Cerebrospinal fluid Coccidioides antigen testing in the diagnosis and management of central nervous system coccidioidomycosis.

The goal of this study was to report on the potential utility of cerebrospinal fluid (CSF) Coccidioides antigen testing in the diagnosis and management of Coccidioides meningitis. We retrospectively reviewed medical records of seven patients with Coccidioides meningitis who had Coccidioides antigen tests performed on CSF. In two severely immunocompromised patients, CSF Coccidioides antigen testing was helpful in the diagnosis when other testing modalities were negative. Coccidioides antigen testing was also useful in the management of patients who had progression of disease due to non-adherence, development of resistance, failure of therapy and the presence of vasculitis. Changing antigen levels helped identify disease complications in three patients that led to alterations in therapy or management. On the basis of our review of these seven patients with Coccidioides meningitis, we concluded that the Coccidioides antigen test contributed to the diagnosis and management of patients with Coccidioides meningitis.

A new method for the treatment of chronic fungal meningitis: continuous infusion into the cerebrospinal fluid for coccidioidal meningitis.

Coccidioidal meningitis is a lethal disease, and current therapy is not curative or is burdened with serious toxicities and logistic difficulties. In a patient with refractory disease, continuous infusion amphotericin B therapy was given via a programmable implanted pump into the cisternal subarachnoid space. The patient progressively responded, evidenced clinically and by laboratory studies. Drug delivery issues were addressed during this course that could guide future use of this modality, which is a promising novel avenue of therapy for chronic meningitis.

Trending serial CSF samples to guide treatment of refractory coccidioidal meningitis with intrathecal liposomal amphotericin.

Intrathecal amphotericin B deoxycholate (AmB-d) can be prescribed as an adjunct to systemic therapy for severe or recalcitrant cases coccidioidal meningitis. Recently intravenous (IV) Liposomal amphotericin B (L-AmB) has been recommended as monotherapy therapy for refractory coccidioidal meningitis based on its advantages over (AmB-d), however, its intrathecal use has not been reported. Moreover, there is nothing in the literature quantifying clinical improvement with objective laboratory data in human patients. Consequently, there are no guidelines on how to monitor regularly for improvement of coccidioidal meningitis with treatment of intrathecal L-AmB. The present case addresses both of these. We report intrathecal use of L-AmB for refractory coccidioidal meningitis. Our data demonstrate that there is a correlation between clinical improvement and a decrease in cerebrospinal fluid (CSF) white blood cells (WBC's), protein, and coccidioidal titers with treatment of intrathecal L-AmB with serial collection of CSF studies at the same site, in our case via collection through an external ventricular drain (EVD). As a result, one may postulate that serial CSF collection can be used to monitor the treatment of coccidioidal meningitis; however this case also addresses the risk of developing ventriculitis with sustained EVD placement.

Eosinophilia in coccidioidomycosis.

Eosinophilia as a manifestation of coccidioidomycosis may be found in blood or cerebrospinal fluid. We report on a case of coccidioidomycosis with pleurisy, skin lesions, and meningitis with concomitant striking eosinophilia in both blood and cerebrospinal fluid that resolved promptly after amphotericin B therapy was started.

Treatment of fungal meningitis with miconazole.

Twelve patients with fungal meningitis (ten cases were due to Coccidioides immitis, two were from Cryptococcus neoformans) were treated with brief courses of intravenous (IV) miconazole. Eleven patients, including patients with severe, chronic disease, had been treated unsuccessfully with amphotericin B. Four patients also received miconazole injected directly into the CSF. The drug was well tolerated by any route, with mild reversible side effects. After IV administration the miconazole concentration in the CSF rarely exceeded the minimal inhibitory concentration (MIC) of the infecting organism. Intra-CSF administration of 20 mg generally produced levels above the MIC for 24 hours. Five of ten patients with coccidiodial meningitis responded clinically. Of these five, four received only IV miconazole; three relapsed after therapy was stopped. Miconazole appears promising as a treatment of fungal meningitis, but trials of longer duration might prevent relapse.

Eosinophilic pleocytosis in coccidioidal meningitis: frequency and significance.

