Newly Recognized Spotted Fever Group Rickettsia as Cause of Severe Rocky Mountain Spotted Fever-Like Illness, Northern California, USA.

The incidence of spotted fever group (SFG) rickettsioses in the United States has tripled since 2010. Rocky Mountain spotted fever, the most severe SFG rickettsiosis, is caused by Rickettsia rickettsii. The lack of species-specific confirmatory testing obfuscates the relative contribution of R. rickettsii and other SFG Rickettsia to this increase. We report a newly recognized rickettsial pathogen, Rickettsia sp. CA6269, as the cause of severe Rocky Mountain spotted fever-like illness in 2 case-patients residing in northern California. Multilocus sequence typing supported the recognition of this pathogen as a novel Rickettsia genotype most closely related to R. rickettsii. Cross-reactivity observed for an established molecular diagnostic test indicated that Rickettsia sp. CA6269 might be misidentified as R. rickettsii. We developed a Rickettsia sp. CA6269-specific real-time PCR to help resolve this diagnostic challenge and better characterize the spectrum of clinical disease and ecologic epidemiology of this pathogen.

Implementation of California COVIDNet - a multi-sector collaboration for statewide SARS-CoV-2 genomic surveillance.

Introduction: The SARS-CoV-2 pandemic represented a formidable scientific and technological challenge to public health due to its rapid spread and evolution. To meet these challenges and to characterize the virus over time, the State of California established the California SARS-CoV-2 Whole Genome Sequencing (WGS) Initiative, or "California COVIDNet". This initiative constituted an unprecedented multi-sector collaborative effort to achieve large-scale genomic surveillance of SARS-CoV-2 across California to monitor the spread of variants within the state, to detect new and emerging variants, and to characterize outbreaks in congregate, workplace, and other settings. Methods: California COVIDNet consists of 50 laboratory partners that include public health laboratories, private clinical diagnostic laboratories, and academic sequencing facilities as well as expert advisors, scientists, consultants, and contractors. Data management, sample sourcing and processing, and computational infrastructure were major challenges that had to be resolved in the midst of the pandemic chaos in order to conduct SARS-CoV-2 genomic surveillance. Data management, storage, and analytics needs were addressed with both conventional database applications and newer cloud-based data solutions, which also fulfilled computational requirements. Results: Representative and randomly selected samples were sourced from state-sponsored community testing sites. Since March of 2021, California COVIDNet partners have contributed more than 450,000 SARS-CoV-2 genomes sequenced from remnant samples from both molecular and antigen tests. Combined with genomes from CDC-contracted WGS labs, there are currently nearly 800,000 genomes from all 61 local health jurisdictions (LHJs) in California in the COVIDNet sequence database. More than 5% of all reported positive tests in the state have been sequenced, with similar rates of sequencing across 5 major geographic regions in the state. Discussion: Implementation of California COVIDNet revealed challenges and limitations in the public health system. These were overcome by engaging in novel partnerships that established a successful genomic surveillance program which provided valuable data to inform the COVID-19 public health response in California. Significantly, California COVIDNet has provided a foundational data framework and computational infrastructure needed to respond to future public health crises.

Trends of Enterovirus D68 Concentrations in Wastewater, California, USA, February 2021-April 2023.

In this retrospective study, we measured enterovirus D68 (EV-D68) genomic RNA in wastewater solids longitudinally at 2 California, USA, wastewater treatment plants twice per week for 26 months. EV-D68 RNA was undetectable except when concentrations increased from mid-July to mid-December 2022, which coincided with a peak in confirmed EV-D68 cases.

Lessons Learned From a COVID-19 Dog Screening Pilot in California K-12 Schools.

This diagnostic study describes a dog screening program used to identify COVID-19 infections among schoolchildren.

Acute Fulminant Cerebral Edema: A Newly Recognized Phenotype in Children With Suspected Encephalitis.

