International Journal of STD & AIDS 1992; 3: 168-172
EDITORIAL REVIEW
Cryptococcal infection in AIDS R
J Coker
MB BS MRCP
Jefferiss Wing, St Mary's Hospital, Paddington, London W2 INY, UK Keywords: Cryptococcosis, AIDS, symptomatology, diagnostic methods, treatment
Cryptococcus neofonnans is an important opportunist pathogen in human immunodeficiency virus (HIV) infection. Cryptococcal meningitis, the most common clinical manifestation of cryptococcosis, is one of the most important neurological manifestations in AIDS and ranks third in frequency behind primary HIV neuropathy and Toxoplasma gondii among infectious causes of neurological disease in patients with AIDS1,2. Extrapulmonary infection due to C. neofonnans has been reported in up to 13% of patients with AIDS3-U, and continues to pose a major therapeutic problem. Treatment, both induction and maintenance, is associated with high failure and relapse rates. This review summarizes the clinical features, diagnostic methods, and recent advances in treatment of cryptococcal infection in AIDS. EPIDEMIOLOGY
Cryptococcus spp. are ubiquitous, though prevalence varies considerably'< 14. Serotypes A and D (var. neoformans) are widespread, but serotypes Band C (var. gattii) have not been isolated from the environment. Of the isolates in the USA, Canada, and Japan 86% are serotype A. Serotype D is the most common in Europe. Var. gattii subtypes tend to occur in tropical and sub-tropical climates, and in Africa, before the AIDS epidemic, var. gatii was more prevalent as a cause of meningitis, but now var. neofonnans predominates. Only 3 cases of var. gattii infection have been reported in AIDS patients in contrast to many thousands due to var. neofomums. In a CDC study the prevalence of cryptococcal meningitis in the USA was highest in intravenous drug users and Haitians. The incidence among blacks was twice that of whites. New Jersey had the most cases, probably related to a higher proportion of Haitian, black and intravenous drug users", With mitochondrial DNA and other probes isolates can now be typed 15 and detailed epidemiological studies are now possible. Methods indicate considerable isolate to isolate variation. CLINICAL FEATURES
The spectrum of disease caused by the fungus ranges from asymptomatic pulmonary cryptococcosis
to widespread disease including meningitis. The lung is the usual site of entry of C. neofonnans. In the immunocompetent host pulmonary cryptococcosis is very variable, often being asymptomatic, and the prevalence is, therefore, unknown. In several series of patients with AIDS who had pneumonia, cryptococcal pneumonia represented 2-15% of all cases l 6-19. Pulmonary cryptococcosis is probably more common than has been previously realized; reports of frequency range between 0% and 50% of ratients with disseminated cryptococcosis 5,6.2o- 2 . Cryptococcal infection may be limited to the lungs, though this is more common in the immunocompetent host. Clark et al. 23 found cryptococcal meningitis in 63% of AIDS patients with pulmonary infection. The most frequent presenting features are fever, cough, dyspnoea and pleuritic chest pain-'. Meningitis is the most common manifestation of cryptococcosis occurring in 63% to 84% of AIDS patients with cryptococcal infectionvv". It is the initial AIDS-defining illness in 40-75% of patients with cryptococcosis4•5•9•23. It may present in an indolent manner or as an acute illness. Fever and headache are the most common symptoms and occur in 80-90% patients. Meningism occurs in approximately 30% patients and altered mental state and photophobia in 20% patients. Signs and symptoms indicating focal neurological disease are uncommon and duration of symptoms prior to diagnosis is often weeks 4•5•7•9,11.12. Complications include hydrocephalus, focal neurological deficits and mental changes. Cryptococcosis may also be found in the genitourinary tract, bone marrow, blood and skin 4,7.24. MICROBIOLOGY AND DIAGNOSIS
C. neojormans is a nonmycelial yeast-like fungus which was first isolated from the juice of the peach in 189425• In meningitis the CSF may show a minimal lymphocytic inflammatory response with mild elevation of protein and normal level of glucosev'", though chemistry and cell counts may be normal5.26 . Lumbar puncture opening pressure may be normal or raised (though papilloedema is unusual). In meningitis the latex agglutination (LA) test for cryptococcal polysaccharide antigen is both sensitive
Coker. Cryptococcal infection in AIDS
