Cryptococcal Antigen Titer Research Articles

Early Mycological Treatment Failure in AIDS‐Associated Cryptococcal Meningitis

Cryptococcal meningitis causes significant morbidity and mortality in persons with AIDS. Of 236 AIDS patients treated with amphotericin B plus flucytosine, 29 (12%) died within 2 weeks and 62 (26%) died before 10 weeks. Just 129 (55%) of 236 patients were alive with negative cerebrospinal fluid (CSF) cultures at 10 weeks. Multivariate analyses identified that titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, together with dose of amphotericin B, had the strongest joint association with failure to achieve negative CSF cultures by day 14. Among patients with similar CSF cryptococcal antigen titers, CD4 cell counts, and serum albumin levels, the odds of failure at week 10 for those without negative CSF cultures by day 14 was five times that for those with negative CSF cultures by day 14 (odds ratio, 5.0; 95% confidence interval, 2.2-10.9). Prognosis is dismal for patients with AIDS-related cryptococcal meningitis. Multivariate analyses identified three components that, along with initial treatment, have the strongest joint association with early outcome. Clearly, more effective initial therapy and patient management strategies that address immune function and nutritional status are needed to improve outcomes of this disease.

Disseminated Cryptococcosis Associated With Adrenal Masses andInsufficiency

A case of primary adrenal insufficiency with bilateral adrenal masses and meningitis due to disseminated cryptococcosis in a patient with mild non-insulin-dependent diabetes is presented. The diagnosis was made by fine-needle aspiration biopsy cytology. Although the meningitis responded to antifungal therapy, the bilateral adrenal gland enlargement did not change. Reflecting this, cryptococcal antigen titers became negative in CSF, but fell to 1:8 in serum. Although antifungal therapy continued, cryptococcal antigen titer increased both in CSF and serum for 50 days. Because the adrenal glands were the apparent focus for the persistent fungemia, bilateral adrenalectomy was performed. Antifungal therapy for an additional 15 months was needed to achieve negative serum cryptococcal antigen titers. Although adrenal insufficiency due to disseminated cryptococcosis is rare in healthy hosts, it should be included in differential diagnosis of unilateral and bilateral adrenal masses.

Severe mycosis-factors with fungus and host

The deep-seated mycosis occurred in immunocompromized patients. Normally, the deep-seated mycosis became sever infection because of the defects of host defense or the adverse effects of antifungal agents. The major factors of the reason on the severity of the deep-seated mycosis depends on the pathogenesity and the drug resistance for antifungal agents in infected fungi. The clinical factors related with hosts defenses are important to the other reason on the severity. We investigated that the multiple drug resistant (MDR) mechanism may be one of the major roles plays in the azole resistant Candida albicans strains isolated form the patients with oropharyngeal candidiasis infected HIV. We analyzed which clinical factors are related with the prognosis of the patients with pulmonary cryptococcosis and aspergilloma. The titer of cryptococcal capsular antigen was earlier improve in the patient without underline disease than in the patients with underline diseases diagnosed pulmonary cryptococcosis. CRP was higher in the death cases in the patients with pulmonary aspergilloma, compared with alive cases.

原発性肺クリプトコックス症に対するfluconazoleによる治療の検討

We treated two cases of primary pulmonary cryptococcosis with fluconazole (FLCZ), the clinical usefulness of FLCZ was evaluated. FLCZ was administered orally in doses of 300 mg daily for about six months. Concentrations of FLCZ were measured in the serum of the two cases and in the bronchoalveolar lavage (BAL) fluid in one case. The following results were obtained: 1. Clinical cures were obtained in the two cases. 2. The serum levels of FLCZ was 15.1 microliters/ml, 13.6 micrograms/ml two hours after administration of 100 mg in case 1, that of levels were 11.1 micrograms/ml, 8.9 micrograms/ml one hour and 4.5 hours, respectively, after administration of 100 mg in case 2. BAL was performed 4.5 hours after administration of 100 mg in case 2, the BAL fluid level of FLCZ was 0.7 microgram/ml. 3. The minimal inhibitory concentration of FLCZ against one strain obtained from the cytology brush in case 1 was 4.0 micrograms/ml. 4. The cryptococcal antigen titer decreased with the improvement of clinical signs and the resolution of chest X-ray abnormalities within about six months, and there was no relapse. From these results, we consider that FLCZ is a useful antifungal agent for primary pulmonary cryptococcosis, and we therefore recommend a six month treatment.