BACKGROUND: Encephalitis is a severe neurological syndrome associated with significant morbidity and mortality. The California Encephalitis Project (CEP) enrolled patients for more than a decade. A subset of patients with acute and fulminant cerebral edema was noted. METHODS: All pediatric encephalitis patients with cerebral edema referred to the CEP between 1998 and 2012 were reviewed. A case definition was developed for acute fulminant cerebral edema (AFCE) that included the CEP case definition for encephalitis and progression to diffuse cerebral edema on neuroimaging and/or autopsy, and no other recognized etiology for cerebral edema (eg, organic, metabolic, toxin). Prodromic features, demographic and laboratory data, neuroimaging, and outcomes were compared with non-AFCE encephalitis cases. RESULTS: Of 1955 pediatric cases referred to the CEP, 30 (1.5%) patients met the AFCE case definition. The median age for AFCE and non-AFCE cases was similar: 8.2 years (1-18 years) and 8.0 years (0.5-18 years), respectively. Asian-Pacific Islanders comprised a larger proportion of AFCE cases (44%) compared with non-AFCE cases (14%, P < .01). AFCE cases often had a prodrome of high fever, vomiting, and profound headache. Mortality among AFCE patients was significantly higher than among non-AFCE patients (80% vs 13%, P < .01). A confirmed etiology was identified in only 2 cases (enterovirus, human herpes virus type 6), while 10 others had evidence of a respiratory pathogen.Thirty pediatric patients referred to the California Encephalitis Project with a unique, and often fatal, form of encephalitis are reported. Demographic and clinical characteristics, possible etiologies and a proposed case definition for acute fulminant cerebral edema (AFCE) are described. CONCLUSIONS: AFCE is a recently recognized phenotype of encephalitis with a high mortality. AFCE may be triggered by common pediatric infections. Here, we propose a case definition.

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.

Incidence, Risk Factors and Outcomes Among Children With Acute Flaccid Myelitis: A Population-based Cohort Study in a California Health Network Between 2011 and 2016.

BACKGROUND: Acute flaccid myelitis (AFM) is defined as an acute onset of limb weakness with longitudinal spinal gray matter lesions. Reporting bias and misdiagnosis confound epidemiologic studies of AFM. We mitigated these confounders by using a large data set to assess AFM incidence, risk factors and outcomes in a fixed population. METHODS: A retrospective cohort study was conducted within Kaiser Permanente Northern California population among children 1-18 years. Cases met radiographic and clinical criteria for AFM and were confirmed by two clinicians. Clinical and demographic data were assessed. RESULTS: A total of 28 patients met study criteria for AFM between January 1, 2011 and December 31, 2016, an overall rate of 1.46 per 100,000 person-years. Incidence increased from 0.30 to 1.43 cases/per 100,000 person-years between 2011 and 2016, respectively. Median age was 9 years. Risk factors included male sex, Asian ancestry and history of asthma, atopic dermatitis or head injury. Risk factors associated with poliomyelitis were absent. Prodromal illness was common; enterovirus was the most common pathogen detected (n = 5). Among the 27 patients with 12-month follow-up, most demonstrated some improvement, 11 (41.0%) had full recovery, but several had significant deficits with one death reported after the study period. CONCLUSIONS: We employed a closed-population study to generate AFM incidence, risk and outcome data. Our findings support previous reports of male sex and atopy as risk factors. Interval increase in incidence, predisposing Asian ancestry and history of head injury were unique findings to this study. Overall prognosis was better than prior reports, but recovery was incomplete in several patients.

Acute flaccid myelitis: A clinical review of US cases 2012-2015.

This review highlights clinical features of the increasing cases of acute flaccid paralysis associated with anterior myelitis noted in the United States from 2012 to 2015. Acute flaccid myelitis refers to acute flaccid limb weakness with spinal cord gray matter lesions on imaging or evidence of spinal cord motor neuron injury on electrodiagnostic testing. Although some individuals demonstrated improvement in motor weakness and functional deficits, most have residual weakness a year or more after onset. Epidemiological evidence and biological plausibility support an association between enterovirus D68 and the recent increase in acute flaccid myelitis cases in the United States. Ann Neurol 2016;80:326-338.

Human neurexin-3α antibodies associate with encephalitis and alter synapse development.