(99%) and specific in serum, though cross reactivity with rheumatoid factor or Trichosporon beigelii can lead to a false positive result". T. beigelii can be part of the normal human flora, however immunosuppressed patients may acquire disseminated trichosporosis-". Cryptococcal antigen titres can be measured in both cerebrospinal fluid (CSF) and in serum, though sensitivity is poorer in the CSf'9. Serum cryptococcal antigen titres may remain high despite therapy though the significance of persistently high serum levels of antigen is unknown in patients with AIDS. CSF cryptococcal antigen titres tend to decrease with therapy though falling titres are not always associated with clinical improvement, and positive CSF antigen test results may be obtained despite failure to isolate organisms from CSF. This may represent the slow clearance of high molecular weight capsular antigen, due to impaired phagocytosis's, or the persistent release of free antigen from dead cells in the CSF. Positive identification of cryptococci in secretions mounted in Indian ink is helpful but negative results do not exclude active infection and weakly encapsulated yeast forms may resemble lymphocytes. The degree of encapsulation in CSF samples is unrelated to prior antifungal therapy or antigen titre 29 • Positive CSF Indian ink stains are found in approximately 75% cases of cryptococcal meningitis 4,9.11,12. CSF smears may remain persistently positive on Indian ink staining despite improvement in clinical status, falling antigen titres and negative CSF cultures and are, therefore, a poor guide to progress. Cryptococcus may be cultured from cerebrospinal fluid (CSF), blood, sputum, bronchial secretions, urine, skin or lung biopsies. Widespread dissemination of infection may occur and multiple sites may be culture positive. Cryptococci are usually grown on Sabouraud's agar at temperatures of 3O-35°C. Incubation periods up to 2 weeks may be necessary, particularly in partially treated cases. Following apparently successful treatment persistent cryptococcal infection of the prostate occurs in up to 29% of patients and mal be visualized in expressed prostatic secretions- suggesting that the prostate may be a sanctuary from which systemic relapse can occur. Chest radiographic features vary from normal, diffuse interstitial infiltrates, nodular/circumscribed infiltrates, pleural effusions, lobar consolidation and cavitation, and lymphadenopathy22,30- 2. Optimally, any patient with proven or suspected HIV infection and neurological dysfunction should undergo a computed tomographic (CT) or magnetic resonance (MR) scan to exclude an intracerebral lesion. However, this is not always feasible and perhaps a more practical approach is to scan all patients with AIDS or those previously asymptomatic with neurological signs. In patients with CNS cryptococcosis the CT scan is usually normal33,34. However, Popovich et aI.35 reported an incidence of cryptococcal intracerebral mass lesions of 11% in
169
patients with cryptococcal meningitis. Infection may spread into the brain substance via perivascular spaces (Virchow-Robin spaces) producing multiple small cysts filled with organisms. Larger lesions may arise from aggregation of smaller lesions and are usually seen in the basal ganglia and thalamus. PROGNOSTIC INDICATORS
In HIV-infected patients prognostic indicators are not clearly elucidated. Chuck and Sande? reviewed the records of 106 patients with cryptococcal infection in AIDS and found that positive extrameningeal cultures and hyponatraemia were associated with poor survival. Abnormal head CT scan and altered mental state were indicative of poor prognosis in another large review of 68 patients with cryptococcal infection11. The prognostic value of serum antigen titres in patients with AIDS is doubt£ul9,11 because, as previously noted, occasional artificial elevations caused by defective elimination occur. Others, however, have suggested that titres > 1: 10,000 are associated with high mortality". In AIDS 17-37% of patients with cryptococcal meningitis die during induction therapy and onIl 18-30% survive for longer than 12 months4,5, 1 • Those patients with lowest CD4 counts may fare worst36. The first line of host defence is the alveolar macrophage and recent work with human monocytes and neutrophils has shown significant differences in monocyte killing between isolates, thou§h differences in neutrophil killing was less marked 7. Isolate variations may play an important role in pathogenesis of disease and ultimately response to treatment and further studies are required to answer these questions. TREATMENT
The treatment of cryptococcosishas been investigated intensively and has been the subject of several large multicentre studies to determine optimum drug combinations and length of therapy. The goals of treatment in AIDS patients with cryptococcosis differ from those in the non-immunocompromised. The primary objectives are to improve the patient's quality of life, and suppress relapses after initial primary treatment. Total eradication of the opportunistic infection is probably impossible. Bennet et al.38 showed that meningeal infection was best treated with a combination of amphotericin B (0.3 mg/kg/d) and flucytosine (150mg/kg/day) in the non-immunocompromised host. Both the higher failure rate among AIDS patients4,1l,39,40 and the relatively high toxicity of flucytosine in these patients means different regimens have been tried, and attention has been focused on other drugs or different formulations of these drugs. Dismukes et aI.41 showed that AIDS patients with cryptococcal meningitis benefited from 6 weeks treatment rather than 4 with amphotericin Band flucytosine.
