Establishing Correlates of Maternal-Fetal Cytomegalovirus Transmission-One Step Closer Through Predictive Modeling.

Background: Determinants of maternal-fetal cytomegalovirus (CMV) transmission and factors influencing the severity of congenital CMV (cCMV) infection are not well understood.

Methods: We conducted a descriptive, multicenter study in pregnant women ≥18 years old with primary CMV infection and their newborns to explore maternal immune responses to CMV and determine potential immunologic/virologic correlates of cCMV following primary infection during pregnancy. We developed alternative approaches looking into univariate/multivariate factors associated with cCMV, including a participant clustering/stratification approach and an interpretable predictive model-based approach using trained decision trees for risk prediction (post hoc analyses).

Incidence of Cytomegalovirus Primary and Secondary Infection in Adolescent Girls: Results From a Prospective Study.

Developing a vaccine to prevent congenital cytomegalovirus (CMV) infection and newborn disability requires an understanding of infection incidence. In a prospective cohort study of 363 adolescent girls (NCT01691820), CMV serostatus, primary infection, and secondary infection were determined in blood and urine samples collected at enrollment and every 4 months for 3 years. Baseline CMV seroprevalence was 58%.

HIV-Negative Cryptococcal Meningoencephalitis Results in a Persistent Frontal-Subcortical Syndrome.

Twenty-seven previously healthy (of 36 consecutive eligible patients), HIV-negative cryptococcal meningoencephalitis (CM) patients underwent comprehensive neuropsychological evaluation during the late post-treatment period (1.3-4 years post diagnosis), assessing attention, language, learning, memory, visuospatial, executive function, information processing, psychomotor functioning, as well as mood symptoms. Seven of eight domains (all except attention) showed increased percentages of CM patients scoring in the less than 16 percentile range compared to standardized normative test averages, adjusted for education level and age.

Audiologic and Otologic Complications of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Patients.

Objective: To identify audiologic and otologic outcomes in previously healthy non-HIV patients with cryptococcal meningoencephalitis (CM).

Study Design: Retrospective case review of a subset of patients recruited in a prospective observational study following previously healthy individuals who developed CM.

Setting: Tertiary referral center, National Institutes of Health Clinical Center.

A Multicenter, Longitudinal Cohort Study of Cryptococcosis in Human Immunodeficiency Virus-negative People in the United States.

Background: Cryptococcosis is increasingly recognized in people without human immunodeficiency virus (HIV).

Methods: A multicenter, prospective cohort study was performed in 25 US centers. Consenting patients were prospectively followed for ≤2 years.

Cryptococcal meningitis is a cause for cross-reactivity in cerebrospinal fluid assays for anti-Histoplasma, anti-Coccidioides and anti-Blastomyces antibodies.

Background/objectives: Antibody detection is commonly used for diagnosis of histoplasmosis, and cross-reactions have been recognised due to endemic mycoses but not cryptococcosis. We observed cross-reactions in an anti-Histoplasma antibody enzyme immunoassay (EIA) in the cerebrospinal fluid (CSF) from a patient with cryptococcal meningitis and sought to assess the risk of cross-reactive anti-Histoplasma antibodies in persons with cryptococcal meningitis.

Methods: An anti-cryptococcal antibody EIA was developed to measure CSF antibody response in HIV-infected subjects from Kampala, Uganda and previously healthy, HIV-negative subjects at the National Institutes of Health (NIH) with cryptococcal meningitis.

Choroid Plexitis and Ependymitis by Magnetic Resonance Imaging are Biomarkers of Neuronal Damage and Inflammation in HIV-negative Cryptococcal Meningoencephalitis.

CNS cryptococcal meningoencephalitis in both HIV positive (HIV+) and HIV negative (HIV-) subjects is associated with high morbidity and mortality despite optimal antifungal therapy. We thus conducted a detailed analysis of the MR imaging findings in 45 HIV- and 11 HIV+ patients to identify imaging findings associated with refractory disease. Ventricular abnormalities, namely ependymitis and choroid plexitis were seen in HIV- but not in HIV+ subjects.

Susceptibility to Cryptococcal Meningoencephalitis Associated With Idiopathic CD4 Lymphopenia and Secondary Germline or Acquired Defects.

Idiopathic CD4 lymphopenia (ICL) predisposes to opportunistic infections (OIs) but can often remain asymptomatic and does not have a strong association with monogenic mutations. Likewise, cryptococcal meningoencephalitis, the most common OI in ICL, is not strongly associated with monogenic mutations. In this study, we describe 2 patients with ICL plus an additional immune defect: one from an E57K genetic mutation in the nuclear factor-κβ essential modulator, and the other with acquired autoantibodies to granulocyte-macrophage colony-stimulating factor.

Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults.

Background: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology.

Methods: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control.

Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy.

HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent.

Combination Antifungal Therapy for Invasive Aspergillosis Revisited.

Invasive aspergillosis (IA) causes significant morbidity and mortality among immunocompromised hosts. Combination therapy with mold-active triazoles and echinocandins has been used with the hope of improving outcomes over monotherapy, especially in the setting of refractory disease. Herein, I update our prior systematic review and meta-analysis on combination therapy for salvage IA in the context of the recently published randomized clinical trial of combination therapy for primary IA.

Fighting the Monster: Applying the Host Damage Framework to Human Central Nervous System Infections.

The host damage-response framework states that microbial pathogenesis is a product of microbial virulence factors and collateral damage from host immune responses. Immune-mediated host damage is particularly important within the size-restricted central nervous system (CNS), where immune responses may exacerbate cerebral edema and neurological damage, leading to coma and death. In this review, we compare human host and therapeutic responses in representative nonviral generalized CNS infections that induce archetypal host damage responses: cryptococcal menigoencephalitis and tuberculous meningitis in HIV-infected and non-HIV-infected patients, pneumococcal meningitis, and cerebral malaria.

The Risk of Nosocomial Transmission of Rift Valley Fever.

In 2000, we investigated the Rift Valley fever (RVF) outbreak on the Arabian Peninsula-the first outside Africa-and the risk of nosocomial transmission. In a cross-sectional design, during the peak of the epidemic at its epicenter, we found four (0.6%) of 703 healthcare workers (HCWs) IgM seropositive but all with only community-associated exposures.

Fungal Infections of the Central Nervous System.

Purpose Of Review: This article summarizes current knowledge on the epidemiology, clinical presentations, diagnosis, and management of selected fungal infections of the central nervous system (CNS). Key syndromes, differential diagnoses, and therapeutic interventions according to host immune status and exposure are reviewed.

Recent Findings: Advancements in imaging of the brain and spinal cord, and molecular DNA and antigen-based laboratory diagnostics afford improved sensitivity for CNS mycoses.

Performance of the Cryptococcal Antigen Lateral Flow Assay in Non-HIV-Related Cryptococcosis.

The cryptococcal antigen lateral flow assay (CrAg LFA) was evaluated for the diagnosis of cryptococcosis in HIV-negative patients. The sensitivity was excellent, suggesting that this assay can replace conventional testing based on latex agglutination (LA). CrAg LFA and LA titers were correlated but were not directly comparable, with implications for conversion between assays.

Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis.

The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease.

Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis.

Objective: The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools.

Enzyme immunoassay versus latex agglutination cryptococcal antigen assays in adults with non-HIV-related cryptococcosis.

We compared paired enzyme immunoassay (EIA) and latex agglutination (LA) assay results with 185 blood and 164 cerebrospinal fluid (CSF) samples from 44 and 33 non-HIV cryptococcosis patients, respectively. The LA assay cutoff of 1:256 in the blood and 1:32 in the CSF was most highly predictive of a positive EIA result. The EIA missed 18.

Salvage combination antifungal therapy for acute invasive aspergillosis may improve outcomes: a systematic review and meta-analysis.

Objective: A meta-analysis was performed to compare mold-active triazoles or lipid amphotericin B plus an echinocandin to non-echinocandin monotherapy for acute invasive aspergillosis (IA).

Methods: We searched PubMed, EMBASE, and other databases through May 2013 unrestricted by language. We included observational and experimental studies wherein patients with proven or probable IA by EORTC/MSG criteria underwent our comparative intervention.

Geoclimatic influences on invasive aspergillosis after hematopoietic stem cell transplantation.

Background: Aspergillus species are ubiquitous. We hypothesized that climatic variables that affect airborne mold counts affect the incidence of invasive aspergillosis (IA).

Methods: Patients who received hematopoietic stem cell transplants (HSCTs) in geographically and climatically diverse regions (Seattle, WA, and Houston, TX) were examined.

Spatio-temporal and healthcare trends of non-endemic, invasive fungal infections in the United States, National Hospital Discharge Survey--1996 to 2006.

Non-endemic, invasive fungal infections (IFI) remain a major cause of morbidity and mortality but their healthcare epidemiologic patterns require further elucidation. The 1996-2006 records in the National Hospital Discharge Survey (NHDS) of a hospitalized sub-cohort of HIV, hematologic malignancy, and transplant patients were analyzed. The objective was to determine independent predictors of non-endemic IFI, apart from other known predisposing host factors.