OBJECTIVE: To report a novel autoimmune encephalitis in which the antibodies target neurexin-3α, a cell adhesion molecule involved in the development and function of synapses. METHODS: Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques. RESULTS: Immunoprecipitation and cell-based assays identified neurexin-3α as the autoantigen of patients' antibodies. All 5 patients (median age 44 years, range 23-50; 4 female) presented with prodromal fever, headache, or gastrointestinal symptoms, followed by confusion, seizures, and decreased level of consciousness. Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had findings suggesting propensity to autoimmunity. CSF was abnormal in all patients (4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal lobes). All received steroids, 1 IV immunoglobulin, and 1 cyclophosphamide; 3 partially recovered, 1 died of sepsis while recovering, and 1 had a rapid progression to death. At autopsy, edema but no inflammatory cells were identified. Cultures of neurons exposed during days in vitro (div) 7-17 to patients' IgG showed a decrease of neurexin-3α clusters as well as the total number of synapses. No reduction of synapses occurred in mature neurons (div 18) exposed for 48 hours to patients' IgG. Neuronal survival, dendritic morphology, and spine density were unaffected. CONCLUSION: Neurexin-3α autoantibodies associate with a severe but potentially treatable encephalitis in which the antibodies cause a decrease of neurexin-3α and alter synapse development.

A clinical approach to diagnosis of autoimmune encephalitis.

Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.

Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study.

BACKGROUND: Epidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS. METHODS AND RESULTS: We enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (≤3 weeks after stroke/trauma); cases had convalescent samples (7-28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1-14.3) years for cases and 10.7 (6.9-13.2) years for controls (P=0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2-4.0; P=0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic. CONCLUSIONS: Herpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship.

Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study.

OBJECTIVES: Minor infection can trigger adult arterial ischemic stroke (AIS) and is common in childhood. We tested the hypotheses that infection transiently increases risk of AIS in children, regardless of stroke subtype, while vaccination against infection is protective. METHODS: The Vascular Effects of Infection in Pediatric Stroke study is an international case-control study that prospectively enrolled 355 centrally confirmed cases of AIS (29 days-18 years old) and 354 stroke-free controls. To determine prior exposure to infections and vaccines, we conducted parental interviews and chart review. RESULTS: Median (interquartile range) age was 7.6 years for cases and 9.3 for controls (p = 0.44). Infection in the week prior to stroke, or interview date for controls, was reported in 18% of cases, vs 3% of controls, conferring a 6.3-fold increased risk of AIS (p < 0.0001); upper respiratory infections were most common. Prevalence of preceding infection was similar across stroke subtypes: arteriopathic, cardioembolic, and idiopathic. Use of vasoactive cold medications was similarly low in both groups. Children with some/few/no routine vaccinations were at higher stroke risk than those receiving all or most (odds ratio [OR] 7.3, p = 0.0002). In an age-adjusted multivariate logistic regression model, independent risk factors for AIS included infection in the prior week (OR 6.3, p < 0.0001), undervaccination (OR 8.2, p = 0.0004), black race (compared to white; OR 1.9, p = 0.009), and rural residence (compared to urban; OR 3.0, p = 0.0003). CONCLUSIONS: Infection may act as a trigger for childhood AIS, while routine vaccinations appear protective. Hence, efforts to reduce the spread of common infections might help prevent stroke in children.

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.

Epilepsy After Resolution of Presumed Childhood Encephalitis.

OBJECTIVE: To evaluate factors associated with the development of epilepsy after resolution of presumed childhood encephalitis. METHODS: A total of 217 patients with suspected encephalitis who met criteria for the California Encephalitis Project were identified. Evaluable outcome information was available for 99 patients (40 girls, 59 boys, ages 2 months to 17 years) without preexisting neurological conditions, including prior seizures or abnormal brain magnetic resonance imaging scans. We identified factors correlated with the development of epilepsy after resolution of the acute illness. RESULTS: Development of epilepsy was correlated with the initial presenting sign of seizure (P < 0.001). With each additional antiepileptic drug used to control seizures, the odds ratio of developing epilepsy was increased twofold (P < 0.001). An abnormal electroencephalograph (P < 0.05) and longer hospital duration (median of 8 versus 21 days) also correlated with development of epilepsy (P < 0.01). The need for medically induced coma was associated with epilepsy (P < 0.001). Seizures in those patients were particularly refractory, often requiring longer than 24 hours to obtain seizure control. Individuals who required antiepileptic drugs at discharge (P < 0.001) or were readmitted after their acute illness (P < 0.001) were more likely to develop epilepsy. Of our patients who were able to wean antiepileptic drugs after being started during hospitalization, 42% were successfully tapered off within 6 months. CONCLUSIONS: Limited data are available on the risk of developing epilepsy after childhood encephalitis. This is the first study that not only identifies risk factors for the development of epilepsy, but also provides data regarding the success rate of discontinuing antiepileptic medication after resolution of encephalitis.

Acute pediatric encephalitis neuroimaging: single-institution series as part of the California encephalitis project.