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International Journal of STD & AIDS Volume 3 May/June 1992
Many different dosages of amphotericin B have been used though dosages higher than the 0.3 mg/kg/day in the conventional combination regimen are required. Most investigators agree that dosages in the 0.5-0.8 mg/kg/day range are appropriate. Significant toxicity, particularly renal which occurs in 80% of patientsv, means that the intensity and duration of treatment may need to be limited, and the dose of amphotericin B has to be individually tailored. Most patients will require a total of at least 1-1.5 g as induction therapy". Intrathecal amphotericin B has no special benefit in cryptococcal meningitis and may cause arachnoiditis and myelitis. The use of flucytosine is contentious. A large retrospective study found no significant difference in survival between patients treated with amphotericin B alone and those treated with combination therapy". Flucytosine had to be discontinued in 53% of patients because of bone marrow toxicity, and the current dosage recommendation of 150 mg/kg/day is perhaps too high, and 75-100 mg/kg/day is more appropriatev. Serum concentrations of flucytosine, if used, should be maintained at 50-100 mg/I 44; marrow toxicity correlates with peak serum concentration. Liposomal encapsulation of amphotericin B reduces the renal toxicity and chills associated with conventional amphotericin B and, in contrast, may be given via a peripheral line without associated phlebitis. Results of trials are awaited for this new formulation but preliminary reports suggest it may be a useful advance45-48• The necessity for prolonged intravenous drug administration predisposes patients to the risk of nosocomial bacteraemia and indwelling intravenous catheters have been identified as a risk factor'". An orally administered alternative is, therefore, attractive. The first cure of C. neoformans meningitis with fluconazole was reported in 198f'50. It is a new orally administered triazole with a high degree of penetration into the CSF (unlike conventional or liposomal amphotericin B, itraconazole or ketoconazole) and other body compartments. Concentrations of fluconazole in the CSF are 60-80% of serum concentrations in the presence of both uninflamed and inflamed meninges51-53. The laboratory sensitivity of azole antifungal drugs is highly dependent on test conditions'S, and it is not unusual to obtain a minimum inhibitory concentration (MIC)for a responsive strain much higher than the concentration of drug attained in the patient. An adequate CSF concentration does not necessarily mean clinical response'", A randomized trial comparing fluconazole with amphotericin Band flucytosine showed the latter regimen has superior mycologic and clinical efficacy in AIDS-associated cryptococcal meningitis 36 • Fourteen patients received fluconazole (400mg/day) and 8 failed in contrast to none of 6 treated in the other arm with amphotericin B (O.7mg/kg/day for 7 days then 3 times per week) and flucytosine (l50mg/kg/day). CD4 counts were,
however, significantly lower in the fluconazole group. Interim analysis of a prospective, randomized study involving 99 patients comparing fluconazole (200 mgt day with the option of increasing to 400 mg/day) with amphotericin B (> 0.3 mg/kg/day three times per week) and flucytosine (150 mg/kg/day) found a similar response in both groups's. Optimal therapy in persistent prostatic infection in AIDS remain to be elucidated, though fluconazole at a dose of 200-600 mg daily in one study produced suppression of cryptococcuria in 50% of patients'". Itraconazole, another triazole, is well absorbed after oral administration and shows a high degree of protein binding and extensive distribution in tissues. Despite poor penetration into CSF, itraconazole is effective in the treatment of cryptococcalmeningitis'". Thirty-two patients with eryptococcosis(26with AIDS), including 24 with meningitis, were given 200 mg twice daily. Sixty-five per cent of assessable patients with meningitis responded completely with clinicalimprovement and negative cultures. High CSF concentrations are not, therefore, mandatory and perhaps itraconazole is found at high concentrations in the brain. Ketoconazole, an imidazole, is not recommended in the treatment of AIDS-associated cryptococcosis because it is poorly absorbed from the stomach, does not readily diffuse into the CSF59,60, and has poor activity in C. neoformans meningitis. Unlike in the immunocompetent patient with pulmonary cryptococcosis, AIDS patients with this manifestation probably always need treatment. The optimal treatment in these cases is uncertain but at present it is wise to treat patients in a similar fashion to those with meningitis. MAINTENANCE The rate of relapse after initial treatment of cryptococcal meningitis approaches 50-65%4,5.41. This means that lifelong maintenance treatment or suppressive therapy is necessary. Different approaches have been used in an effort to prevent relapse and achieve cure. A comparison study between fluconazole (200 mg/day) and amphotericin B (1 mg/kg/week) as maintenance therapy showed that of 183 evaluable patients, 2 of 106 taking fluconazole relapsed, compared with 13 of 77 receiving amphotericin 8 56• Denning et al. 58 reported suppression of disease with itraconazole (400 mg/day) in 10 of 15 patients with meningitis. Other small studies show similar results 61,62.
PROPHYLAXIS The Widespread use of azole drugs in AIDS, particularly either for treatment or prophylaxis of oral candidosis, does not appear to convey complete protection in preventing the development of cryptococcal meningitis63,64 . A recent open label study comparing primary prophylaxis with fluconazole with historical controls, however, showed a reduction in the incidence of systemic fungal infections including cryptococcosise''.
Coker.
CONCLUSION
Cryptococcal meningitis is the most common serious fungal infection in AIDS patients and is associated with a high mortality. Diagnosis is generally straightforward but may be delayed because clinical features are often muted. There are still many unanswered questions concerning the pathogenesis of this disease. Treatment, both induction and maintenance, is still unsatisfactory; however further clinicalstudies using the azoles and newer liposomal formulations of amphotericin Bmay help solve some of the unanswered questions. Prophylaxis, unlike for other opportunist infections, does not appear to convey protection.
