Aerosol infection of Balb/c mice with eastern equine encephalitis virus; susceptibility and lethality.

BACKGROUND: Eastern equine encephalitis virus is an alphavirus that naturally cycles between mosquitoes and birds or rodents in Eastern States of the US. Equine infection occurs by being bitten by cross-feeding mosquitoes, with a case fatality rate of up to 75% in humans during epizootic outbreaks. There are no licensed medical countermeasures, and with an anticipated increase in mortality when exposed by the aerosol route based on anecdotal human data and experimental animal data, it is important to understand the pathogenesis of this disease in pursuit of treatment options. This report details the clinical and pathological findings of mice infected with EEEV by the aerosol route, and use as a model for EEEV infection in humans. METHODS: Mice were exposed by the aerosol route to a dose range of EEEV to establish the median lethal dose. A pathogenesis study followed whereby mice were exposed to a defined dose of virus and sacrificed at time-points thereafter for histopathological analysis and virology. RESULTS: Clinical signs of disease appeared within 2 days post challenge, culminating in severe clinical signs within 24 h, neuro-invasion and dose dependent lethality. EEEV was first detected in the lung 1 day post challenge, and by day 3 peak viral titres were observed in the brain, spleen and blood, corresponding with severe meningoencephalitis, indicative of encephalitic disease. Lethality follows severe neurological signs, and may be linked to a threshold level of virus replication in the brain. Effective medical countermeasures for EEEV may necessitate early inoculation to inhibit infection of the brain in zoonotic incidents, and be able to traverse the blood-brain barrier to sufficiently interrupt replication in the brain in cases of aerosol infection. CONCLUSIONS: There is little human data on the hazard posed by aerosol infection with encephalitic alphaviruses, and use of EEEV as a bioweapon may be by the aerosol route. A well characterized model of aerosol exposure that recapitulates some of the most severe human clinical features is necessary to evaluate the efficacy of putative medical countermeasures, and to increase our understanding about how this route of infection induces such rapid neuro-invasion and resulting disease.

Correlations of cytokine levels in cerebrospinal fluid and peripheral blood with outcome of HHV-6B encephalitis after hematopoietic stem cell transplantation.

BACKGROUND: Human herpesvirus (HHV)-6B encephalitis has been recognized as a serious complication after allogeneic hematopoietic cell transplantation (allo-HCT). Little is known about the pathogenic mechanism for its progression. STUDY DESIGN: We retrospectively evaluated the 16 kinds of cytokines and chemokines in cerebrospinal fluid (CSF) and plasma in patients who developed HHV-6B encephalitis. Among a total of 20 patients, 12 were categorized as the poor prognosis group (died of encephalitis; n = 8 and retained sequelae; n = 4), and other eight patients were categorized as the good prognosis group (complete recovery; n = 8). RESULTS: Concentrations of CSF IL-6 and IL-8 at the onset of encephalitis were significantly higher in the poor prognosis group than in the good prognosis group (median CSF IL-6, 28.27 pg/mL vs 14.32 pg/mL, P = .004; median CSF IL-8, 128.70 pg/mL vs 59.43 pg/mL, P = .043). Regarding plasma, the concentration of each cytokine at the onset of encephalitis was not significantly different between the two groups, except IL-5. However, higher levels of IL-6, IL-7, and MCP-1 and lower levels of IL-12 were observed 1 week before the development of encephalitis in patients with poor prognosis (median IL-6; 464.17 pg/mL vs 47.82 pg/mL, P = .02; median IL-12; 1.63 pg/mL vs 6.57 pg/mL, P = .03). CONCLUSION: We found that one week before onset of HHV-6B encephalitis, poor prognosis patients had high plasma concentrations of IL-6, IL-7, and MCP-1 and low concentrations of IL-12. At the onset of encephalitis, high concentrations of IL-6 and IL-8 in CSF were more common in the poor prognosis group, consistent with other evidence that IL-6 can have a role in CNS disturbances. Our findings show that specific cytokine status is associated with severe brain damage in patients with HHV-6B encephalitis, demonstrate prognostic value of plasma IL-6 concentrations, and suggest evaluation of anti-cytokine therapeutics in patients with HHV-6B encephalitis.

Analysis of exotic squirrel trade and detection of human infections with variegated squirrel bornavirus 1, Germany, 2005 to 2018.