PURPOSE: Diagnosing pediatric encephalitis is challenging because of varied clinical presentation, nonspecific neuroimaging features, and rare confirmation of causality. We reviewed acute neuroimaging of children with clinically suspected encephalitis to identify findings that may correlate with etiology and length of stay. METHODS: Imaging of 141 children with clinically suspected encephalitis as part of The California Encephalitis Project from 2005 to 2012 at a single institution was reviewed to compare the extent of neuroimaging abnormalities to patient age, gender, length of stay, and unknown, possible, or confirmed pathogen. Scan review was blinded and categorized by extent and distribution of abnormal findings. RESULTS: Abnormal findings were evident on 23% (22/94) of computed tomography and 50% (67/134) of magnetic resonance imaging studies in the acute setting. Twenty children with normal admission computed tomography had abnormal findings on magnetic resonance imaging performed within 2 days. Length of stay was significantly longer among children with abnormal acute magnetic resonance imaging (P < 0.001) and correlated with increased complexity (Spearman rho = 0.4, P < 0.001) categorized as: no imaging abnormality, meningeal enhancement and/or focal nonenhancing lesion, multifocal lesions, confluent lesions, and lesions plus diffusion restriction, hemorrhage, or hydrocephalus. There was no correlation between neuroimaging findings and an identifiable pathogen (P = 0.8). CONCLUSION: Abnormal magnetic resonance imaging findings are more common than abnormal computed tomography findings in pediatric encephalitis. Increasing complexity of magnetic resonance imaging findings correlated with disease severity as evidenced by longer length of stay, but were not specific for an identifiable pathogen using a standardized diagnostic encephalitis panel.

Use of clinical and neuroimaging characteristics to distinguish temporal lobe herpes simplex encephalitis from its mimics.

BACKGROUND: We describe the spectrum of etiologies associated with temporal lobe (TL) encephalitis and identify clinical and radiologic features that distinguish herpes simplex encephalitis (HSE) from its mimics. METHODS: We reviewed all adult cases of encephalitis with TL abnormalities on magnetic resonance imaging (MRI) from the California Encephalitis Project. We evaluated the association between specific clinical and MRI characteristics and HSE compared with other causes of TL encephalitis and used multivariate logistic modeling to identify radiologic predictors of HSE. RESULTS: Of 251 cases of TL encephalitis, 43% had an infectious etiology compared with 16% with a noninfectious etiology. Of infectious etiologies, herpes simplex virus was the most commonly identified agent (n = 60), followed by tuberculosis (n = 8) and varicella zoster virus (n = 7). Of noninfectious etiologies, more than half (n = 21) were due to autoimmune disease. Patients with HSE were older (56.8 vs 50.2 years; P = .012), more likely to be white (53% vs 35%; P = .013), more likely to present acutely (88% vs 64%; P = .001) and with a fever (80% vs 49%; P < .001), and less likely to present with a rash (2% vs 15%; P = .010). In a multivariate model, bilateral TL involvement (odds ratio [OR], 0.38; 95% confidence interval [CI], .18-.79; P = .010) and lesions outside the TL, insula, or cingulate (OR, 0.37; 95% CI, .18-.74; P = .005) were associated with lower odds of HSE. CONCLUSIONS: In addition to HSE, other infectious and noninfectious etiologies should be considered in the differential diagnosis for TL encephalitis, depending on the presentation. Specific clinical and imaging features may aid in distinguishing HSE from non-HSE causes of TL encephalitis.

Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015.

IMPORTANCE: There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology. OBJECTIVE: To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury. DESIGN, SETTING, AND PARTICIPANTS: Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing. MAIN OUTCOMES AND MEASURES: Case incidence and infectious agent association. RESULTS: Fifty-nine cases were identified. Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100,000 person-years) compared with other monitoring periods (0.028 cases per 100,000 person-years; P <.001). CONCLUSIONS AND RELEVANCE: In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.

Emerging and reemerging neurologic infections.

The list of emerging and reemerging pathogens that cause neurologic disease is expanding. Various factors, including population growth and a rise in international travel, have contributed to the spread of pathogens to previously nonendemic regions. Recent advances in diagnostic methods have led to the identification of novel pathogens responsible for infections of the central nervous system. Furthermore, new issues have arisen surrounding established infections, particularly in an increasingly immunocompromised population due to advances in the treatment of rheumatologic disease and in transplant medicine.