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References 1 Gabuzda DH, Hirsch MS. Neurologic manifestations of infection with human immunodeficiency virus. Clinical features and pathogenesis. Ann Intern Med 1987;107:383-91 2 Levy RM, Bredesden DE, Rosenblum ML. Neurologic manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. ] Neurosurg 1985;62:475-95 3 Snider WD, Simpson OM, Nielsen S, Gold JWM, Metroka CE, Posner}B. Neurologic complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 1983;14:403-18 4 Kovacs JA, Kovacs AA, Polis M, et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 1985;103:533-8. 5 Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal H. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med 1986;104:234-40 6 Eng RHK, Bishburg E, Smith SM, Kapila R. Cryptococcal infection in patients with acquired immune deficiency syndrome. Am J Med 1986;81:19-23 7 Dismukes WE. Cryptococcal meningitis in patients with AIDS. , Infect Dis 1988;157:624-8 8 Levy RM, Janssen RS, Bush 11, Rosenblum M1. Neuroepidemiology of acquired immunodeficiency syndrome. , AIDS 1988;1:31-40 9 Chuck S, Sande M. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl] Med 1989;321:794-9 10 Weinke T, Rogier G, Sixt C, et al. Cryptococcosis in AIDS patients; observations concerning CNS involvement. JNeural 1989;236:38-42 11 Clark RA, Greer D, Atkinson W, Valainis GT, Hyslop N. Spectrum of Cryptococcus neojormans infection in 68 patients infected with human immunodeficiency virus. Rev Infect Dis 1990;12:768-77 12 Nelson MR, Bower M, Smith 0, Reed C, Shanson D, Gazzard B. The value of serum cryptococcal antigen in the diagnosis of cryptococcal infection in patients infected with the human immunodeficiency virus. J Infect 1990;21:175-81 13 Bergman F. Occurrence of Cryptococcus neoformans in Sweden. Acta Med Scand 1963;174:651-5 14 Emmons CWo Prevalence of Cryptococcus neoformans in pigeon habitats. Public Health Rep 1960;75:362-4 15 Kwon-Chung KJ, Varma A, Howard DH. Ecology of Cryptococcus neoformans and prevalence of its two varieties in AIDS and non-AIDS associated cryptococcosis. In: Vanden Bossche H, Mackenzie DWR, Cauwenbergh G,
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Van Cutsem J. Drouhet E, Dupont B. eds. Mycoses in AIDS patients. New York: Plenum Press, 1990:10313 McCauley 01, Naidich DP, Leitman BS, Reede DL, Laubenstein 1. Radiographic patterns of opportunistic lung infections and Kaposi's sarcoma in homosexual men. AJR Am] RoentgenoI1982;139:653-8 Murray JF, Felton CP, Garay SM, et al. Pulmonary complications of the acquired immunodeficiency syndrome: report of a National Heart, Lung and Blood Institute workshop. N Engl J Med 1984;310:1682-8 Cohen BA, Pomeranz 5, Rabinowitz JG, et al. Pulmonary complications of AIDS: radiographic features. AJR 1984; 143:115-22 Hollerman H, Bernstein MA, Beute GH. Thoracic manifestations of AIDS. Am Fam Physician 1987;35:109-18 Gal AA, Koss MN, Hawkins J, Evans S, Einstein H. The pathology of pulmonary cryptococcal infections in the acquired immunodeficiency syndrome. Arch Pathol Lab Med 1986;110:502-7 Chechani V, Kamholz S1. Pulmonary manifestations of disseminated cryptococcosis in patients with AIDS. Chest 1990;98:1060-6 Cameron ML, Bartlett JA, Gallis HA, Waskin HA. Manifestations of pulmonary cryptococcosis in patients with acquired immunodeficiency syndrome. Rev Infect Dis 1991;13:64-7 Clark RA, Greer DL, Valainis G'I, Hyslop NE. Cryptococcus neojormans pulmonary infection in HIV-1-infected patients. J Acquir Immune Defic Syndr 1990;3:480-4 Larsen RA, Bozzette S, McCutchan JA, Chiu J, Leal MA, Richman DO. Persistent Cryptococcus neoformans infection of the prostate after successful treatment of meningitis. Ann Intern Med 1989;111:125-8 San Felice F. Contribute alia morfologica e biologica dei blastomiceti che si sviluppano nei succhi di alcuni frutti. Ann Ig Sperimentale 1894;5:239-62 Shaunak S, Schell WA, Perfect JR. Cryptococcal meningitis with normal cerebrospinal fluid. J Infect Dis 1989;160:912 Haupt HM, Merz WG, Berschorner WE, et al. Colonization and infection with trichosporon species in the immunosuppressed host. J Infect Dis 1983;147:199 Kozel TR. Non-encapsulated variant of Cryptococcus neoiormans. Il. Surface receptors for cryptococcal polysaccharide and their role in inhibition of phagocytosis by polysaccharide. Infect Immun 1977;16:99-106 Gal AA, Evans 5, Meyer PRo The clinical and laboratory evaluation of cryptococcal infections in the acquired immunodeficiency syndrome. Diagn Microbiol Infect Dis 1987;7:249-54 Khoury MB, Godwin JD, Ravin eE, Gallis HA, Halvorsen RA, Putman CEo Thoracic cryptococcosis: immunologic competence and radiologic appearance. AIR Am J Roentgenol 1984;142:893-6 Wasser L, Talavera W. Pulmonary cryptococcosis in AIDS. Chest 1987;92:692-5 Miller WT, Edelman J, Miller W. Cryptococcal pulmonary infection in patients with AIDS: radiographic appearance. Radiology 1990;175: 725-8 Post MJD, Sheldon H, Hensley GT, et al. Central nervous system disease in acquired immunodeficiency syndrome: prospective correlation using CT, MR imaging, and pathologic studies. Radiology 1986;158:141-8 Elkin CM, Leon E, Grenell SL, Leeds NE. Intracranial lesions in the acquired immunodeficiency syndrome. Radiological (computed tomographic) features. JAMA 1985;253:393-6 Popovich MJ, Arthur RH, Helmer E. CT of intracranial cryptococcosis. AJR Am J Roentgenol 1990;154:603-6
