uncertain whether the immune recovery might act better than continuing chemoprophylaxis in this setting, since no extensive data are available about the incidence of cryptococcosis and its relapses after HAART introduction [1,2,13]. AIDS-related opportunism including cryptococcosis still occurs, especially in subjects who have untreated HIV infection and those who refused antiretrovirals or took HAART with insufficient compliance [12]. Cases occurring in the first few months of HAART may reflect a rapid immune recovery leading to an exaggerated response to microbial antigens. This may indicate a reactivation of latent infections, atypical localization and course, or an abnormal local inflammatory response (the so-called ‘immune reconstitution syndrome’) [4 /6,8 /10]. The extended time to presentation since HAART initiation may depend on the different dynamics of Tcell quantitative and functional recovery [4 /6,8 /11] and, in the event of HIV-related mycoses, the concurrent
452
R. Manfredi et al. / International Journal of Antimicrobial Agents 22 (2003) 449 /452
antifungal administration. Seven of eight cases of HIVrelated cryptococcosis, occurred since 1997, had an atypical presentation, leading to a late recognition and a delayed treatment. While an isolated positive cryptococcal antigen test, especially limited to CSF, was an extremely rare event before HAART introduction [1,7], as were repeatedly negative cultures and direct CSF microscopy, these features are more common during HAART years. The pathogenic interactions in HIV disease, immune system reaction to HAART administration and clinical and laboratory features of cryptococcosis deserve further investigation. A broad spectrum of co-factors may play a contributing role conditioning abnormal and inconsistent clinical and microbiological features producing a flare-up of endogenous infections that remained silent for a long time. From a practical point of view, because of the reliability of cryptococcal antigen assay [7,14] and histopathological studies [9,11], all patients who test positive must be considered as infected even when culture remains negative. As a consequence, they deserve an immediate and aggressive antifungal treatment, and strict clinical and mycological monitoring to confirm complete cure and avoid disease relapses [1,2]. Waiting for controlled prospective data coming from large patient samples, a prolonged negative laboratory workout (especially persistently negative cultures) cannot exclude a cryptococcosis when facing HIV-infected patients at risk for this infection due to a severe immunodeficiency or a rapid immune recovery, and showing atypical signs and symptoms (including absence of neurological involvement) [9 /12]. A recent detection of HIV infection, an incomplete or otherwise exaggerated immunological response to HAART and a disease pathomorphism supported by a broad range of contributing factors may hamper a prompt clinical recognition of HIV-associated cryptococcosis, and lead to a delayed diagnosis and treatment, although visceralization and a lethal outcome are becoming rare in the HAART era.
References [1] Oursler KA, Moore RD, Chaisson RE. Risk factors for cryptococcal meningitis in HIV-infected patients. AIDS Res Hum Retroviruses 1999;15:625 /31. [2] Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000;30:710 /8. [3] Sacktor N, Lyles RH, Skolasky R, et al. HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990 /1998. Neurology 2001;56:257 /60. [4] Behrens GM, Meyer D, Stoll M, Schmidt RE. Immune reconstitution syndromes in human immunodeficiency virus infection following effective antiretroviral therapy. Immunobiology 2000;202:186 /93. [5] Nguyen QD, Kempen JH, Bolton SG, Dunn JP, Jabs DA. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000;129:634 /9. [6] Domingo P, Torres OH, Ris J, Vazquez G. Herpes zoster as an immune reconstitution disease after initiation of combination antiretroviral therapy in patients with human immunodeficiency virus type-1 infection. Am J Med 2001;110:605 /9. [7] Feldmesser M, Harris C, Reichberg S, Kahn S, Casadevall A. Serum cryptococcal antigen in patients with AIDS. Clin Infect Dis 1996;23:827 /30. [8] Woods ML, MacGinley R, Eisen DP, Allworth AM. HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection. AIDS 1998;12:1491 /4. [9] Michelet C, Arvieux C, Franc¸ois C. Opportunistic infections occurring during highly active antiretroviral treatment. AIDS 1998;12:1815 /22. [10] Blanche P, Gombert B, Ginsburg C, et al. HIV combination therapy: immune restitution causing cryptococcal lymphadenitis dramatically improved by anti-inflammatory therapy. Scand J Infect Dis 1998;30:615 /6. [11] Lanzafame A, Trevenzoli M, Carretta G, Lazzarini L, Vento S, Concia E. Mediastinal lymphadenitis due to cryptococcal infection in HIV-positive patients on highly active antiretroviral therapy. Chest 1999;16:848 /9. [12] Manfredi R, Calza L, Chiodo F. Lack of change in the distribution of AIDS-defining opportunistic diseases and the related degree of immunodeficiency during the periods before and after the introduction of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2001;20:410 /3. [13] Martı´nez E, Garcia-Viejo MA, Marcos MA, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIVinfected patients responding to highly active antiretroviral therapy. AIDS 2000;14:2615 /7. [14] Tanner DC, Weinstein MP, Fedorciw B, Joho KL, Thorpe JJ, Reller LB. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol 1994;32:1680 /4.
