Cerebrospinal Fluid Cryptococcal Antigen Research Articles

Cutaneous Cryptococcus Infection and AIDS

Cryptococcal infections occur in 6% to 13% of patients with acquired immunodeficiency syndrome (AIDS), most commonly infecting the central nervous system. Cutaneous lesions have been described morphologically as umbilicated papules, nodules, and violaceous plaques and can mimic molluscum contagiosum and Kaposi's sarcoma. Cutaneous lesions can present months prior to other signs of systemic infection. Cases of infection with cutaneous Cryptococcus and AIDS were reviewed and compared with cases reported in the literature. Among patients with Cryptococcus infection and AIDS seen at our institutions, 5.9% had skin lesions. All patients with cutaneous lesions had systemic involvement. Women were less commonly infected than men. There was no apparent predisposition associated with age, race, or human immunodeficiency virus infection risk factors. The median CD4 helper T-cell count was 0.024 X 10(9)/L (24/microL), and 44% (16/36) of the patients had previous opportunistic infections. Lesions were most commonly seen on the head and neck (78% [36/46]) and often mimicked molluscum contagiosum (54% [25/46]). The median serum and cerebrospinal fluid cryptococcal antigen titers were 1:32,768 and 1:512, respectively. Patients in our group did well with therapy (one death at 6 weeks, compared with 38% [13/34] mortality in the literature). There was no correlation between onset of lesions, number of lesions, CD4 helper T-cell count, or histopathologic characteristics. Disseminated Cryptococcus infection in AIDS presents with cutaneous lesions in up to 6% of cases. Clinicians need to be aware of the varied morphologic characteristics, since cutaneous lesions may present well in advance of other signs of systemic infection.

High-Dose Fluconazole Therapy for Cryptococcal Meningitis in Patients with AIDS

Fluconazole (800-1,000 mg i.v.) was administered to 14 consecutive patients with AIDS and cryptococcal meningitis. At 10 weeks the rate of clinical success was 54.5% (six of 11 patients responded to fluconazole); the Kaplan-Meier estimate of the response rate was 67.1%, and the overall mortality rate was 18.2% (two of 11 patients died). At the end of treatment, eight (72.7%) of 11 patients responded to fluconazole. The median time to the first negative cerebrospinal fluid (CSF) culture was 33.5 days (95% confidence interval, 18.3-67.3); the median time for patients with initial CSF cryptococcal antigen titers of > or = 1:1,024 was 66 days compared with 18 days for patients with initial CSF cryptococcal antigen titers of < 1:1,024 (P = .06). The median time to the first negative CSF culture for patients with an isolate for which the minimum inhibitory concentration (MIC) was 4 micrograms/mL was 56 days compared with 16 days for patients with an isolate for which the MIC was < 4 micrograms/mL (P = .11). The mean serum and CSF levels of fluconazole at steady state were 42.47 +/- 26.31 micrograms/mL and 36.63 +/- 21.08 micrograms/mL, respectively (ratio of CSF:serum, 0.86). No treatment was interrupted and no dose was tapered because of side effects. High-dose fluconazole might be an effective and well-tolerated therapeutic option for patients with AIDS and acute cryptococcal meningitis.

Initial Therapy for Acquired Immunodeficiency Syndrome-Associated Cryptococcosis With Fluconazole

Published opinion has generally favored amphotericin B over fluconazole as initial therapy for acquired immunodeficiency syndrome-associated cryptococcosis, although data that support this recommendation are limited. Retrospective review of 30 consecutive patients with acquired immunodeficiency syndrome-associated cryptococcosis seen at a single institution over a 1-year period and given fluconazole, 400 mg/d, as initial therapy. No patient died within the first 30 days of therapy, and none of the 14 patients who died within 1 year had clinically detectable infection when last seen or at death. Pretreatment blood cultures were positive in 26 of 27 patients; cerebrospinal fluid cryptococcal antigen titer was greater than 1:1024 in 12 of 23 patients; and five of 30 patients presented with altered mental status. The median CD4 count at diagnosis was 0.042 x 10(9)/L (42/microL). Eight of 25 patients who were followed up for more than 30 days relapsed, as evidenced by a positive culture; all relapses were successfully treated with fluconazole, either by reinstitution of therapy or by increase of dosage. This experience supports the use of fluconazole as initial therapy for acquired immunodeficiency syndrome-associated cryptococcosis.