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36 Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. Ann Intern Med 1990;113:183-7 37 Miller MF, Mitchell TG. Killing of Cryptococcus neoformans strains by human neutrophils and monocytes. Infect Immun 1991;59:24-8 38 Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979; 301:126-31 39 Diamond RD, Bennett JE. Prognostic factors in cryptococcal meningitis: a study in 111 cases. Ann Intern Med 1974; 80:176-81 40 Kaplan MH, Rosen PP, Armstrong D. Cryptococcosis in a cancer hospital: clinical and pathological correlates in fortysix patients. Cancer 1977;39:2265-74 41 Dismukes WE, Cloud G, Gallis HA, et al. Treatment of cryptococcalmeningitis with combination amphotericin Band flucytosine for four as compared with six weeks. N Engl J Med 1987;317:334-41 42 Butler WT, Bennett JE, Alling DW, Wertlake PT, Utz JP, Hill GJ m. Nephrotoxicity of amphotericin B: early and late effects in 81 patients. Ann Intern Med 1964;61:175-87 43 Shaunak S, Cohen J. Oinical management of fungal infection in patients with AIDS. JAntimicrob Chemother 1991;28:(suppl A):67-81 44 Stamm AM, Diasio RB, Dismukes WE, et al. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med 1987;83:236-42 45 Coker R, Tomlinson D, Harris J. Successful treatment of cryptococcal meningitis with liposomal amphotericin B after failure of treatment with fluconazole and conventional amphotericin B. AIDS 1991;5:231-2 46 Schurmann D, de Matos Marques B, Grunewald T, Pohle HD, Hahn H, Ruf B. Safety and efficacy of liposomal amphotericin B in treating AIDS-associated disseminated cryptococcosis. J Infect Dis 1991;164:620-2 47 Coker RJ, Murphy SM, Harris JRW. Experience with liposomal amphotericin B (AmBisome) in cryptococcal meningitis in AIDS. J Antimicrob Chemother 1991;28(suppl B): 105-9 48 Coker R], Horner Pl. Short course treatment and response to liposomal amphotericin B in AIDS-associated cryptococcosis. J Infect Dis 1992;165:593 49 Jacobson MA, Gellermann H, Chambers H. Staphylococcus aureus bacteremia and recurrent staphylococcal infection in patients with acquired immunodeficiency syndrome and AIDS-related complex. Am J Med 1988;85:172-6 50 Dupont B, Drouhet E. Cryptococcal meningitis and fluconazole. Ann Intern Med 1987;106:778
51 Perfect JR, Durack DT. Penetration of imidazolesand triazoles into cerebrospinal fluid of rabbits. J Antimicrob Chemother 1985;16:81-6 52 Arndt CAS, Walsh TJ, McCully CL, Balis FM, Pizzo PA, Poplack DG. Fluconazolepenetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system. J Infect Dis 1988;157:178-80 53 Tucker RM, WilliamsPL, Arathoon EG, Levine BE,Hartstein AI, Hanson LH, Stevens DA. Pharmacokinetics offluconazole in cerebrospinal fluid and serum in human COCcidioidal meningitis. Antimicrob Agents Chemother 1988;32:369-73 54 Odds Fe. Laboratory tests for the activity of imidazole and triazoleantifungal agents in vitro. Semin DermatoI1985;4:260-70 55 Coker RJ, Harris JRW. Failure of fluconazole treatment in cryptococcal meningitis despite adequate CSF levels. J Infect 1991;23:101-3 56 Galgiani IN. Fluconazole, a new antifungal agent. Ann Intern Med 1990;113:177-9 57 Bozzette SA, Larsen RA, Chiu J, et al. Fluconazole treatment of persistent Cryptococcus neoformans prostatic infection in AIDS. Ann Intern Med 1991;115:285-6 58 Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA. Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med 1989;149:2301 59 Sugar AM, Alsip SG, Galgiani IN, et al. Pharmacology and toxicity of high-dose ketoconazole. Antimicrob Agents Chemother 1987;31:1874-8 60 Lake-Bazaar G, Tom W, Lake-Bazaar D, et al. Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988;109: 471-3 61 Viviani MA, Tortorano AM, Langer M, et Ill. Experience with itraconazole in cryptococcosis and aspergillosis. J Infect 1989;18:151-65 62 de Gans J, Eeftinck Schattenkerk JKM, van Ketel RJ. Itraconazole as maintenance treatment for cryptococcal meningitis in the acquired immune deficiencysyndrome. BMJ 1988;296:339 63 van't Wout ]W, de Graef-Meeder ER, Paul LC, Kuis W, van Furth R. Treatment of two cases of cryptococcal meningitis with fluconazole. Scand J Infect Dis 1988;20: 193-8 64 Coker RJ, Moulopolos D, Main J, Murphy M, Pinching AJ, Harris JRW. Cryptococcal meningitis in AIDS occurring despite systemic antifungal therapy. J Infect 1992;23:107 65 Nightingale SD, Cal SX, Peterson DM, et al. Primary prophylaxis with fluconazole against systemic fungal infections in HlV-positive patients. AIDS 1992;6:191-4
(Accepted 8 January 1992)
EDITORIAL REVIEW
Cryptococcal infection in AIDS R
J Coker
MB BS MRCP