AIDS-associated Cryptococcus infection before and after the highly active antiretroviral therapy era: emerging management problems Roberto Manfredi *, Leonardo Calza, Francesco Chiodo Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Bologna, S. Orsola Hospital, Via Massarenti 11, I40138 Bologna, Italy Received 31 October 2002; accepted 28 January 2003
Abstract The frequency, the microbiology and clinical features of AIDS-related primary episodes and relapses of cryptococcosis, before and after the introduction of highly active antiretroviral therapy (HAART), were compared. The study covered 58 cases diagnosed before the introduction of HAART, and eight episodes since 1997. Because of negative cultures, we sought a sensitive laboratory assay such as detection of polysaccharide antigen. Despite later diagnosis, there was reduced disease mortality. Clinical suspicion for HIV-associated cryptococcosis should be maintained in immunocompromised subjects. The introduction of HAART has led to significant clinical and laboratory changes of HIV-related cryptococcosis. # 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Cryptococcosis; Culture; Polysaccharide antigen search; HIV infection; Highly active antiretroviral therapy
1. Introduction Cryptococcus neoformans disease is characterized by insidious clinical and diagnostic features due to its slowly progressive and often atypical presentation. A specific effort should be made to exclude this fungal disease in all patients with a severe T-cell immunodeficiency (such as subjects with advanced HIV disease), and suspicious signs and symptoms. Lumbar puncture with direct cerebrospinal fluid (CSF) microscopy, culture of CSF, blood or other clinical specimens, or search of the specific capsular polysaccharide antigen in different pathological samples, contrast-enhanced brain CT scan or cerebral MRI and eventually histopathologic studies allow recognition of cryptococcosis in all immunocompromised hosts including HIV-infected patients, as well as in the infrequent cases of cryptococcosis occurring in non-immunocompromised subjects [1,2]. The cryptococcal antigen assay is the most sensitive test (positive in /97% of cases), followed by
* Corresponding author. Tel.: /39-051-63-63-355; fax: /39-05134-35-00. E-mail address: [email protected] (R. Manfredi).
CSF and blood cultures (81 and 44% rate) according to a recently published study reporting on a period immediately preceding the highly active antiretroviral therapy (HAART) era [1]. HAART introduction in late 1996 led to a sharp drop of frequency, relapses and mortality rate of all opportunistic diseases including cryptococcosis [3]. However, the rapid immune recovery following HAART may be responsible for varied presentations of AIDS-related opportunism [4 /6], making diagnosis and treatment more difficult. The aim of our study was to compare the frequency and the microbiological and clinical features of AIDSrelated primary episodes and relapses of cryptococcosis, before and after the introduction of HAART as the standard care of HIV infection. 1.1. Patients and methods All episodes of HIV-associated cryptococcosis diagnosed by direct CSF microscopy examination, positive CSF and/or blood culture, polysaccharide antigen search and/or histopathological studies were assessed. The introduction in 1992 of specific antigen testing as a screening procedure of all HIV-infected patients with an unexplained headache and/or fever identified episodes
0924-8579/03/$30 # 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/S0924-8579(03)00113-4
450
R. Manfredi et al. / International Journal of Antimicrobial Agents 22 (2003) 449 /452
