State of the Art: Acute Encephalitis.

Encephalitis is a devastating neurologic disease often complicated by prolonged neurologic deficits. Best practices for the management of adult patients include universal testing for a core group of etiologies, including herpes simplex virus (HSV)-1, varicella zoster virus (VZV), enteroviruses, West Nile virus, and anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody encephalitis. Empiric acyclovir therapy should be started at presentation and in selected cases continued until a second HSV-1 polymerase chain reaction test is negative. Acyclovir dose can be increased for VZV encephalitis. Supportive care is necessary for other viral etiologies. Patients in whom no cause for encephalitis is identified represent a particular challenge. Management includes repeat brain magnetic resonance imaging, imaging for occult malignancy, and empiric immunomodulatory treatment for autoimmune conditions. Next-generation sequencing (NGS) or brain biopsy should be considered. The rapid pace of discovery regarding autoimmune encephalitis and the development of advanced molecular tests such as NGS have improved diagnosis and outcomes. Research priorities include development of novel therapeutics.

Gram stain to the rescue: a case report of cerebral phaeohyphomycosis by Cladophialophora bantiana in an immunocompetent 24-year-old.

BACKGROUND: Fungal brain abscesses in immunocompetent patients are exceedingly rare. Cladophialophora bantiana is the most common cause of cerebral phaeohyphomycosis, a dematiaceous mold. Radiological presentation can mimic other disease states, with diagnosis through surgical aspiration and growth of melanized fungi in culture. Exposure is often unknown, with delayed presentation and diagnosis. CASE PRESENTATION: We present a case of cerebral phaeohyphomycosis in a 24-year-old with no underlying conditions or risk factors for disease. He developed upper respiratory symptoms, fevers, and headaches over the course of 2 months. On admission, he underwent brain MRI which demonstrated three parietotemporal rim-enhancing lesions. Stereotactic aspiration revealed a dematiaceous mold on staining and the patient was treated with liposomal amphotericin B, 5-flucytosine, and posaconazole prior to culture confirmation. He ultimately required surgical excision of the brain abscesses and prolonged course of antifungal therapy, with clinical improvement. CONCLUSIONS: Culture remains the gold standard for diagnosis of infection. Distinct microbiologic findings can aid in identification and guide antimicrobial therapy. While little guidance exists on treatment, patients have had favorable outcomes with surgery and combination antifungal therapy. In improving awareness, clinicians may accurately diagnose disease and initiate appropriate therapy in a more timely manner.

Monoclonal antibody treatment for COVID-19 in solid organ transplant recipients.

Solid organ transplant (SOT) recipients are at high risk for severe coronavirus disease 2019 (COVID-19). Studies suggest that early intervention with monoclonal antibody (MAB) treatment directed against the SARS-CoV-2 spike protein may reduce the risk of emergency department visits or hospitalization for COVID-19, especially in high-risk patients. Herein, we describe our single-center experience of 93 SOT (50 kidney, 17 liver, 11 lung, nine heart, and six dual-organ) recipients with mild to moderate COVID-19 who were treated with bamlanivimab or casirivimab-imdevimab per emergency use authorization guidelines. Median age of recipients was 55 [(Interquartile range) 44-63] years, and 41% were diabetic. Median time from transplant to MAB was 64 (IQR 24-122) months and median time from the onset of COVID-19 symptoms to the infusion was 6 (IQR 4-7) days. All patients had a minimum 30 days of study follow-up. The 30-day hospitalization rate for COVID-19-directed therapy was 8.7%. Infusion-related adverse events were rare and generally mild. Biopsy-proven organ rejection occurred in two patients, and there were no graft losses or deaths. A comparator group of 72 SOT recipients diagnosed with COVID-19 who were eligible but did not receive MAB treatment had a higher 30-day hospitalization rate for COVID-19-directed therapy (15.3%), although this difference was not statistically significant, after adjustment for age (Odds Ratio 0.49 [95% Confidence Interval 0.18-1.32], p = 0.16). Our experience suggests that MAB treatment, with respect to the available MAB formulations and circulating viral variants present during our study period, may provide favorable outcomes for mild to moderate COVID-19 in SOT recipients.

Central nervous system infections associated with neurologic devices.