Jefferiss Wing, St Mary's Hospital, Paddington, London W2 INY, UK Keywords: Cryptococcosis, AIDS, symptomatology, diagnostic methods, treatment
Cryptococcus neofonnans is an important opportunist pathogen in human immunodeficiency virus (HIV) infection. Cryptococcal meningitis, the most common clinical manifestation of cryptococcosis, is one of the most important neurological manifestations in AIDS and ranks third in frequency behind primary HIV neuropathy and Toxoplasma gondii among infectious causes of neurological disease in patients with AIDS1,2. Extrapulmonary infection due to C. neofonnans has been reported in up to 13% of patients with AIDS3-U, and continues to pose a major therapeutic problem. Treatment, both induction and maintenance, is associated with high failure and relapse rates. This review summarizes the clinical features, diagnostic methods, and recent advances in treatment of cryptococcal infection in AIDS. EPIDEMIOLOGY
Cryptococcus spp. are ubiquitous, though prevalence varies considerably'< 14. Serotypes A and D (var. neoformans) are widespread, but serotypes Band C (var. gattii) have not been isolated from the environment. Of the isolates in the USA, Canada, and Japan 86% are serotype A. Serotype D is the most common in Europe. Var. gattii subtypes tend to occur in tropical and sub-tropical climates, and in Africa, before the AIDS epidemic, var. gatii was more prevalent as a cause of meningitis, but now var. neofonnans predominates. Only 3 cases of var. gattii infection have been reported in AIDS patients in contrast to many thousands due to var. neofomums. In a CDC study the prevalence of cryptococcal meningitis in the USA was highest in intravenous drug users and Haitians. The incidence among blacks was twice that of whites. New Jersey had the most cases, probably related to a higher proportion of Haitian, black and intravenous drug users", With mitochondrial DNA and other probes isolates can now be typed 15 and detailed epidemiological studies are now possible. Methods indicate considerable isolate to isolate variation. CLINICAL FEATURES
The spectrum of disease caused by the fungus ranges from asymptomatic pulmonary cryptococcosis
to widespread disease including meningitis. The lung is the usual site of entry of C. neofonnans. In the immunocompetent host pulmonary cryptococcosis is very variable, often being asymptomatic, and the prevalence is, therefore, unknown. In several series of patients with AIDS who had pneumonia, cryptococcal pneumonia represented 2-15% of all cases l 6-19. Pulmonary cryptococcosis is probably more common than has been previously realized; reports of frequency range between 0% and 50% of ratients with disseminated cryptococcosis 5,6.2o- 2 . Cryptococcal infection may be limited to the lungs, though this is more common in the immunocompetent host. Clark et al. 23 found cryptococcal meningitis in 63% of AIDS patients with pulmonary infection. The most frequent presenting features are fever, cough, dyspnoea and pleuritic chest pain-'. Meningitis is the most common manifestation of cryptococcosis occurring in 63% to 84% of AIDS patients with cryptococcal infectionvv". It is the initial AIDS-defining illness in 40-75% of patients with cryptococcosis4•5•9•23. It may present in an indolent manner or as an acute illness. Fever and headache are the most common symptoms and occur in 80-90% patients. Meningism occurs in approximately 30% patients and altered mental state and photophobia in 20% patients. Signs and symptoms indicating focal neurological disease are uncommon and duration of symptoms prior to diagnosis is often weeks 4•5•7•9,11.12. Complications include hydrocephalus, focal neurological deficits and mental changes. Cryptococcosis may also be found in the genitourinary tract, bone marrow, blood and skin 4,7.24. MICROBIOLOGY AND DIAGNOSIS
C. neojormans is a nonmycelial yeast-like fungus which was first isolated from the juice of the peach in 189425• In meningitis the CSF may show a minimal lymphocytic inflammatory response with mild elevation of protein and normal level of glucosev'", though chemistry and cell counts may be normal5.26 . Lumbar puncture opening pressure may be normal or raised (though papilloedema is unusual). In meningitis the latex agglutination (LA) test for cryptococcal polysaccharide antigen is both sensitive
Coker. Cryptococcal infection in AIDS