Cytokine Profiles in Cerebrospinal Fluid of Human Immunodeficiency Virus ‐Infected Patients with Cryptococcal Meningitis: No Leukocytosis despite High Interleukin‐8 Levels

Cytokine levels were studied in the cerebrospinal fluid (CSF) of 16 adults with cryptococcal meningitis (CM). Low levels of tumor necrosis factor (TNF)-alpha and interferon-gamma, high levels of interleukin (IL)-1beta, IL-6, and IL-8, and the presence of IL-10 were documented. There were no significant differences in levels of TNF-alpha and interferon-gamma for CM and control patients. Mean CSF levels of IL-1beta (139.5 pg/mL), IL-6 (346 pg/mL), IL-8 (1160 pg/mL), and IL-10 (9.27 pg/mL) were significantly (P < .01) elevated in CM patients compared with levels in control patients. Despite the high CSF levels of IL-8, minimal leukocytosis was seen. Significant correlations between cryptococcal antigen titers and IL-10 levels (r = .8, P < .05), protein and cryptococcal antigen titer (r = .9, P < .05), and protein and IL-10 levels (r = .8, P < .05) were found.

Cryptococcal infection in cats: factors influencing treatment outcome, and results of sequential serum antigen titers in 35 cats.

The relationship between treatment outcome and location of cryptococcal infection, gender, magnitude of pretreatment cryptococcal antigen titers, results of feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) serology, and serial changes in antigen titers during and after treatment were evaluated in a prospective and nonrandomized study of 35 cats with cryptococcosis. A commercial cryptococcal latex agglutination kit (CALAS; Meridian Diagnostic Inc, Cincinnati, OH) was used to detect cryptococcal antigen in sera. All cats were treated with itraconazole (Sporanox; Janssen Pharmaceutica Inc, Titusville, NJ). Pretreatment mean log titers for serum cryptococcal antigen were not influenced by location of the infection. Treatment outcome was not influenced by gender, location of the infection, or magnitude of pretreatment serum antigen titer. Treatment outcome was influenced by FeLV and FIV status; cats seropositive for FeLV or FIV had a higher likelihood of treatment failure (P = .008). The cryptococcal antigen titers of cats successfully treated decreased with significant linearity over time during treatment (r = -.64, P < .000001), whereas the corresponding titers for cats not treated successfully did not decrease with significant linearity (r = -.03, P > .9). For cats in which treatment was successful, antigen titers decreased significantly from pretreatment values by 1.3 orders of magnitude at 2 months after initiation of treatment. By 10 months after initiating treatment, log titers decreased by at least 2 orders of magnitude in all cats successfully treated, and 9 of 16 cats had undetectable titers. In contrast, in 5 of 6 cats in which treatment failed, antigen titers were unchanged or increased in magnitude even after at least 6 months of treatment.

Visual loss in immunocompetent patients with Cryptococcus neoformans var. gattii meningitis

In Papua New Guinea cryptococcal meningitis occurs predominantly in immunocompetent patients in whom Cryptococcus neoformans var. gattii is implicated in 95% of cases. Ocular complications are common. We have reviewed ophthalmic findings in 82 immunocompetent patients and have attempted to identify those features of the disease that predict an unfavourable visual outcome. Visual loss occurred in 52·6% of survivors and was associated with optic atrophy following optic disc swelling in 60·9%. Progression of disc swelling to optic atrophy was predicted by the presence of an abducens palsy ( P = 0·049) and cerebrospinal fluid (CSF) cryptococcal antigen titres >;1:1024 ( P = 0·036). Raised intracranial pressure (defined as opening CSF pressure ≥300 mm on admission) was not associated with visual loss. Vision deteriorated in 17·3% of patients despite anticryptococcal therapy and in 3·7% it followed curative therapy. The high rate of visual loss in immunocompetent patients with C. neoformans var. gattii infection contrasts with others' experience of immunosuppressed patients with C. neoformans var. neoformans infection, in whom visual loss was rare. This difference may reflect immune mediated optic nerve dysfunction in C. neoformans var. gattii meningitis caused by either compression due to arachnoid adhesions or oedema and inflammatory cell-mediated damage.