characterized (at least initially) by an isolated positive antigen test on either CSF, blood or other clinical specimens, in the absence of positive cultures. The present study considered patients who underwent the same diagnostic procedures in the 58 episodes diagnosed in the period 1992/1996 (pre-HAART era) versus the eight episodes occurred during the years 1997 /2001 (HAART period). Special attention was paid to laboratory testing for cryptococcosis and time to mycological diagnosis. Cryptococcal polysaccharide antigen search was performed by a latex agglutination assay (CryptoLA, International Biological Labs, Cranbury, NJ). All available data were assessed using Student’s t-test, Mantel-Haenszel Chi-square test and Fisher exact test, where appropriate. 1.2. Results When considering our cohort of approximately 1000 HIV-infected patients followed per year, during the HAART period (1997 /2001), only eight patients suffered from cryptococcosis, seven cases were newly diagnosed case and one was a relapse compared with 32 new cases and 26 recurrences observed in the period immediately preceding HAART introduction (1992 / 1996; Table 1). Between the two study periods, the newly diagnosed episodes declined from 6.4 and 5.2 cases per 1000 patients-year to 1.4 and 0.2 cases per 1000 patients-year, for new diagnoses and relapses, respectively (P B/0.0001). Of eight episodes diagnosed since 1997, C. neoformans meningoencephalitis was the first AIDS-defining disease in seven cases, while the remaining patient suffered from a focal recurrence, involving subcutaneous tissue and related lymph nodes only. Notwithstanding suggestive clinical and neurological features,
six of seven patients suffering from their first episode of neurocryptococcosis had repeatedly negative direct CSF microscopy, and CSF and blood cultures over 3/10 weeks. Only one ‘classical’ neurocryptococcosis characterized by early positive CSF microscopy, culture and antigen assay was observed in the years 1997 /2001, compared with 52 of 58 patients in the pre-HAART period (P B/0.0001). In the HAART era, among seven patients with delayed recognition, in six cases the diagnosis was indicated by an isolated positive antigen assay on either CSF and/or blood (obtained after 3 /16 weeks of repeated microbiological attempts), while the last patient had a history of cryptococcal meningoencephalitis 4 years before and experienced an abnormal disease relapse. This consisted of multiple, subcutaneous and lymph node exudative abscesses in the absence of neurological involvement, a positive histopathological biopsy study associated with a late, slight positive serum antigen test (16 weeks after the first appearance of the disease), confirming the diagnosis, in the absence of positive cultures on both blood and drainage material. When compared with the years 1992 /1996, an isolated positive CSF antigen test, accompanied by persistingly negative cultures during 5/19 weeks, led to a diagnosis in only five patients of 32 with primary disease (15.6%; P B/0.0001 versus patients followed during the HAART period), and in one more patient with a relapse out of 26 (3.8%; P B/0.0001 versus subjects diagnosed after 1996). In particular, the episodes of HIV-related cryptococcosis characterized by persistingly negative cultures rose from 10.3% of years 1992/1996 to 87.5% after 1997, and among 13 culture-negative patients, the time to diagnosis of cryptococcosis (based on positive antigen and/ or histopathological studies) proved significantly longer
Table 1 Changing epidemiological, diagnostic and clinical features of AIDS-related cryptococcosis between the pre-HAART and the HAART era in our population of around 1000 HIV-infected patients followed from 1992 until September 30, 2001 Disease features
Number of cases of newly diagnosed cryptococcosis Number of cases of relapses of cryptococcosis Number of cases with positive CSF microscopy and/or positive CSF or blood culture, and/or positive CSF or serum antigen assay during the first week of disease Number of cases with persistently negative cultures Time to mycological diagnosis in these last patients (weeks9/S.D. (range)) Mean CD4/ lymphocyte count at the occurrence of episodes (cells/ml9/S.D. (range)) Number of cases occurring in patients who took antifungal agents in the month preceding disease onset Number of episodes of cryptococcosis with a lethal outcome
Years 1992 /1996 (pre-HAART Years 1997 /2001 (HAART period) (58 episodes) period) (eight episodes) 32 26 52 (89.7%)
7 1 1 (12.5%)
6 (10.3%) 6.79/2.3 (5 /19) 29.69/26.5 (2 /51)
7 (87.5%) 9.59/2.0 (3 /16) 127.99/36.2 (32 /328)
42 (72.4%)
3 (37.5%)
39 (67.2%)
1 (12.5%)
58 episodes diagnosed during years 1992 /1996 are compared with those detected from 1997 to 2001.