(99%) and specific in serum, though cross reactivity with rheumatoid factor or Trichosporon beigelii can lead to a false positive result". T. beigelii can be part of the normal human flora, however immunosuppressed patients may acquire disseminated trichosporosis-". Cryptococcal antigen titres can be measured in both cerebrospinal fluid (CSF) and in serum, though sensitivity is poorer in the CSf'9. Serum cryptococcal antigen titres may remain high despite therapy though the significance of persistently high serum levels of antigen is unknown in patients with AIDS. CSF cryptococcal antigen titres tend to decrease with therapy though falling titres are not always associated with clinical improvement, and positive CSF antigen test results may be obtained despite failure to isolate organisms from CSF. This may represent the slow clearance of high molecular weight capsular antigen, due to impaired phagocytosis's, or the persistent release of free antigen from dead cells in the CSF. Positive identification of cryptococci in secretions mounted in Indian ink is helpful but negative results do not exclude active infection and weakly encapsulated yeast forms may resemble lymphocytes. The degree of encapsulation in CSF samples is unrelated to prior antifungal therapy or antigen titre 29 • Positive CSF Indian ink stains are found in approximately 75% cases of cryptococcal meningitis 4,9.11,12. CSF smears may remain persistently positive on Indian ink staining despite improvement in clinical status, falling antigen titres and negative CSF cultures and are, therefore, a poor guide to progress. Cryptococcus may be cultured from cerebrospinal fluid (CSF), blood, sputum, bronchial secretions, urine, skin or lung biopsies. Widespread dissemination of infection may occur and multiple sites may be culture positive. Cryptococci are usually grown on Sabouraud's agar at temperatures of 3O-35°C. Incubation periods up to 2 weeks may be necessary, particularly in partially treated cases. Following apparently successful treatment persistent cryptococcal infection of the prostate occurs in up to 29% of patients and mal be visualized in expressed prostatic secretions- suggesting that the prostate may be a sanctuary from which systemic relapse can occur. Chest radiographic features vary from normal, diffuse interstitial infiltrates, nodular/circumscribed infiltrates, pleural effusions, lobar consolidation and cavitation, and lymphadenopathy22,30- 2. Optimally, any patient with proven or suspected HIV infection and neurological dysfunction should undergo a computed tomographic (CT) or magnetic resonance (MR) scan to exclude an intracerebral lesion. However, this is not always feasible and perhaps a more practical approach is to scan all patients with AIDS or those previously asymptomatic with neurological signs. In patients with CNS cryptococcosis the CT scan is usually normal33,34. However, Popovich et aI.35 reported an incidence of cryptococcal intracerebral mass lesions of 11% in
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patients with cryptococcal meningitis. Infection may spread into the brain substance via perivascular spaces (Virchow-Robin spaces) producing multiple small cysts filled with organisms. Larger lesions may arise from aggregation of smaller lesions and are usually seen in the basal ganglia and thalamus. PROGNOSTIC INDICATORS
In HIV-infected patients prognostic indicators are not clearly elucidated. Chuck and Sande? reviewed the records of 106 patients with cryptococcal infection in AIDS and found that positive extrameningeal cultures and hyponatraemia were associated with poor survival. Abnormal head CT scan and altered mental state were indicative of poor prognosis in another large review of 68 patients with cryptococcal infection11. The prognostic value of serum antigen titres in patients with AIDS is doubt£ul9,11 because, as previously noted, occasional artificial elevations caused by defective elimination occur. Others, however, have suggested that titres > 1: 10,000 are associated with high mortality". In AIDS 17-37% of patients with cryptococcal meningitis die during induction therapy and onIl 18-30% survive for longer than 12 months4,5, 1 • Those patients with lowest CD4 counts may fare worst36. The first line of host defence is the alveolar macrophage and recent work with human monocytes and neutrophils has shown significant differences in monocyte killing between isolates, thou§h differences in neutrophil killing was less marked 7. Isolate variations may play an important role in pathogenesis of disease and ultimately response to treatment and further studies are required to answer these questions. TREATMENT
The treatment of cryptococcosishas been investigated intensively and has been the subject of several large multicentre studies to determine optimum drug combinations and length of therapy. The goals of treatment in AIDS patients with cryptococcosis differ from those in the non-immunocompromised. The primary objectives are to improve the patient's quality of life, and suppress relapses after initial primary treatment. Total eradication of the opportunistic infection is probably impossible. Bennet et al.38 showed that meningeal infection was best treated with a combination of amphotericin B (0.3 mg/kg/d) and flucytosine (150mg/kg/day) in the non-immunocompromised host. Both the higher failure rate among AIDS patients4,1l,39,40 and the relatively high toxicity of flucytosine in these patients means different regimens have been tried, and attention has been focused on other drugs or different formulations of these drugs. Dismukes et aI.41 showed that AIDS patients with cryptococcal meningitis benefited from 6 weeks treatment rather than 4 with amphotericin Band flucytosine.
