Improvement in Diagnosis of Histoplasma Meningitis by Combined Testing for Histoplasma Antigen and Immunoglobulin G and Immunoglobulin M Anti-Histoplasma Antibody in Cerebrospinal Fluid.

Background: Central nervous system (CNS) histoplasmosis is a life-threatening condition and represents a diagnostic and therapeutic challenge. Isolation of Histoplasma capsulatum from cerebrospinal fluid (CSF) or brain tissue is diagnostic; however, culture is insensitive and slow growth may result in significant treatment delay. We performed a retrospective multicenter study to evaluate the sensitivity and specificity of a new anti-Histoplasma antibody enzyme immunoassay (EIA) for the detection of IgG and IgM antibody in the CSF for diagnosis of CNS histoplasmosis, the primary objective of the study. The secondary objective was to determine the effect of improvements in the Histoplasma galactomannan antigen detection EIA on the diagnosis of Histoplasma meningitis. Methods: Residual CSF specimens from patients with Histoplasma meningitis and controls were tested for Histoplasma antigen and anti-Histoplasma immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody using assays developed at MiraVista Diagnostics. Results: A total of 50 cases and 157 controls were evaluated. Fifty percent of patients with CNS histoplasmosis were immunocompromised, 14% had other medical conditions, and 36% were healthy. Histoplasma antigen was detected in CSF in 78% of cases and the specificity was 97%. Anti-Histoplasma IgG or IgM antibody was detected in 82% of cases and the specificity was 93%. The sensitivity of detection of antibody by currently available serologic testing including immunodiffusion and complement fixation was 51% and the specificity was 96%. Testing for both CSF antigen and antibody by EIA was the most sensitive approach, detecting 98% of cases. Conclusions: Testing CSF for anti-Histoplasma IgG and IgM antibody complements antigen detection and improves the sensitivity for diagnosis of Histoplasma meningitis.

Fungal infection in cerebrospinal fluid from some patients with multiple sclerosis.

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system and spinal cord, leading to axonal demyelination of neurons. Recently, we have found a correlation between fungal infection and MS in peripheral blood of patients. The present work provides evidence of fungal infection in the cerebrospinal fluid (CSF) of some MS patients. Thus, fungal antigens can be demonstrated in CSF, as well as antibodies reacting against several Candida species. Comparison was made between CSF and blood serum for the presence of fungal antigens (proteins) and antibodies against different Candida spp. Analyses of both CSF and serum are complementary and serve to better evaluate for the presence of disseminated fungal infection. In addition, PCR analyses indicate the presence of DNA from different fungal species in CSF, depending on the patient analyzed. Overall, these findings support the notion that fungal infection can be demonstrated in CSF from some MS patients. This may constitute a risk factor in this disease and could also help in understanding the pathogenesis of MS.

Central nervous system histoplasmosis: Multicenter retrospective study on clinical features, diagnostic approach and outcome of treatment.

Central nervous system (CNS) involvement occurs in 5 to 10% of individuals with disseminated histoplasmosis. Most experience has been derived from small single center case series, or case report literature reviews. Therefore, a larger study of central nervous system (CNS) histoplasmosis is needed in order to guide the approach to diagnosis, and treatment.A convenience sample of 77 patients with histoplasmosis infection of the CNS was evaluated. Data was collected that focused on recognition of infection, diagnostic techniques, and outcomes of treatment.Twenty nine percent of patients were not immunosuppressed. Histoplasma antigen, or anti-Histoplasma antibodies were detected in the cerebrospinal fluid (CSF) in 75% of patients. One year survival was 75% among patients treated initially with amphotericin B, and was highest with liposomal, or deoxycholate formulations. Mortality was higher in immunocompromised patients, and patients 54 years of age, or older. Six percent of patients relapsed, all of whom had the acquired immunodeficiency syndrome (AIDS), and were poorly adherent with treatment.While CNS histoplasmosis occurred most often in immunocompromised individuals, a significant proportion of patients were previously, healthy. The diagnosis can be established by antigen, and antibody testing of the CSF, and serum, and antigen testing of the urine in most patients. Treatment with liposomal amphotericin B (AMB-L) for at least 1 month; followed by itraconazole for at least 1 year, results in survival among the majority of individuals. Patients should be followed for relapse for at least 1 year, after stopping therapy.