Initial therapy for acquired immunodeficiency syndrome-associated cryptococcosis with fluconazole

<h3>Background:</h3> Published opinion has generally favored amphotericin B over fluconazole as initial therapy for acquired immunodeficiency syndrome—associated cryptococcosis, although data that support this recommendation are limited. <h3>Method:</h3> Retrospective review of 30 consecutive patients with acquired immunodeficiency syndrome— associated cryptococcosis seen at a single institution over a 1-year period and given fluconazole, 400 mg/d, as initial therapy. <h3>Results:</h3> No patient died within the first 30 days of therapy, and none of the 14 patients who died within 1 year had clinically detectable infection when last seen or at death. Pretreatment blood cultures were positive in 26 of 27 patients; cerebrospinal fluid cryptococcal antigen titer was greater than 1:1024 in 12 of 23 patients; and five of 30 patients presented with altered mental status. The median CD4 count at diagnosis was 0.042 ×10⁹/L (42/μL). Eight of 25 patients who were followed up for more than 30 days relapsed, as evidenced by a positive culture; all relapses were successfully treated with fluconazole, either by reinstitution of therapy or by increase of dosage. <h3>Conclusion:</h3> This experience supports the use of fluconazole as initial therapy for acquired immunodeficiency syndrome—associated cryptococcosis. (Arch Intern Med. 1995;155:538-540)

Cryptococcal Disease of the CNS in Immunocompetent Hosts: Influence of Cryptococcal Variety on Clinical Manifestations and Outcome

We performed a retrospective review of cases of cerebral cryptococcosis among patients admitted to 12 Australian teaching hospitals between 1985 and 1992. Of 118 cases identified, 35 occurred in immunocompetent hosts. When cases due to Cryptococcus neoformans variety neoformans were compared with those due to Cryptococcus neoformans variety gattii, we found that the latter tended to occur in healthy hosts whose residence or job was located in a rural area, and cerebral mass lesions and/or hydrocephalus and pulmonary mass lesions were more common. For a subgroup of patients with infection due to C. neoformans variety gattii, multiple enhancing lesions were observed on cerebral computed tomograms, and papilledema, high CSF and serum cryptococcal antigen titers, and a worse prognosis (despite prolonged amphotericin B therapy and intraventricular shunt insertion) were also noted. No significant difference in clinical course or outcome in terms of variety of C. neoformans was noted for patients with cryptococcal meningitis whose computed tomographic scans appeared normal on presentation.

Production of the hexitol D-mannitol by Cryptococcus neoformans in vitro and in rabbits with experimental meningitis

We studied the ability of Cryptococcus neoformans to produce the hexitol D-mannitol in vitro and in rabbits with experimental meningitis. Twelve of twelve human isolates of C. neoformans produced D-mannitol in yeast nitrogen base plus 1% glucose and released D-mannitol into the medium. In a pilot study, pooled cerebrospinal fluid (CSF) from cortisone-treated rabbits given 3 x 10(7) C. neoformans H99 intracisternally contained more D-mannitol (identified by gas chromatography and enzymatically) than CSF from normal controls or cortisone-untreated rabbits with self-limited meningitis. In a second experiment, cortisone-treated rabbits given C. neoformans intracisternally had significantly higher CSF D-mannitol concentrations than controls given cortisone alone at 4, 6, and 8 days after infection. Moreover, log10 CSF D-mannitol correlated well with log10 CSF CFU (r = 0.81) and log10 CSF cryptococcal antigen titers (r = 0.78). Lastly, the initial volume of distribution and elimination half-life of D-mannitol given intracisternally to normal rabbits suggested that D-mannitol was distributed in total CSF and was removed by CSF bulk flow. Thus, C. neoformans produces D-mannitol in vitro and in vivo, and D-mannitol is a quantitative marker for experimental cryptococcal meningitis. D-Mannitol produced by C. neoformans may also contribute to brain edema and interfere with phagocyte killing by scavenging hydroxyl radicals.