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Many different dosages of amphotericin B have been used though dosages higher than the 0.3 mg/kg/day in the conventional combination regimen are required. Most investigators agree that dosages in the 0.5-0.8 mg/kg/day range are appropriate. Significant toxicity, particularly renal which occurs in 80% of patientsv, means that the intensity and duration of treatment may need to be limited, and the dose of amphotericin B has to be individually tailored. Most patients will require a total of at least 1-1.5 g as induction therapy". Intrathecal amphotericin B has no special benefit in cryptococcal meningitis and may cause arachnoiditis and myelitis. The use of flucytosine is contentious. A large retrospective study found no significant difference in survival between patients treated with amphotericin B alone and those treated with combination therapy". Flucytosine had to be discontinued in 53% of patients because of bone marrow toxicity, and the current dosage recommendation of 150 mg/kg/day is perhaps too high, and 75-100 mg/kg/day is more appropriatev. Serum concentrations of flucytosine, if used, should be maintained at 50-100 mg/I 44; marrow toxicity correlates with peak serum concentration. Liposomal encapsulation of amphotericin B reduces the renal toxicity and chills associated with conventional amphotericin B and, in contrast, may be given via a peripheral line without associated phlebitis. Results of trials are awaited for this new formulation but preliminary reports suggest it may be a useful advance45-48• The necessity for prolonged intravenous drug administration predisposes patients to the risk of nosocomial bacteraemia and indwelling intravenous catheters have been identified as a risk factor'". An orally administered alternative is, therefore, attractive. The first cure of C. neoformans meningitis with fluconazole was reported in 198f'50. It is a new orally administered triazole with a high degree of penetration into the CSF (unlike conventional or liposomal amphotericin B, itraconazole or ketoconazole) and other body compartments. Concentrations of fluconazole in the CSF are 60-80% of serum concentrations in the presence of both uninflamed and inflamed meninges51-53. The laboratory sensitivity of azole antifungal drugs is highly dependent on test conditions'S, and it is not unusual to obtain a minimum inhibitory concentration (MIC)for a responsive strain much higher than the concentration of drug attained in the patient. An adequate CSF concentration does not necessarily mean clinical response'", A randomized trial comparing fluconazole with amphotericin Band flucytosine showed the latter regimen has superior mycologic and clinical efficacy in AIDS-associated cryptococcal meningitis 36 • Fourteen patients received fluconazole (400mg/day) and 8 failed in contrast to none of 6 treated in the other arm with amphotericin B (O.7mg/kg/day for 7 days then 3 times per week) and flucytosine (l50mg/kg/day). CD4 counts were,
however, significantly lower in the fluconazole group. Interim analysis of a prospective, randomized study involving 99 patients comparing fluconazole (200 mgt day with the option of increasing to 400 mg/day) with amphotericin B (> 0.3 mg/kg/day three times per week) and flucytosine (150 mg/kg/day) found a similar response in both groups's. Optimal therapy in persistent prostatic infection in AIDS remain to be elucidated, though fluconazole at a dose of 200-600 mg daily in one study produced suppression of cryptococcuria in 50% of patients'". Itraconazole, another triazole, is well absorbed after oral administration and shows a high degree of protein binding and extensive distribution in tissues. Despite poor penetration into CSF, itraconazole is effective in the treatment of cryptococcalmeningitis'". Thirty-two patients with eryptococcosis(26with AIDS), including 24 with meningitis, were given 200 mg twice daily. Sixty-five per cent of assessable patients with meningitis responded completely with clinicalimprovement and negative cultures. High CSF concentrations are not, therefore, mandatory and perhaps itraconazole is found at high concentrations in the brain. Ketoconazole, an imidazole, is not recommended in the treatment of AIDS-associated cryptococcosis because it is poorly absorbed from the stomach, does not readily diffuse into the CSF59,60, and has poor activity in C. neoformans meningitis. Unlike in the immunocompetent patient with pulmonary cryptococcosis, AIDS patients with this manifestation probably always need treatment. The optimal treatment in these cases is uncertain but at present it is wise to treat patients in a similar fashion to those with meningitis. MAINTENANCE The rate of relapse after initial treatment of cryptococcal meningitis approaches 50-65%4,5.41. This means that lifelong maintenance treatment or suppressive therapy is necessary. Different approaches have been used in an effort to prevent relapse and achieve cure. A comparison study between fluconazole (200 mg/day) and amphotericin B (1 mg/kg/week) as maintenance therapy showed that of 183 evaluable patients, 2 of 106 taking fluconazole relapsed, compared with 13 of 77 receiving amphotericin 8 56• Denning et al. 58 reported suppression of disease with itraconazole (400 mg/day) in 10 of 15 patients with meningitis. Other small studies show similar results 61,62.
PROPHYLAXIS The Widespread use of azole drugs in AIDS, particularly either for treatment or prophylaxis of oral candidosis, does not appear to convey complete protection in preventing the development of cryptococcal meningitis63,64 . A recent open label study comparing primary prophylaxis with fluconazole with historical controls, however, showed a reduction in the incidence of systemic fungal infections including cryptococcosise''.
Coker.
CONCLUSION
Cryptococcal meningitis is the most common serious fungal infection in AIDS patients and is associated with a high mortality. Diagnosis is generally straightforward but may be delayed because clinical features are often muted. There are still many unanswered questions concerning the pathogenesis of this disease. Treatment, both induction and maintenance, is still unsatisfactory; however further clinicalstudies using the azoles and newer liposomal formulations of amphotericin Bmay help solve some of the unanswered questions. Prophylaxis, unlike for other opportunist infections, does not appear to convey protection.
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(Accepted 8 January 1992)