Following the discovery in 2015 of the variegated squirrel bornavirus 1 (VSBV-1) in fatal encephalitis cases among exotic squirrel breeders and a zoo animal caretaker in Germany, a case definition was developed. It was employed during trace-back animal trade investigations and sero-epidemiological studies among breeders and zoo animal caretakers of holdings with VSBV-1 infected squirrels. During the investigation, two possible human cases who had died of encephalitis were identified retrospectively among the squirrel breeders. Moreover, one probable human case was detected among the breeders who had a positive memory T-cell response to VSBV-1 antigen and antibodies against VSBV-1. The low rate of seropositivity found among living persons in risk groups that handle exotic squirrels privately or at zoos may reflect rareness of exposure to VSBV-1 during animal contact, a high lethality of infection or a combination of these factors. As a precaution against human exposure, testing of exotic squirrels for VSBV-1 infection and/or avoiding direct contact with exotic squirrels in zoos and private holdings is strongly advised.

Transmission of rabies through solid organ transplantation: a notable problem in China.

BACKGROUND: Due to the increasing number of DCD transplantations since 2015, the transmission of rabies through solid organ transplantation has become a notable problem in China and has attracted the attention of the public. CASE PRESENTATION: From 2015 to 2017, four solid organ recipients in our centre were successively diagnosed with rabies that was considered to have been transmitted from two donors who died due to viral encephalitis of unknown cause and acute disseminated encephalomyelitis. The incubation periods were 44, 48, 158 and 303 days. The four patients had neurological symptoms associated with rabies and died. The survival times were 44, 34, 8 and 6 days. Another kidney transplant recipient received timely post-exposure prophylaxis and has remained asymptomatic. CONCLUSIONS: Organs should be discarded whenever rabies is confirmed or suspected, especially in cases diagnosed as encephalitis of unknown cause. It is important to establish a supervisory system to manage donor-derived infectious diseases. When rabies-infected donor organs are inadvertently transplanted, the recipients must receive post-exposure prophylaxis in a timely manner, which may be the only possible effective method to prevent the transmission of rabies.

Critical West Nile Neuroinvasive Disease.

BACKGROUND: Data to guide neurointensivists seeing patients with West Nile Neuroinvasive disease (WNND) are lacking. We present a comparatively large series of patients with WNND admitted to the intensive care unit (ICU) and provide data on their early diagnosis, triage to the ICU and predictors of short-term outcomes. METHODS: We retrospectively identified patients aged ≥ 18 years old with WNND from January 1999 to November 2016. Demographic and clinical data, the modified Rankin Scale at discharge and disposition were collected. Univariate analysis was performed to find predictors of ICU admission and to assess the impact of ICU admission on the short-term outcomes. P values < 0.05 were considered significant. RESULTS: Among 26 patients, 16 were admitted to the ICU. Age < 60 years and the presentation with encephalitis and acute flaccid paralysis predicted ICU admission (P = 0.044 and 0.0007). Among patients requiring ICU admission, four died and no one was discharged home. ICU admission predicted longer hospital stay (P = 0.021), inhospital death (P = 0.034), survival with inability to walk independently (P = 0.0094), and discharge disposition other than home (P = 0.007). In the ICU group, older age was associated with longer hospital stay (P = 0.0001) and inhospital death (P = 0.035). CONCLUSION: WNND requiring ICU care has a high morbidity and mortality, especially among older patients. Survivors are highly disabled at discharge, but many improve over time. Therefore, more data on the long-term prognosis of survivors are needed to guide the goals of care in the acute setting.

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection.

