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.

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.

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.

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.

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.

A murine model of coccidioidal meningitis.

Coccidioidal meningitis is lethal in humans. A reproducible murine model was established by lumbar intrathecal injection of Coccidioides immitis arthroconidia. Cerebrospinal fluid (CSF) samples were obtained by cisternal puncture. Lethal infection developed in all mice given 10-60 colony-forming units (cfu). Lethargy, ataxia, or paralysis preceded death. Temporal studies after challenge with 27 cfu revealed positive brain (4/5 mice) and spinal cord (2/5 mice) cultures on day 3; CSF samples contained 688 leukocytes/mm(3) and 33 cfu/mL. The results of histopathologic analysis were unremarkable. By day 8, all mice were culture positive (5.0 log(10) cfu in brain tissue and 4.1 log(10) cfu in spinal cord tissue); CSF samples contained 4833 leukocytes/mm(3) and 3425 cfu/mL. Histopathologic examinations showed acute meningitis of the brain and spinal cord, some parenchymal invasion and abscesses, and meningeal arteritis. Groups of mice given ketoconazole had prolonged survival and suppressed lung disease; histopathologic examination demonstrated granulomatous meningitis, possibly a more chronic form. With the development of these models, studies of pathogenesis, host response, and therapy are possible.

Efficacy of intravenous liposomal amphotericin B (AmBisome) against coccidioidal meningitis in rabbits.

The efficacy of intravenously administered liposomal amphotericin B (AmBisome [AmBi]) for the treatment of experimental coccidioidal meningitis was compared with those of oral fluconazole (FLC) and intravenously administered conventional amphotericin B (AMB). Male New Zealand White rabbits were infected by intracisternal inoculation of arthroconidia of Coccidioides immitis. Starting 5 days postinfection, animals received one of the following: 5% dextrose water diluent; AMB given at 1 mg/kg of body weight; AmBi given at 7.5, 15, or 22.5 mg/kg intravenously three times per week for 3 weeks; or oral FLC given at 80 mg/kg for 19 days. One week after the cessation of therapy, all survivors were euthanatized, the numbers of CFU remaining in the spinal cord and brain were determined, and histological analyses were performed. All AmBi-, FLC-, or AMB-treated animals survived and had prolonged lengths of survival compared with those for the controls (P < 0.0001). Treated groups had significantly lower numbers of white blood cells and significantly lower protein concentrations in the cerebrospinal fluid compared with those for the controls (P < 0.01 to 0.0005) and had fewer clinical signs of infection (e.g., weight loss, elevated temperature, and neurological abnormalities including motor abnormalities). The mean histological scores for AmBi-treated rabbits were lower than those for FLC-treated and control rabbits (P < 0.016 and 0.0005, respectively); the scores for AMB-treated animals were lower than those for the controls (P < 0.0005) but were similar to those for FLC-treated rabbits. All regimens reduced the numbers of CFU in the brain and spinal cord compared with those for the controls (P < or =0.0005). AmBi-treated animals had 3- to 11-fold lower numbers of CFU than FLC-treated rabbits and 6- to 35-fold lower numbers of CFU than AmB-treated rabbits. Three of eight animals given 15 mg of AmBi per kg had no detectable infection in either tissue, whereas other doses of AmBi or FLC cleared either the brain or the spinal cord of infection in fewer rabbits. In addition, clearance of the infection from both tissues was achieved in none of the rabbits, and neither tissue was cleared of infection in AMB-treated animals. Overall, these data indicate that intravenously administered AmBi is superior to oral FLC or intravenous AMB and that FLC is better than AMB against experimental coccidioidal meningitis. These data indicate that AmBi may offer an improvement in the treatment of coccidioidal meningitis. Additional studies are warranted.

Hyphal forms in the central nervous system of patients with coccidioidomycosis.

Coccidioides immitis is a dimorphic fungus that grows as a filamentous mold in soil and as a spherule at human body temperature. The hyphal or soil form is found rarely in human tissue. We report 5 cases of coccidioidomycosis in which hyphae were found in brain tissue or spinal fluid. The presence of central nervous system plastic devices appears to be associated with morphological reversion to the saprophytic form. This reversion has implications for diagnosis and therapy and may increase the risk of obstruction of the device(s).

Coccidioides immitis: Infección primaria del sistema nervioso central. Informe de un caso y revisión de la literatura / Case report and literature review of primary coccidioidal meningitis

Se presenta un caso de meningitis primaria (sin afección pulmonar, ósea o dérmica) por el hongo Coccidioides immitis en un hombre de 27 años de edad que acudió por un síndrome de cráneo hipertensivo de un mes de evolución atendido en nuestra institución. El paciente provenía del norte de California y era previamente sano, sin antecedentes para sospechar inmunodeficiencia. La punción lumbar mostró glucosa 22 mg/dL, proteínas totales 62 mg/dL, leucocitos 110 células/mm3 97 por ciento polimorfonucleares, 3 por ciento mononucleares. La tomografía axial computada de cráneo evidenció dilatación ventricular bilateral. Se hizo el diagnóstico de meningitis por coccidioides immitis mediante la detección de anticuerpos (IgM 6.8 mg/dL e IgG 4.9 mg/dL; normal < 2 mg/dL) y cultivo de líquido cerebroespinal. La radiografía de tórax no mostró alteración alguna. La detección de anticuerpos contra el virus de la inmunodeficiencia humana fue negativa. Se colocó una válvula de derivación ventrículo-peritoneal y se manejó con anfotericina B intravenosa e intratecal a través de un reservorio de Ommaya. A pesar de este tratamiento, el paciente se deterioró neurológicamente y falleció dos semanas después de su egreso en su lugar de origen

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.

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.

Cerebrospinal fluid antibodies detected by ELISA against a 33-kDa antigen from spherules of Coccidioides immitis in patients with coccidioidal meningitis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group.

Antibodies against a 33-kDa antigen from Coccidioides immitis were detected by ELISA in patients' cerebrospinal fluid (CSF). Anti-33-kDa antibodies were detected at dilutions > 1:80 in only 1 (1.4%) of 73 patients without coccidioidal meningitis but in 74 (71.8%) of 103 with meningitis. Anti-33-kDa antibodies were detected in 53 (91.4%) of 58 patients whose anti-coccidioidal complement-fixing (CF) antibodies were detectable and in 21 (46.7%) of 45 patients whose CSF was negative by CF test (positive predictive value, 99%; negative predictive value, 71%; sensitivity, 72%; specificity, 99%). Anti-33-kDa antibodies, among which IgG1 was the dominant subclass, increased when infections worsened and decreased when patients' conditions improved. Antibody concentration appeared to be independent of most baseline findings, although only 1 of 5 patients coinfected with human immunodeficiency virus had initially detectable antibodies. Measurement of anti-33-kDa antibodies is a sensitive indicator of coccidioidal meningitis and of its clinical course.

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.

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.