PURPOSE OF REVIEW: To review recent data on the epidemiology, microbiology, diagnosis, and management of central nervous system (CNS) infections associated with neurologic devices. RECENT FINDINGS: The increasing use of implanted neurologic devices has led to an increase in associated infections. Cerebrospinal fluid (CSF) inflammation may be present after a neurosurgical procedure, complicating the diagnosis of CNS infection. Newer biomarkers such as CSF lactate and procalcitonin show promise in differentiating infection from other causes of CSF inflammation. Molecular diagnostic tests including next-generation or metagenomic sequencing may be superior to culture in identifying pathogens causing healthcare-associated ventriculitis and meningitis. SUMMARY: Neurologic device infections are serious, often life-threatening complications. Rapid recognition and initiation of antibiotics are critical in decreasing morbidity. Device removal is usually required for cure.

Meningoencephalitis due to Spotted Fever Rickettsioses, Including Rocky Mountain Spotted Fever.

BACKGROUND: The spotted fever rickettsioses (SFR), including Rocky Mountain spotted fever, are tick-borne infections with frequent neurologic involvement. High morbidity and mortality make early recognition and empiric treatment critical. Most literature on SFR meningoencephalitis predates widespread magnetic resonance imaging (MRI) utilization. To better understand the contemporary presentation and outcomes of this disease, we analyzed clinical and radiographic features of patients with SFR meningoencephalitis. METHODS: Patients were identified through hospital laboratory-based surveillance or through the Tennessee Unexplained Encephalitis Study. Cases meeting inclusion criteria underwent medical records review and, when available, independent review of the neuroimaging. RESULTS: Nineteen cases (11 children, 8 adults) met criteria for SFR meningoencephalitis. Rash was significantly more common in children than adults (100% vs 50%, respectively), but other clinical features were similar between the 2 groups. Cerebrospinal fluid pleocytosis and protein elevation were each seen in 87.5% of cases, and hypoglycorrhachia was present in 18.8% of cases. The "starry sky" sign (multifocal, punctate diffusion restricting or T2 hyperintense lesions) was seen on MRI in all children, but no adults. Ninety percent of patients required intensive care unit admission and 39% were intubated. Outcomes were similar between adults and children, with only 46% making a complete recovery by the time of discharge. CONCLUSIONS: SFR meningoencephalitis is a life-threatening infection. The clinical presentation varies between adults and children based on the presence of rash and brain MRI findings. The starry sky sign was ubiquitous in children and should prompt consideration of empiric treatment for SFR when present.

Targeted Metagenomics for Clinical Detection and Discovery of Bacterial Tick-Borne Pathogens.

Tick-borne diseases, due to a diversity of bacterial pathogens, represent a significant and increasing public health threat throughout the Northern Hemisphere. A high-throughput 16S V1-V2 rRNA gene-based metagenomics assay was developed and evaluated using >13,000 residual samples from patients suspected of having tick-borne illness and >1,000 controls. Taxonomic predictions for tick-borne bacteria were exceptionally accurate, as independently validated by secondary testing. Overall, 881 specimens were positive for bacterial tick-borne agents. Twelve tick-borne bacterial species were detected, including two novel pathogens, representing a 100% increase in the number of tick-borne bacteria identified compared to what was possible by initial PCR testing. In three blood specimens, two tick-borne bacteria were simultaneously detected. Seven bacteria, not known to be tick transmitted, were also confirmed to be unique to samples from persons suspected of having tick-borne illness. These results indicate that 16S V1-V2 metagenomics can greatly simplify diagnosis and accelerate the discovery of bacterial tick-borne pathogens.

Update on fungal infections of the central nervous system: emerging pathogens and emerging diagnostics.

PURPOSE OF REVIEW: Fungal infections of the central nervous system (CNS) are relatively uncommon but associated with significant morbidity and mortality. We reviewed recent literature highlighting new approaches to management of these complex patients. RECENT FINDINGS: Fungal infections are increasingly recognized as important causes of CNS disease in both immunocompromised and immunocompetent hosts. Globally, cryptococcal meningitis remains a leading cause of death in HIV-infected persons in resource-limited settings. Emerging fungal pathogens with increased virulence and resistance to numerous classes of antifungal agents have been identified and represent a management challenge. Newer diagnostic techniques focused on antigen detection or molecular amplification of fungal pathogens offer promise in the expediated diagnosis and treatment of CNS fungal infections. SUMMARY: Meningitis and brain abscess because of invasive fungal pathogens are frequently fatal infections. Newer laboratory tests allowing antigen detection or molecular amplification from cerebrospinal fluid are more sensitive than culture and allow earlier initiation of effective therapy.