Cerebrospinal Fluid (CSF) TRAP: A Method to Improve CSF Laboratory Efficiency

Establishment of a procedure termed cerebrospinal fluid (CSF) TRAP ("Transport and Rapid Accessioning for Additional Procedures") allows clinicians to appropriately store, at -75 degrees C, and rapidly access CSF specimens. The CSF TRAP enhances patient care by decreasing the need for repeat lumbar punctures and providing reserve fluid for the following: (1) further CSF testing; (2) repeating questionable test results; and (3) laboratory accidents. The CSF TRAP has been approved for third-party payment because it promotes efficient laboratory utilization by encouraging clinicians to review initial CSF findings before ordering low-yield CSF assays such as the venereal disease research laboratory (VDRL) and cryptococcal antigen latex agglutination tests. Currently, CSF TRAP samples are being obtained with 40% of all CSF acquisitions at the Duke University Medical Center. The availability of the CSF TRAP was associated with a significant decrease in the ordering of CSF VDRL and cryptococcal antigen assays (P less than 0.05); however, there was no significant change in the proportion of those studies being performed on normal CSF. The CSF TRAP procedure provides the framework for an overall restructuring of CSF testing that is being investigated.

Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients

Cryptococcus neoformans causes infections in up to 10 percent of patients with the acquired immunodeficiency syndrome (AIDS). Nearly 50 percent of AIDS patients with previously treated cryptococcal meningitis will experience a relapse within six months. To reduce the likelihood of relapse, a maintenance regimen of amphotericin B is often administered weekly. However, the drug's intravenous route of administration and considerable toxicity have led to a search for alternative antifungal agents. In this report, we document our experience with fluconazole, a new oral triazole antifungal agent. Twenty-two patients with AIDS and various forms of cryptococcosis were treated in an open-label study with 50 to 400 mg/day of fluconazole. The following laboratory studies were done on a monthly basis: complete blood cell count, liver function tests, serum creatinine level, serum cryptococcal antigen level, and serum fluconazole level. Lumbar puncture was performed in patients with meningitis every four to eight weeks to evaluate cerebrospinal fluid cryptococcal antigen, India ink preparation findings, fungal culture, fluconazole level, and protein, glucose, and cell count. Of seven patients with active culture-positive infections, four showed clinical and microbiologic responses (three of four with meningitis, one of three with extraneural cryptococcosis). Fifteen patients who had already undergone successful amphotericin B therapy for either meningitis (n = 14) or pneumonia (n = 1) received fluconazole as prophylaxis against relapse. Fourteen patients remained free of infection during 11 to 64 weeks of suppressive therapy; one patient with meningitis experienced relapse after 26 weeks of treatment. Reverse reactions were limited to increases in hepatic enzyme levels in four patients. These results appear sufficiently encouraging to warrant further trials of this oral agent in the suppression of chronic cryptococcosis and perhaps in the treatment of acute infection.

Cryptococcal meningitis in patients with AIDS.