R. Manfredi et al. / International Journal of Antimicrobial Agents 22 (2003) 449 /452
in HAART versus the pre-HAART period (P B/0.04; Table 1). All eight episodes of cryptococcosis observed after HAART introduction involved patients with a lesssevere immunodeficiency compared with the preHAART period, as expressed by their mean CD4/ lymphocyte count (P B/0.0001). The cases occurred in the absence of prior antifungal treatment performed in five cases of eight (compared with the 16 cases of 58 of the pre-HAART era (P B/0.05; Table 1). The patients diagnosed since 1997 took an effective HAART regimen for 4 /41 months (mean: 15.19/7.2), as expressed by a significant (]/2 log10) reduction of plasma HIV-RNA levels or a complete viral suppression (HIV-RNA B/50 copies/ml, using a branched-DNA ultrasensitive assay). This led to an immune recovery shown by an increase of CD4/ count of 40/170% over baseline levels. All episodes of cryptococcosis were promptly treated with systemic antifungals. In patients belonging to the HAART group, following diagnostic confirmation, a high-dose antimycotic treatment with liposomal amphotericin B or fluconazole was administered. These courses achieved a complete clinical and mycological cure in 4/ 11 weeks and no clinical and/or mycological relapses in 8 /43-month follow-up. Although antifungal regimens were not comparable between the pre-HAART and the HAART era, a reduced mortality was observed during recent years (one case only in the HAART era, compared with 39 episodes during years 1992 /1996; P B/0.007).
2. Discussion Until HAART introduction, cryptococcosis was a common AIDS-related opportunistic infection, but clinical and microbiological management proved effective, especially when the different available assays were combined [1,2,7]. After the sharp drop of both morbidity and mortality of cryptococcosis following HAART introduction [2,3], these epidemiological changes were associated with a change in pattern of disease. To our knowledge, only 10 cases of AIDS-related cryptococcosis have been described in detail in patients who received HAART, and the great majority of them showed abnormal clinical and/or laboratory findings [8 /11]. Our experience describing eight episodes of cryptococcosis occurred during HAART administration confirms the dramatic drop of incidence of primary and relapsing disease after the introduction of potent antiretroviral combinations [2,3] and an increasing importance of polysaccharide antigen test; a positive result was often delayed, up to 16 weeks in our series, compared with direct CSF microscopy, and CSF and blood cultures, which tested positive in only one case of eight treated with HAART. In the patient with an
451
abnormal clinical relapse, the diagnosis was obtained after histopathological studies and a late serum antigenpositive result. Repeatedly, negative cultures occurred in five of eight evaluable literature episodes [8,10,11], as well as in seven cases of eight in our series. The apparent absence of viable organisms might be explained by the increased immune response against a latent infection due to HAART use, the co-administration of suppressive antifungal therapy and the pro-inflammatory role played by cryptococcal antigen, even in the absence of active fungal replication. Until HAART introduction, histopathological data essentially came from necropsy surveys [1], while in vivo biopsy has become an essential diagnostic tool in recently diagnosed cases [9,11]. As a result, confirmation of a potentially severe HIV-associated disease and its specific treatment have been increasingly delayed during recent years thus leading to an increased crypticity of AIDS-related cryptococcosis. After the introduction of HAART, an atypical clinical presentation of primary or relapsing cryptococcosis was seen in six cases of 10 in the literature [8 /11]. Isolated lymph node localization was an emerging feature noticed in four patients of 10 described during HAART [10,11] and in one patient of ours. Cutaneous involvement reported by Michelet et al. [9] and characterizing our patient with relapsing disease while on HAART became more frequent. While disease dissemination was common during end-stage cryptococcosis occurring before HAART introduction, HIV-associated isolated focal disease without neurological involvement was exceedingly rare in the years preceding HAART use [1,3]. The immune restoration obtained by HAART achieved more evident benefit in patients suffering from or at the risk for opportunistic infections including cryptococcosis [1,2,12]. However, it remains uncertain whether the immune recovery might act better than continuing chemoprophylaxis in this setting, since no extensive data are available about the incidence of cryptococcosis and its relapses after HAART introduction [1,2,13]. AIDS-related opportunism including cryptococcosis still occurs, especially in subjects who have untreated HIV infection and those who refused antiretrovirals or took HAART with insufficient compliance [12]. Cases occurring in the first few months of HAART may reflect a rapid immune recovery leading to an exaggerated response to microbial antigens. This may indicate a reactivation of latent infections, atypical localization and course, or an abnormal local inflammatory response (the so-called ‘immune reconstitution syndrome’) [4 /6,8 /10]. The extended time to presentation since HAART initiation may depend on the different dynamics of Tcell quantitative and functional recovery [4 /6,8 /11] and, in the event of HIV-related mycoses, the concurrent