Clinical and serologic evaluation of cats with cryptococcosis

Objective To evaluate the long-term clinical outcomes and serologic changes in cryptococcal antigen and antibody titers in cats with confirmed Cryptococcus neoformans infection. Design Prospective case series. Animals 47 cats with cryptococcosis. Procedure Cats included in this study were determined to have cryptococcosis on the basis of identification of C neoformans on histologic or cytologic examination, isolation of C neoformans in culture, or positive serologic test results for cryptococcal antigens. Information concerning the signalment, history, physical examination findings, FeLV and feline immunodeficiency virus status, serologic testing, treatment, and outcome for each cat was requested on a survey form. Follow-up measurements of serum cryptococcal antigen and antibody titers were requested for all surviving cats. Results Signalment and clinical signs of cats with cryptococcosis reported here were consistent with previous reports. Treatment consisted primarily of azole antifungal drugs. All cats were seronegative for cryptococcal antibodly titers, whether tested initially or at follow-up examination. All but 1 cat tested were seropositive for cryptococeal antigens when initially tested. Cats with and without clinical signs of C neoformans infection were seropositive for cryptococcal antigens months to years after initial diagnosis of cryptococcosis. Clinical Implications The results of this study indicate that serum titers to cryptococcal antigens in cats can persist with or without clinical signs for months to years after an initial diagnosis of cryptococcosis is made. Repeated evaluation of serum cryptococcal antigen titers is advised during the treatment of cats to monitor progress, evaluate prognosis, and guide cessation of treatment. (J Am Vet Med Assoc 1996;209:1110-1113)

Predictors of outcome in Cryptococcus neoformans var. gattii meningitis.

In Papua New Guinea, Cryptococcus neoformans var. gattii meningitis has a high fatality rate even in immunocompetent patients. Our retrospective study attempted to identify marker of poor prognosis. Of 88 immunocompetent patients, 30 (34.1%) died, usually soon after admission, and mortality was higher in men (p = 0.025) and older patients (p = 0.039). Death was associated with altered consciousness (p < 0.001), a history of convulsions prior to treatment (p = 0.002) and a maximum systolic blood pressure of > 150 mmHg (p = 0.017). These data suggest that death results from raised intracranial pressure and subsequent tentorial herniation. However, CSF opening pressure measured on admission was raised in 29/36 (81%) patients and did not predict outcome. In survivors, relapse was uncommon and was not predicted by discharge serum cryptococcal antigen titres, which were frequently raised on completion of therapy in asymptomatic patients. Mortality may be reduced if efforts are made to lower intracranial pressure in those patients who present with markers of poor prognosis.

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.

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.

D-mannitol in cerebrospinal fluid of patients with AIDS and cryptococcal meningitis.

Cryptococcal meningitis (CM) is associated with raised intracranial pressure which is linked with serious neurological sequelae. Cryptococcus neoformans produces D-mannitol in vitro and in experimental meningitis in rabbits. Mannitol present in the cerebrospinal fluid (CSF) of CM patients could exacerbate raised intracranial pressure and contribute to neurological damage. To link CSF mannitol to cryptococcal infection, levels of mannitol in the CSF of AIDS patients with CM were measured by gas-liquid chromatography. Mannitol was detected in 19 of 21 samples (range, 1.5 to 26.2 mg/liter), but there was no quantitative correlation between the mannitol concentration and the cryptococcal antigen titer.

Pulmonary Cryptococcosis: Localized and Disseminated Infections in 27 Patients with AIDS

We reviewed the records of 85 patients infected with both human immunodeficiency virus and Cryptococcus neoformans. Twenty-seven patients (32%) had pulmonary cryptococcosis. C. neoformans was cultured from bronchoalveolar lavage (BAL) or pleural fluid in 25 cases; the remaining two patients had cryptococcal antigen (CA) detected in BAL fluid and C. neoformans cultured from other sites. All but one of the 27 patients had detectable CA in serum. The CD4+ lymphocyte count was low in all cases (median, 24/mm3). Clinical manifestations of pulmonary cryptococcosis included fever (94%), cough (71%), dyspnea (7%), expectoration (4%), chest pain (2%), and hemoptysis (1%). Diffuse interstitial opacities (70.5%), focal interstitial abnormalities, alveolar opacities, adenopathies, cavitary lesions, and pleural effusions were evident. Outcome was poor (mean survival time, 23 weeks) despite treatment. Patients with localized pulmonary cryptococcosis appeared to have a higher CD4+ lymphocyte count, an earlier diagnosis, lower serum CA titers, fewer previous or concomitant infections, and a better prognosis than patients with disseminated cryptococcosis.