The Cryptococcus has become a major cause of meningitis in patients infected with the human immunodeficiency virus (HIV), and the expression of cryptococcal infection in this population of patients is quite unique. Often the infection is devoid of inflammatory response and is associated with very high antigen and fungal titers. Response to amphotericin therapy is erratic, and relapse is common. We have asked Dr. William E. Dismukes, principal investigator of the NIAID Mycoses Study Group, to discuss the following clinical questions: When and how does cryptococcal infection in HIV-infected patients present? How does it differ in HIV-infected and non-HIV-infected individuals? How is the diagnosis established? What is the sensitivity of the CSF cryptococcal antigen test? Is the serum antigen test of any value? What is the best way to treat patients--the recommended drugs, dosages, and duration of therapy? Is maintenance therapy necessary, and finally, what drugs are available for it? [Please note that an AIDS training program is now available for members of the Infectious Diseases Society of America and that details of this program appear in the Notices section of this Journal issue (pages 859-60).]

The clinical laboratory evaluation of cryptococcal infections in the acquired immunodeficiency syndrome.

The medical and laboratory records were reviewed in 37 acquired immunodeficiency syndrome (AIDS) patients with cryptococcal infections. In 24 patients with the presentation of cryptococcal meningitis, the initial cerebrospinal fluid (CSF) culture was positive. The initial India ink mount demonstrated organisms in 79% of culture positive CSF specimens. After therapy the subsequent India ink mounts demonstrated 84% sensitivity and 53% specificity with respect to culture outcome. Cultures of blood, bronchoalveolar lavage fluid, and brain were more likely to be positive than cultures from other sites. The initial blood cultures were positive in eight of eight patients at presentation of cryptococcal meningitis. When the initial CSF titer was greater than 1:2, the corresponding CSF culture was always positive. A negative culture during therapy did not necessarily indicate eradication of infection. The initial cerebrospinal fluid and serum cryptococcal antigen titers varied significantly and could not be correlated with survival. In three instances when the CSF cryptococcal antigen titers and cultures were negative, a positive serum cryptococcal antigen greater than 1:8 suggested disseminated infection.

Intraventricular therapy of cryptococcal meningitis via a subcutaneous reservoir

Intraventricular administration of amphotericin B for meningitis due to Cryptococcus neoformans is usually reserved for selected, seriously ill patients with recurrent disease. Between September 1973 and November 1983, 10 of 23 patients treated for cryptococcal meningitis at Memorial Sloan-Kettering Cancer Center received intraventricular amphotericin B through subcutaneous reservoirs, in addition to systemic therapy. The value of intraventricular amphotericin B was assessed in the 13 patients treated for first episodes of meningitis with systemic amphotericin B and flucytosine. Death during therapy occurred in one of six patients with intraventricular and systemic therapy compared with six of seven patients with systemic therapy alone (p = 0.025). The cerebrospinal fluid was sterilized in six of six patients given systemic and intraventricular therapy compared with three of seven given systemic therapy alone (p = 0.049), and the cerebrospinal fluid cryptococcal antigen titer declined in six of six patients given systemic and intraventricular therapy compared with two of seven given systemic therapy alone (p = 0.016). In the 10 patients who received intraventricular therapy, there were no complications related to reservoir insertion; however, complications related to reservoir use requiring replacement or revision occurred in two patients, and bacterial infection occurred in one but was treated successfully without removal of the reservoir. Although these data are retrospective, they suggest that early therapy with intraventricular amphotericin B in combination with systemic therapy may be beneficial and relatively safe in patients with cryptococcal meningitis and a poor prognosis.

Prognostic Factors in Cryptococcal Meningitis

Results of amphotericin B therapy were correlated with laboratory and clinical findings in 111 patients with cryptococcal meningitis. Compared with patients who were to be cured, patients who were to die during therapy more often had the following features on admission: lymphoreticular malignancy or corticosteroid therapy; cerebrospinal fluid with high opening pressure, a low glucose level, less than 20 leukocytes/mm3 and cryptococci seen in smear; cryptococci isolated from extraneural sites; and high titers of cryptococcal antigen in cerebrospinal fluid and serum. These last two features also characterized admission findings in the group of patients who were to be discharged with negative cultures after therapy but who later relapsed. Patients who were to relapse also had high, persistent posttreatment titers of cryptococcal antigen in serum or cerebrospinal fluid.