452
R. Manfredi et al. / International Journal of Antimicrobial Agents 22 (2003) 449 /452
antifungal administration. Seven of eight cases of HIVrelated cryptococcosis, occurred since 1997, had an atypical presentation, leading to a late recognition and a delayed treatment. While an isolated positive cryptococcal antigen test, especially limited to CSF, was an extremely rare event before HAART introduction [1,7], as were repeatedly negative cultures and direct CSF microscopy, these features are more common during HAART years. The pathogenic interactions in HIV disease, immune system reaction to HAART administration and clinical and laboratory features of cryptococcosis deserve further investigation. A broad spectrum of co-factors may play a contributing role conditioning abnormal and inconsistent clinical and microbiological features producing a flare-up of endogenous infections that remained silent for a long time. From a practical point of view, because of the reliability of cryptococcal antigen assay [7,14] and histopathological studies [9,11], all patients who test positive must be considered as infected even when culture remains negative. As a consequence, they deserve an immediate and aggressive antifungal treatment, and strict clinical and mycological monitoring to confirm complete cure and avoid disease relapses [1,2]. Waiting for controlled prospective data coming from large patient samples, a prolonged negative laboratory workout (especially persistently negative cultures) cannot exclude a cryptococcosis when facing HIV-infected patients at risk for this infection due to a severe immunodeficiency or a rapid immune recovery, and showing atypical signs and symptoms (including absence of neurological involvement) [9 /12]. A recent detection of HIV infection, an incomplete or otherwise exaggerated immunological response to HAART and a disease pathomorphism supported by a broad range of contributing factors may hamper a prompt clinical recognition of HIV-associated cryptococcosis, and lead to a delayed diagnosis and treatment, although visceralization and a lethal outcome are becoming rare in the HAART era.
References [1] Oursler KA, Moore RD, Chaisson RE. Risk factors for cryptococcal meningitis in HIV-infected patients. AIDS Res Hum Retroviruses 1999;15:625 /31. [2] Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000;30:710 /8. [3] Sacktor N, Lyles RH, Skolasky R, et al. HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990 /1998. Neurology 2001;56:257 /60. [4] Behrens GM, Meyer D, Stoll M, Schmidt RE. Immune reconstitution syndromes in human immunodeficiency virus infection following effective antiretroviral therapy. Immunobiology 2000;202:186 /93. [5] Nguyen QD, Kempen JH, Bolton SG, Dunn JP, Jabs DA. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000;129:634 /9. [6] Domingo P, Torres OH, Ris J, Vazquez G. Herpes zoster as an immune reconstitution disease after initiation of combination antiretroviral therapy in patients with human immunodeficiency virus type-1 infection. Am J Med 2001;110:605 /9. [7] Feldmesser M, Harris C, Reichberg S, Kahn S, Casadevall A. Serum cryptococcal antigen in patients with AIDS. Clin Infect Dis 1996;23:827 /30. [8] Woods ML, MacGinley R, Eisen DP, Allworth AM. HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection. AIDS 1998;12:1491 /4. [9] Michelet C, Arvieux C, Franc¸ois C. Opportunistic infections occurring during highly active antiretroviral treatment. AIDS 1998;12:1815 /22. [10] Blanche P, Gombert B, Ginsburg C, et al. HIV combination therapy: immune restitution causing cryptococcal lymphadenitis dramatically improved by anti-inflammatory therapy. Scand J Infect Dis 1998;30:615 /6. [11] Lanzafame A, Trevenzoli M, Carretta G, Lazzarini L, Vento S, Concia E. Mediastinal lymphadenitis due to cryptococcal infection in HIV-positive patients on highly active antiretroviral therapy. Chest 1999;16:848 /9. [12] Manfredi R, Calza L, Chiodo F. Lack of change in the distribution of AIDS-defining opportunistic diseases and the related degree of immunodeficiency during the periods before and after the introduction of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2001;20:410 /3. [13] Martı´nez E, Garcia-Viejo MA, Marcos MA, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIVinfected patients responding to highly active antiretroviral therapy. AIDS 2000;14:2615 /7. [14] Tanner DC, Weinstein MP, Fedorciw B, Joho KL, Thorpe JJ, Reller LB. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol 1994;32:1680 /4.