PURPOSE: Coccidioidal meningitis (CM) is a major source of morbidity and mortality in endemic regions. The diagnosis of CM is a clinical challenge. Eosinophilic pleocytosis (EP) is an uncommon finding and present in a relatively limited number of conditions. In order to determine the frequency and the prognostic significance of EP in CM, we conducted the present study. PATIENTS AND METHODS: Retrospective chart review of all patients diagnosed as having CM between 1986 and 1991 at Kern Medical Center. All patients had clinical and cerebrospinal fluid (CSF) findings confirmatory of CM. RESULTS: Nineteen patients (70%) in the study group had EP, and of these, 8 patients (30%) met the criteria for eosinophilic meningitis (greater than or equal to 10 eosinophils/mm3). No correlation was found between EP and age, sex, race, results of complement fixation test for coccidioidal antigen in CSF or serum, peripheral eosinophilia, or outcome. CONCLUSION: The presence of EP is a frequent observation in CM. Although we did not demonstrate any prognostic correlation with EP, this finding is of major diagnostic significance and its presence should bring attention to the diagnosis of CM.

False-positive reactions of cerebrospinal fluid and diluted sera with the coccidioidal latex-agglutination test.

Most samples of cerebrospinal fluid from 49 patients with or without coccidioidomycosis yielded positive agglutination with the Hyland ("CM") latex-particle agglutination test. Furthermore, simple dilution of sera from patients with or without coccidioidomycosis yielded a strong agglutination reaction with the latex particle agglutination test reagent. These reactions were found with three lots of the latex-particle agglutination test reagent. One lot latex particles was found to give agglutination reactions merely by addition of saline solution or water, though a second lot did not. It is advisable, therefore, that the latex-particle agglutination test not be applied to cerebrospinal fluid, and that it be applied cautiously, particularly with diluted sera.

Ketoconazole treatment of coccidioidal meningitis.

Fifteen patients with coccidioidal meningitis were treated with high doses of ketoconazole for up to 4 years. Five patients were treated with ketoconazole alone. One clinically failed, one developed hepatotoxicity, and three achieved remission of meningitis. One patient received intrathecal AMB in addition to ketoconazole for only 2 weeks before continuing on ketoconazole alone. He improved, but discontinued ketoconazole because of nausea and vomiting, and suffered a lethal relapse. Nine patients received ketoconazole in combination with prolonged courses of intrathecal AMB. Two patients were failures from nausea and vomiting, and the remaining seven either improved or experienced remission. The clinical responses appeared to be similar in patients receiving high-dose ketoconazole, either alone or combined with AMB, suggesting that there is no clinically significant antagonism of the drugs. Nausea and vomiting are significant limitations of high-dose ketoconazole. Ketoconazole alone is effective in some patients with coccidioidomycotic meningitis.

Coccidiodal meningitis and pregnancy: a case report.

A woman with coccidiodal meningitis had two successive pregnancies and was treated with intrathecal amphotericin B. The outcome was successful.

Coccidioides immitis presenting as a hyphal form in cerebrospinal fluid.

This article reports a case of Coccidioides immitis that presented as a hyphal form in a 38-year-old patient. The organism was observed growing exclusively as hyphae in the cerebrospinal fluid by microscopic examination. Coccidioides immitis was the only organism cultured. The identification of C immitis was confirmed by both standard culture methods and DNA probe studies.

[Fluconazole in meningeal coccidioidomycosis]. / El fluconazol en la coccidioidomicosis meníngea.

We report our experience with ten virgin cases (5 children, 5 adults) with coccidioidal meningitis treated with fluconazole. The diagnosis was confirmed by a positive culture of the cerebrospinal fluid. Fluconazole at doses of 6/mg/kg/day for children and 400 mg/day for adults were given. All responded well, in five it was discontinued and four relapsed but responded well to fluconazole. We conclude that fluconazole is useful for coccidioidal meningitis.

Routine CSF analysis in coccidioidomycosis is not required.

Although routinely done, there has been no evaluation of the utility of performing routine cerebrospinal fluid (CSF) examination in patients with active coccidioidomycosis and high complement fixation (IgG) antibody titers or other risk factors for disseminated infection. In our review 100% of patients diagnosed with coccidioidal meningitis had at least one sign or symptom consistent with infection of the central nervous system, headache was present in 100% of those with meningitis, while no patients without signs/symptoms of CNS infection were found to have coccidioidal meningitis, irrespective of antibody titers or other risk factors. Thus routine lumbar puncture may be unnecessary for patients with coccidioidomycosis who lack suggestive clinical symptoms.

Coccidioidal meningitis: clinical presentation and management in the fluconazole era.