[A case of histoplasmosis with chronic basilar meningitis diagnosed relatively early].

A 41-year-old man left for Mexico in May 2015. Right pulmonary nodule was detected at a health examination in May 2016, and he subsequently showed headache and slight fever. Contrast-enhanced magnetic resonance imaging of the brain revealed basilar meningitis, so he was admitted to our hospital. We considered imported mycosis due to his travel history to Mexico. We diagnosed histoplasmosis based on the presence of antibodies against Histoplasma in both serum and cerebrospinal fluid. Symptoms almost completely recovered with a liposomal formulation of amphotericin B. Central nervous system histoplasmosis is very rare in Japan. Immunocompetent hosts can develop histoplasmosis, and this pathology is important to consider in patients presenting with basilar meningitis and a positive travel history.

Antifungal activity of the local complement system in cerebral aspergillosis.

Dissemination of aspergillosis into the central nervous system is associated with nearly 100% mortality. To study the reasons for the antifungal immune failure we analyzed the efficacy of cerebral complement to combat the fungus Aspergillus. Incubation of Aspergillus in non-inflammatory cerebrospinal fluid (CSF) revealed that complement levels were sufficient to obtain a deposition on the surface, but opsonization was much weaker than in serum. Consequently complement deposition from normal CSF on fungal surface stimulated a very low phagocytic activity of microglia, granulocytes, monocytes and macrophages compared to stimulation by conidia opsonized in serum. Similarly, opsonization of Aspergillus by CSF was not sufficient to induce an oxidative burst in infiltrating granulocytes, whereas conidia opsonized in serum induced a clear respiratory signal. Thus, granulocytes were capable of considerably reducing the viability of serum-opsonized Aspergillus conidia, but not of conidia opsonized in CSF. The limited efficacy of antifungal attack by cerebral complement can be partly compensated by enhanced synthesis, leading to elevated complement concentrations in CSF derived from a patient with cerebral aspergillosis. This inflammatory CSF was able to induce (i) a higher complement deposition on the Aspergillus surface than non-inflammatory CSF, (ii) an accumulation of complement activation products and (iii) an increase in phagocytic and killing activity of infiltrating granulocytes. However, levels and efficacy of the serum-derived complement were not reached. These data indicate that low local complement synthesis and activation may represent a central reason for the insufficient antifungal defense in the brain and the high mortality rate of cerebral aspergillosis.

Analysis of antibody response to Cryptococcus neoformans in five patients with AIDS and cryptococcosis by immunoblotting.

OBJECTIVES: The serological response of five patients with AIDS and cryptococcosis to non capsular antigens from Cryptococcus neoformans var. neoformans has been investigated. METHODS: Pressates of different isolates of C. neoformans were used as antigenic preparation for immunoblotting of patient samples. RESULTS: Multiple sera and cerebrospinal fluids sequentially collected from five AIDS patients with cryptococcosis showed a wide heterogeneity in antibody response with bands at 48. 43, 38 and 26 kD being present in all clinical samples of all five patients. The variation in banding patterns of the sequential samples from three patients was correlated with a decrease of the antigen titre and with an amelioration of the cryptococcal infection. CONCLUSIONS: We identified antibodies to four immunodominant non-capsular antigens, which might represent major target molecules of the humoral response of patients with cryptococcosis.

Meningitis caused by Absidia corymbifera.

A 56-year-old man developed mucormycotic meningitis caused by Absidia corymbifera and which followed a penetrating head injury. Antibodies to it were detected in the cerebrospinal fluid at titres higher than those found in the serum, thereby suggesting local production of antibody in the subarachnoid space.