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)

Intravascular cryptococcal culture filtrate (CneF) and its major component, glucuronoxylomannan, are potent inhibitors of leukocyte accumulation

Disseminated cryptococcosis is characterized by high titers of cryptococcal polysaccharides in serum and minimal cellular infiltrates in infected tissues of patients. The main objective of this study was to determine whether the circulating cryptococcal polysaccharides could contribute to the lack of cellular infiltration into infected tissues. To assess this possibility, a gelatin sponge implantation model was used. We found that intravenous (i.v.) injection of mice with cryptococcal culture filtrate antigen (CneF) inhibited migration of leukocytes (neutrophils, lymphocytes, and monocytes) into the intrasponge sites of acute inflammation induced by CneF, tumor necrosis factor alpha, or formylmethionyl leucyl phenylalanine. In addition, i.v. administration of CneF inhibited leukocyte migration into the intrasponge sites of a cell-mediated immune reaction irrespective of whether the delayed-type hypersensitivity response was to CneF or the mycobacterial antigen purified protein derivative. Glucuronoxylomannan, a major constituent of CneF and a major cryptococcal antigen detected in the sera of patients with disseminated cryptococcosis, when given i.v. to mice, inhibited leukocyte migration into the sponges. Our results suggest that the minimal cellular infiltrates observed in infected tissues of cryptococcosis patients may be due, in part, to the circulating cryptococcal polysaccharide functioning as we have demonstrated in the mouse model. Furthermore, the high titers of cryptococcal antigen in the sera of patients may diminish leukocyte migration in response to stimuli other than Cryptococcus neoformans, a point that may be relevant in AIDS patients with cryptococcosis.

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.

Cryptococcus infection of the hand

A 67-year-old, insulin-dependent diabetic woman developed acute renal failure and hemolytic uremic syndrome. As treatment for the hemolytic uremic syndrome, she was managed initially with plasmapheresis and steroids. She subsequently went on to develop end-stage renal disease. She underwent hemodialysis after the placement of a synthetic arteriovenous fistula in the left forearm. Several months after fistula placement, she developed left hand edema and abscess formation that was unresponsive to multiple antibiotics. The lesions were drained and cultured at an outside institution. Bacterial cultures were negative, but fungal cultures revealed Cryptococcus neoformans. Human immunodeficiency virus test results were negative. She was started on fluconazole and later switched to amphotericin B. After transfer to our institution, serum cryptococcal antigen titer was 1: 256. New pustules developed while the patient was taking amphotericin-B, and 5-flucytosine was added to the regimen. Erythema and induration of the left hand were present (Fig. 1). Open drainage was performed on two occasions 2 months later, and thick. tenacious fluid was re-

High detection rates of cryptococcal antigen in pulmonary cryptococcosis by Eiken Latex Agglutination test with pronase pretreatment

Two different kits for the detection of serum cryptococcal antigen in patients with pulmonary cryptococcosis were evaluated. The Eiken test (the Eiken Co., Tokyo), which uses pronase for pretreatment of serum, was compared with the Crypto-LA test (International Biological Laboratories, Cranbury, NJ), which did not use pronase prior to testing. Cryptococcal antigen was detected in 21 of 23 patients (91%) with the Eiken test and in only 10 of 23 patients (43%) with the Crypto-LA test (p < 0.01 by McNemar test). However, the sensitivity of two tests was identical without use of pronase, as both tests could detect as little as 10(4) cells/ml of Cryptococcus neoformans and 10 ng/ml of capsular polysaccharide of C. neoformans. In those serum specimens for which both tests were positive, titers were much higher for the Eiken test, but there was a statistically significant correlation between the two tests (coefficient correlation 0.79, p < 0.01). Cryptococcal antigen titer levels measured by the Eiken test correlated well with clinical courses. There was one false-positive reaction among 82 sera of non-cryptococcal patients. Pronase enhanced the sensitivity of the Eiken test, which appeared to be useful in patients with pulmonary cryptococcal disease, and its use may prevent unneeded lung biopsies.

Evidence for interference by immune complexes in the serodiagnosis of cryptococcosis.

The latex agglutination test was used to compare cryptococcal antigen titers before and after protease treatment in 19 patients with pulmonary cryptococcosis. Antigen was detected by the LA test in 13 of 33 serum samples before protease treatment, and in an additional 13 samples following treatment. Of 26 antigen-positive serum samples, 22 (84.6%) showed an increased antigen titer after protease treatment. Using the cell slide agglutination test, antibody was detected in 3 of 19 cases. In one of these 3, antigen could only be detected after protease treatment. Soluble immune complex was prepared in vitro using anti-C. neoformans rabbit antiserum and polysaccharide antigen of C. neoformans, and the effects of immune complexes on the LA test were examined. In this experimental model, soluble immune complexes seemed to be observed in antibody excess region, because the antigen titers were increased after the protease treatment. We concluded that C. neoformans capsular polysaccharide antigen and anti-C. neoformans antibody formed soluble immune complexes in patients' sera, which interfered with antigen detection by the latex agglutination test without protease treatment.