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.

Detection of (1,3)-ß-d-Glucan in Cerebrospinal Fluid in Histoplasma Meningitis.

The diagnosis of central nervous system (CNS) histoplasmosis is often difficult. Although cerebrospinal fluid (CSF) (1,3)-ß-d-glucan (BDG) is available as a biological marker for the diagnosis of fungal meningitis, there are limited data on its use for the diagnosis of Histoplasma meningitis. We evaluated CSF BDG detection, using the Fungitell assay, in patients with CNS histoplasmosis and controls. A total of 47 cases and 153 controls were identified. The control group included 13 patients with a CNS fungal infection other than histoplasmosis. Forty-nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. The median CSF BDG level was 85 pg/ml for cases, compared to <31 pg/ml for all controls (P < 0.05) and 82 pg/ml for controls with other causes of fungal meningitis (P = 0.27). The sensitivity for detection of BDG in CSF was 53.2%, whereas the specificity was 86.9% versus all controls and 46% versus other CNS fungal infections. CSF BDG levels of ≥80 pg/ml are neither sensitive nor specific to support a diagnosis of Histoplasma meningitis.

Encephalitis Surveillance through the Emerging Infections Program, 1997-2010.

Encephalitis is a devastating illness that commonly causes neurologic disability and has a case fatality rate >5% in the United States. An etiologic agent is identified in <50% of cases, making diagnosis challenging. The Centers for Disease Control and Prevention Emerging Infections Program (EIP) Encephalitis Project established syndromic surveillance for encephalitis in New York, California, and Tennessee, with the primary goal of increased identification of causative agents and secondary goals of improvements in treatment and outcome. The project represents the largest cohort of patients with encephalitis studied to date and has influenced case definition and diagnostic evaluation of this condition. Results of this project have provided insight into well-established causal pathogens and identified newer causes of infectious and autoimmune encephalitis. The recognition of a possible relationship between enterovirus D68 and acute flaccid paralysis with myelitis underscores the need for ongoing vigilance for emerging causes of neurologic disease.

Monitoring Effect of Human Papillomavirus Vaccines in US Population, Emerging Infections Program, 2008-2012.

In 2007, five Emerging Infections Program (EIP) sites were funded to determine the feasibility of establishing a population-based surveillance system for monitoring the effect of human papillomavirus (HPV) vaccine on pre-invasive cervical lesions. The project involved active population-based surveillance of cervical intraepithelial neoplasia grades 2 and 3 and adenocarcinoma in situ as well as associated HPV types in women >18 years of age residing in defined catchment areas; collecting relevant clinical information and detailed HPV vaccination histories for women 18-39 years of age; and estimating the annual rate of cervical cancer screening among the catchment area population. The first few years of the project provided key information, including data on HPV type distribution, before expected effect of vaccine introduction. The project's success exemplifies the flexibility of EIP's network to expand core activities to include emerging surveillance needs beyond acute infectious diseases. Project results contribute key information regarding the impact of HPV vaccination in the United States.

Cardiac implanted electronic device-related infective endocarditis: clinical features, management, and outcomes of 80 consecutive patients.

BACKGROUND: The use of cardiac implantable electronic devices (CIEDs) has expanded dramatically over the past decade, but net clinical benefit has been curtailed by increasing infectious complications. In particular, CIED-related infectious endocarditis (IE) is a serious condition with significant morbidity and mortality. METHODS: We performed a single-center, retrospective study between July 2006 and February 2011 with CIED-related IE, defined by either lead vegetations detected on echocardiography or by fulfilling Duke criteria for definite endocarditis. Clinical parameters and outcomes were detailed by electronic medical record review and vital status was confirmed by the Social Security Death Index. RESULTS: Eighty patients (median age 67, interquartile range 56-75, 58 M/22 F) were diagnosed with CIED-related IE. Overall mortality was 36% with a median time to death of 95 days from presentation. Over half (52%) of the deaths were infection related with a median time to death of 29 days. Multivariate analysis showed methicillin-resistant Staphylococcus aureus (MRSA) infection (odds ratio [OR] 0.158; 95% confidence interval [CI], 0.047-0.534; P = .003) and concomitant valve endocarditis (OR 0.141, CI 0.041-0.491, P = .002) independently predicted mortality. CONCLUSION: In this contemporary series, all-cause mortality in patients with CIED-related IE was high with a short time to death from onset of infection. MRSA and concomitant valve infection were the most powerful independent predictors of mortality.