Chronic Aspergillus sp. meningitis successfully treated with fluconazole. Case report.

We a case of chronic Aspergillus sp. meningitis in a healthy 43-year-old woman successfully treated with fluconazole given orally (300 ms/day). The diagnosis was made by detection of anti-aspergillus antibodies and positive culture to Aspergillus sp. in the cerebrospinal fluid.

Neuro-ophthalmic presentations and treatment of Cryptococcal meningitis-related increased intracranial pressure.

OBJECTIVE: To illustrate three different ophthalmic presentations of cryptococcal meningitis (CM). INTRODUCTION: CM is the most common manifestation of extra-pulmonary cryptococcosis. Intracranial hypertension occurs in up to 75% of patients with CM and is associated with increased mortality. CM can present to the ophthalmologist as vision loss, papilledema, abducens palsy, and/or other cranial neuropathies. PARTICIPANTS AND METHODS: We report three cases, two C. neoformans and one C. gattii, highlighting the various CM presentations. The first was a woman immunosuppressed following kidney transplantation in whom idiopathic intracranial hypertension (IIH) was initially suspected. The second was a man immunocompromised by previously undiagnosed HIV/AIDS who presented with signs and symptoms of increased intracranial pressure. The third case is an immunocompetent man with bilateral disc edema and an incomplete macular star diagnosed with presumed neuroretinitis. Further evaluation revealed positive CSF cryptococcal antigen with culture positive for C. gattii. CONCLUSIONS: Ophthalmologists should be aware that cryptococcosis can mimic more benign etiologies including IIH and neuroretinitis. Additionally, C. gattii, an emerging organism, can infect immunocompetent patients. In contrast to the typical treatment of increased ICP, serial lumbar punctures are recommended while acetazolamide and surgical CSF shunting may be harmful.

Neuroendoscopic diagnosis of central nervous system histoplasmosis with basilar arachnoiditis.

OBJECTIVE: Histoplasmosis of the central nervous system (CNS) is seen in 10% to 20% of patients with disseminated histoplasmosis and/or in association with immunocompromised patients. Meningitis, arachnoiditis, and hydrocephalus are the most common clinical manifestations of CNS histoplasmosis. Patients with CNS histoplasmosis present similarly to other infectious etiologies, and confirmatory diagnosis is important in the management of these patients. However, diagnosis of CNS histoplasmosis can be difficult, and sometimes performing a parenchymal biopsy is necessary to confirm the diagnosis. METHODS AND RESULTS: We describe the case of a 41-year-old man with HIV/AIDS who presented with the signs, symptoms, and radiologic evidence of basal meningitis and hydrocephalus. Cerebrospinal fluid (CSF) analysis from multiple lumbar punctures was negative. The patient underwent a neuroendoscopic procedure with diagnostic and therapeutic goals. Internal CSF diversion (endoscopic third ventriculostomy) and biopsy of the floor of the third ventricle and subarachnoid space were performed; surgical biopsies identified noncaseating granulomas, and ventricular CSF was positive for Histoplasmosis antibodies. The patient was treated with liposomal amphotericin B and itraconazole. The patient had resolution of his symptoms immediately after surgery, and 1-month follow-up computed tomography of the head demonstrated resolution of the hydrocephalus. At the last follow-up 12 months postoperatively, the patient has not required insertion of a ventriculoperitoneal shunt. CONCLUSION: Clinicians should maintain a high index of suspicion for fungal basal meningitis in patients with AIDS and hydrocephalus. With nondiagnostic lumbar CSF sampling, neuroendoscopy can be considered as an alternative for diagnosis and treatment of basal meningitis and hydrocephalus.

Coccidioides immitis meningitis in a patient with hyperimmunoglobulin E syndrome due to a novel mutation in signal transducer and activator of transcription.

Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin and lung infections. We report the first case of Coccidioides immitis meningitis in a patient with HIES. Coccidioides should be included in the differential diagnosis for central nervous system infections in HIES patients.