Despite the advent of new antifungal agents, coccidioidal meningitis (CM) remains a difficult-to-treat condition with significant morbidity and mortality. In this study we directly compare the clinical presentation and management of patients with Coccidioides immitis meningitis in the azole era (after 1980) to that of a cohort of patients from the pre-azole era. We reviewed 30 CM cases seen at 3 Los Angeles hospitals between the years 1993 to 2008 ("2008 cohort") and compared them to 31 patients ("1980 cohort") described by Bouza et al in a previous study. The demographics and clinical presentation of patients in the 2008 cohort were similar to those of the 1980 cohort except for a higher incidence of Hispanic patients (2008: 53% vs. 1980: 6%) and a greater percentage of patients with underlying, predisposing clinical conditions (2008: 66% vs. 1980: 32%). Ten patients in the 2008 cohort had human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), a condition not reported in the earlier study. Laboratory findings were similar between the 2 groups except for a lower incidence of peripheral leukocytosis and eosinophilia in the 2008 group.There were marked differences in drug treatment between the 2 eras. In the 2008 cohort, 29 patients received fluconazole therapy: 13 were treated with fluconazole monotherapy, and 16 received a combination of fluconazole and intravenous amphotericin B. Although almost all patients (29/31) in the 1980 cohort received intrathecal amphotericin B, only 3 patients in the 2008 study received amphotericin B via this route. With respect to complications of CM, a similar percentage of patients in each cohort developed complications such as stroke and hydrocephalus. The 2008 cohort (40%) had similar mortality compared to patients in the 1980 study (39%); survivors in both groups experienced significant impairment of activities of daily living. Although recommended as first-line therapy for CM, azole-based therapies are not curative and do not necessarily prevent complications associated with the disease.CM remains a serious illness with a high rate of morbidity and mortality. Immunocompromised individuals, especially those with HIV/AIDS, are at special risk for CM and represent a greater share of the overall population with this condition. Despite the clear advantages of azole treatment in CM, new therapeutic approaches are needed to provide definitive cure and to reduce the need for long-term suppressive therapy.

Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis.

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.

Tumor necrosis factor-alpha and interleukin-1 beta in cerebrospinal fluid of patients with coccidioidal meningitis during therapy with fluconazole. National Institute of Allergy and Infectious Diseases Mycoses Study Group.

The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1 beta in the cerebrospinal fluid (CSF) of 66 patients with coccidioidal meningitis during therapy with fluconazole were measured by ELISA. The median concentration of TNF-alpha was 15.2 pg/mL for 322 samples; for IL-1 beta, it was 4.7 pg/mL for 316 samples. There were no significant changes in the level of either cytokine over 24 months of follow-up nor was there an association between the initial CSF concentrations of TNF-alpha and IL-1 beta and subsequent fluconazole treatment failure. Over time, concentrations of IL-1 beta were significantly associated with both clinical symptoms and white blood cell counts in CSF. These results indicate that CSF levels of TNF-alpha and IL-1 beta are relatively low compared with those associated with acute bacterial meningitis.

The natural history of coccidioidal meningitis: VA-Armed Forces cooperative studies, 1955-1958.

From records on the clinical course of 699 military and veteran patients who had coccidioidomycosis before the advent of effective antifungal therapy, we identified 25 cases in which the manifestations of meningeal dissemination were described. Of 21 patients who had an identifiable initial infection, 16 developed meningeal symptoms (most frequently headache, vomiting, and nuchal rigidity) within the next 6 months. Associated pulmonary lesions were significantly more frequent in the right than in the left lung, as was also the case among 47 matched control patients who had coccidioidomycosis but not meningitis. Of 17 patients whose meningeal symptoms developed during the period studied, all died within 31 months. However, four of eight patients whose onset of symptoms preceded the study period survived for 55-146 months. Patients whose extrapulmonary dissemination involved only the meninges survived significantly longer than did those with more extensive infections. Even without therapy, the white blood cell count in cerebrospinal fluid markedly decreased during the course of the infection. The quantitative analysis provided herein offers a basis for meaningful comparisons with patients enrolled in current and future trials of therapy for coccidioidal meningitis.

A model of coccidioidal meningoencephalitis and cerebrospinal vasculitis in the rabbit.

Coccidiodal meningitis is a devastating complication of disseminated coccidioidomycosis. An animal model of this infection could enhance understanding of the pathogenesis of the disease and lead to improvements in therapy. A rabbit model of central nervous system infection simulating human disease was established using a blind cisternal tap technique to inoculate 4 x 10(3)-1 x 10(6) arthroconidia of Coccidioides immitis into the cisterna magna. Systemic, neurologic, and histopathologic findings of meningitis were observed in all rabbits, but an inoculum of 2 x 10(4) arthroconidia produced a chronic illness in which meningeal endarteritis obliterans was consistently observed. Serial sampling of cerebrospinal fluid demonstrated an inflammatory response. Growth of C. immitis was demonstrated by quantitative fungal culture from brains and proximal spinal cords.