Human papillomavirus genotypes in high-grade cervical lesions in the United States.

BACKGROUND: Two vaccines protect against human papillomaviruses (HPV) 16 and 18, which cause 70% of cervical cancer and 50% of cervical intraepithelial neoplasia 2/3 and adenocarcinoma in situ (CIN2+). Monitoring HPV types in CIN2+ may be used to assess HPV vaccine impact. METHODS: As part of a multisite vaccine impact monitoring project (HPV-IMPACT), biopsy specimens used to diagnose CIN2+ were obtained for HPV DNA typing for women aged 18-39 years. RESULTS: Among 4,121 CIN2+ cases reported during 2008-2009 in 18- to 39-year-old women 3058 (74.2%) were tested; 96% were HPV DNA positive. HPV 16 was most common (49.1%), followed by HPV 31 (10.4%) and HPV 52 (9.7%). HPV 18 prevalence was 5.5% overall. Proportion of CIN2+ cases associated with HPV 16/18 was highest (56.3%) in 25- to 29-year-old women. HPV 16/18-associated lesions were less common in non-Hispanic blacks (41.9%) and Hispanics (46.3%) compared with non-Hispanic whites (59.1%) (P < .0001); the difference remained significant when adjusted for covariates. Compared to non-Hispanic whites, HPV 35 and 58 were significantly more common in non-Hispanic blacks (14.5% vs 4.2%; 12.3% vs 3.4%) and HPV 45 was higher in Hispanics (3.7% vs 1.5%). CONCLUSIONS: Age and racial/ethnic differences in HPV type distribution may have implications for vaccine impact and should be considered in monitoring trends.

The HPV vaccine impact monitoring project (HPV-IMPACT): assessing early evidence of vaccination impact on HPV-associated cervical cancer precursor lesions.

The following paper describes a collaboration between the Centers for Disease Control and Prevention and five Emerging Infections Program sites to develop a comprehensive population-based approach to monitoring human papillomavirus (HPV) vaccine impact on cervical cancer precursors and associated HPV genotypes. The process of establishing this novel monitoring system is described, and development details such as enumeration of sources for reporting cervical intraepithelial neoplasia 2/3 and adenocarcinoma in situ, approaches to case ascertainment, electronic reporting, and HPV typing are outlined. Implementation of a feasible and sustainable surveillance system for HPV-associated cervical precancers will enable evaluation of the direct impact of HPV vaccination.

Rickettsiosis subcommittee report to the tick-borne disease working group.

Tick-borne rickettsial infections are serious, common, and difficult to diagnose. Among the most important factors leading to failure to diagnose and treat tick-borne rickettsioses effectively is a lack of consideration of the potential diagnosis by primary caregivers and emergency department physicians in patients presenting with undifferentiated acute febrile illness during tick season. This situation exists because of insufficient primary and continuing medical education of medical students, primary care and emergency medicine residents, and practicing physicians regarding tick-borne rickettsioses specific to the region where they practice. Delayed initiation of treatment with an appropriate antibiotic is associated with adverse outcomes including increased rates of hospitalization, admission to an intensive care unit, and mortality. The earliest symptoms are nonspecific, consisting of fever, headache, myalgias, and nausea and/or vomiting. Laboratory abnormalities are typically absent at this time when the therapeutic response to an appropriate antibiotic would be optimal. There is a mistaken idea among a substantial portion of physicians that the best antibiotic available, doxycycline, should not be administered to children 8 years of age or younger or during pregnancy. For all of the above reasons, there is unnecessary morbidity and mortality caused by tick-borne rickettsioses. This report proposes measures to address these critical issues regarding tick-borne rickettsioses.

Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis.

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, ß-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1ß in response to ß-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1ß and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1ß-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

Varicella reinfection in a seropositive physician following occupational exposure to localized zoster.

A 32-year-old physician with a history of chickenpox at age 5 and seropositivity to varicella-zoster virus (VZV) at age 30 developed fever and vesicular rash 14 days after examining an immunocompetent patient with localized herpes zoster ophthalmicus. Vesicular viral culture grew VZV, and the physician was diagnosed with VZV reinfection.