Diagnosis of neuroparacoccidioidomycosis by detection of circulating antigen and antibody in cerebrospinal fluid.

Neuroparacoccidioidomycosis (neuroPCM) is the central nervous system infection by the fungus Paracoccidioides brasiliensis. Its diagnosis is a difficult task that depends on neuroimaging techniques such as computed tomography and magnetic resonance imaging. However, the detection of circulating P. brasiliensis antigens in body fluids by inhibition enzyme-linked immunosorbent assay (inh-ELISA) has provided encouraging results. In this study, 14 cerebrospinal fluid (CSF) and 11 serum samples of patients with neuroPCM were analyzed by inh-ELISA for detection of circulating glycoprotein antigens of 43 kDa (gp43) and 70 kDa (gp70). Circulating gp43 and gp70 antigens were detected in all CSF samples from patients with neuroPCM at mean concentrations of 19.3 and 6.8 mug/ml, respectively. In addition, both gp43 and gp70 antigens were detected in 10 of 11 serum samples analyzed at mean concentrations of 4.6 and 4.0 mug/ml, respectively. By immunodiffusion test, CSF samples were determined to be negative in 13 of 14 samples. The detection of anti-gp43 and anti-gp70 antibodies by conventional ELISA showed positive results for all CSF samples, with titers ranging from 1:50 to 1:51,200. Therefore, the high sensitivity of the inh-ELISA technique in detecting gp43 and gp70 antigens in the CSF of neuroPCM patients strongly indicates that this assay can be considered as a powerful diagnostic tool. In addition, the finding of anti-gp43 and anti-gp70 antibodies in CSF samples by conventional ELISA also seems to be a promising diagnostic method for this special modality of PCM.

Development of an enzyme-linked immunosorbent assay for the serodiagnosis of several clinical forms of sporotrichosis.

We performed a serological study with sera from 92 patients with confirmed sporotrichosis registered between 1999 and 2004 in two hospitals in Rio de Janeiro State, Brazil. The clinical presentation of sporotrichosis was distributed as follows: lymphocutaneous, 67%; fixed cutaneous, 23%; disseminated cutaneous, 8%; and extracutaneous, 2%. Sera were assayed by ELISA against a cell wall antigen of Sporothrix schenckii, SsCBF, that we have previously described. The cross-reactivity was determined with 77 heterologous sera. The serological test showed a sensitivity of 90% and a global efficiency of 86%. A group of 55 patients with several clinical presentations of sporotrichosis was clinically and serologically followed-up for at least 6 months. We observed by ELISA data a decrease in the antibody serum titers which correlated with the progress in healing. An HIV-positive patient with meningeal sporotrichosis was serologically followed-up for over 2 years. Serum and cerebrospinal fluid specimens were examined and significant antibodies levels against the antigen SsCBF were detected. Our results strongly suggest that this serological test is valuable for the differential diagnosis and follow-up of all clinical forms of sporotrichosis.

Alternatives to the standardized laboratory branch complement fixation test for detection of antibodies to Coccidioides immitis.

Antibody titers to Coccidioides immitis, using coccidioidin antigen, were determined by three methods: the standardized Laboratory Branch complement fixation method (LBCF), a modified version of the Viral and Rickettsial Disease Laboratory complement fixation test (VRDL-CF), and a quantitative immunodiffusion test (QID). Of the 133 samples evaluated, 72 were negative by each method and 57 (42 serum samples, 15 cerebrospinal fluid samples) were positive by all three methods. Four additional specimens (1 serum sample, 3 cerebrospinal fluid samples) were positive by QID alone. All positive patients were diagnosed clinically as having pulmonary or extrapulmonary coccidioidomycosis or both. When titers from two methods were compared, the agreement within +/- 1 dilution was VRDL-CF/QID, 88.5%; VRDL-CF/LBCF, 85.2%; and LBCF/QID, 82.0%. The agreement of these methods within +/- 2 dilutions was VRDL-CF/QID, 98.4%; VRDL-CF/LBCF, 96.7%; and LBCF/QID, 93.4%. The VRDL-CF and QID methods are simpler to perform; however, they are yet unrecognized as suitable alternatives to the more cumbersome LBCF. Our data show that they should be considered as options for C. immitis serology.

[Intrathecal synthesis of specific antibodies in Candida albicans meningoencephalitis]. / Synthèse intrathécale d'anticorps spécifiques au cours d'une méningo-encéphalite à Candida albicans.

Titration of IgG, albumin, and specific antibodies, both in serum and CSF, during the course of a Candidal meningoencephalitis allowed to demonstrate intrathecal synthesis of specific IgG antibodies against C. albicans.

Serologic studies in the diagnosis and management of meningitis due to Sporothrix schenckii.

Eight patients have previously been reported to have central nervous system infections caused by Sporothrix schenckii. In those patients the fungus proved quite difficult to culture, delaying correct diagnosis and treatment. We describe seven additional patients with sporotrichosis meningitis, all of whom had antibody to this fungus in cerebrospinal fluid and serum. The antibody in the cerebrospinal fluid was most likely produced locally, as evidenced by its oligoclonality and the relatively high ratio of immunoglobulin to albumin in the cerebrospinal fluid as compared with the serum. Only one of these seven patients, who had active sporotrichosis of the knee joint, had obvious extrameningeal infection. None of 130 patients with meningitis known to be caused by other agents and none of 170 patients with other neurologic disorders had antibody to S. schenckii in their cerebrospinal fluid. We suggest that cerebrospinal fluid should be tested for S. schenckii antibody (in addition to other fungal agents) in any patient with chronic meningitis for which no cause is discovered by the usual diagnostic tests.

Opsonic activity of cerebrospinal fluid in experimental cryptococcal meningitis.

The role of antibody in protection against infection with Cryptococcus neoformans is undefined. In this paper we describe the development of opsonic activity in the cerebrospinal fluid (CSF) of rabbits in response to cryptococcal meningitis. The opsonin appeared to be immunoglobulin G (IgG); the activity was heat stable, copurified with the IgG fraction during protein A separation, and could be absorbed by encapsulated cryptococci. Immunosuppression with cyclosporine could be administered to prevent or allow in vivo deposition of IgG on the polysaccharide capsule of yeast in the CSF. Both early and late cyclosporine regimens resulted in prolonged, severe meningeal infections corresponding to the complete absence of in vitro opsonic activity in the CSF. While the production of opsonic antibody is part of the successful host response against C. neoformans in the central nervous system of rabbits, the presence of specific immunoglobulin by itself is insufficient for complete protection.

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.

Itraconazole therapy for chronic coccidioidal meningitis.

STUDY OBJECTIVE: To assess the efficacy of orally administered itraconazole in the treatment of coccidioidal meningitis. DESIGN: Prospective, nonrandomized open trial. SETTING: Multicenter trial at an urban county hospital, a university referral center, and referring institutions. PATIENTS: Ten patients with culture or serologic evidence of coccidioidal meningitis refractory to standard therapy. Patients receiving other systemic antifungal therapy were excluded. INTERVENTION: Itraconazole was administered orally at doses of 300 to 400 mg/d for a median duration of 10 months. Disease activity and drug efficacy were evaluated at initiation of therapy and at the most recent follow-up using a standardized scoring system. MEASUREMENTS AND MAIN RESULTS: Eight of ten patients are evaluable. Of five patients receiving itraconazole as sole therapy, four have responded. All three patients receiving intrathecal amphotericin B have had that therapy discontinued and have no evidence of active disease in the absence of intrathecal therapy. Toxicity has been minimal; one patient had mild nausea. CONCLUSIONS: Itraconazole shows impressive activity in this series of patients with refractory coccidioidal meningitis. Itraconazole in this and other fungal meningitides should be evaluated further.