BACKGROUND: Viral encephalitis is a dangerous compromise between the need to robustly clear pathogen from the brain and the need to protect neurons from bystander injury. Theiler's murine encephalomyelitis virus (TMEV) infection of C57Bl/6 mice is a model of viral encephalitis in which the compromise results in hippocampal damage and permanent neurological sequelae. We previously identified brain-infiltrating inflammatory monocytes as the primary driver of this hippocampal pathology, but the mechanisms involved in recruiting these cells to the brain were unclear. METHODS: Chemokine expression levels in the hippocampus were assessed by microarray, ELISA, RT-PCR, and immunofluorescence. Monocyte infiltration during acute TMEV infection was measured by flow cytometry. CCL2 levels were manipulated by immunodepletion and by specific removal from neurons in mice generated by crossing a line expressing the Cre recombinase behind the synapsin promoter to animals with floxed CCL2. RESULTS: Inoculation of the brain with TMEV induced hippocampal production of the proinflammatory chemokine CCL2 that peaked at 6 h postinfection, whereas inoculation with UV-inactivated TMEV did not elicit this response. Immunofluorescence revealed that hippocampal neurons expressed high levels of CCL2 at this timepoint. Genetic deletion of CCR2 and systemic immunodepletion of CCL2 abrogated or blunted the infiltration of inflammatory monocytes into the brain during acute infection. Specific genetic deletion of CCL2 from neurons reduced serum and hippocampal CCL2 levels and inhibited inflammatory monocyte infiltration into the brain. CONCLUSIONS: We conclude that intracranial inoculation with infectious TMEV rapidly induces the expression of CCL2 in neurons, and this cellular source is necessary for CCR2-dependent infiltration of inflammatory monocytes into the brain during the most acute stage of encephalitis. These findings highlight a unique role for neuronal production of chemokines in the initiation of leukocytic infiltration into the infected central nervous system.

Holocranohistochemistry enables the visualization of α-synuclein expression in the murine olfactory system and discovery of its systemic anti-microbial effects.

Braak and Del Tredici have proposed that typical Parkinson disease (PD) has its origins in the olfactory bulb and gastrointestinal tract. However, the role of the olfactory system has insufficiently been explored in the pathogeneses of PD and Alzheimer disease (AD) in laboratory models. Here, we demonstrate applications of a new method to process mouse heads for microscopy by sectioning, mounting, and staining whole skulls ('holocranohistochemistry'). This technique permits the visualization of the olfactory system from the nasal cavity to mitral cells and dopamine-producing interneurons of glomeruli in the olfactory bulb. We applied this method to two specific goals: first, to visualize PD- and AD-linked gene expression in the olfactory system, where we detected abundant, endogenous α-synuclein and tau expression in the olfactory epithelium. Furthermore, we observed amyloid-ß plaques and proteinase-K-resistant α-synuclein species, respectively, in cranial nerve-I of APP- and human SNCA-over-expressing mice. The second application of the technique was to the modeling of gene-environment interactions in the nasal cavity of mice. We tracked the infection of a neurotropic respiratory-enteric-orphan virus from the nose pad into cranial nerves-I (and -V) and monitored the ensuing brain infection. Given its abundance in the olfactory epithelia, we questioned whether α-synuclein played a role in innate host defenses to modify the outcome of infections. Indeed, Snca-null mice were more likely to succumb to viral encephalitis versus their wild-type littermates. Moreover, using a bacterial sepsis model, Snca-null mice were less able to control infection after intravenous inoculation with Salmonella typhimurium. Together, holocranohistochemistry enabled new discoveries related to α-synuclein expression and its function in mice. Future studies will address: the role of Mapt and mutant SNCA alleles in infection paradigms; the contribution of xenobiotics in the initiation of idiopathic PD; and the safety to the host when systemically targeting α-synuclein by immunotherapy.

Clinical manifestations of severe enterovirus 71 infection and early assessment in a Southern China population.

BACKGROUND: Enterovirus 71 (EV-A71) shows a potential of rapid death, but the natural history of the infection is poorly known. This study aimed to examine the natural history of EV-A71 infection. METHODS: This was a prospective longitudinal observational study performed between January 1st and October 31st, 2012, at three hospitals in Guangdong, China. Subjects with positive EV-A71 RNA laboratory test results were included. Disease progression was documented with MRI, autopsies, and follow-up. Symptoms/signs with potential association with risk of death were analyzed. RESULTS: Among the 288 patients, neurologic symptoms and signs were observed (emotional movement disorders, dyskinesia, involuntary movements, autonomic dysfunction, and disturbance of consciousness). Some of them occurred as initial symptoms. Myoclonic jerks/tremors were observed among >50% of the patients; nearly 40% of patients presented fatigue and 25% were with vomiting. Twenty-eight patients (9.7%) presented poor peripheral perfusion within 53.4 ± 26.1 h; 23 patients (8.0%) presented pulmonary edema and/or hemorrhage within 62.9 ± 28.6 h. Seventeen (5.9%) patients were in a coma. Seven (2.4%) patients died within 62.9 ± 28.6 h. Seventy-seven survivors underwent head and spinal cord MRI and 37.7% (29/77) showed abnormalities. Two fatal cases showed neuronal necrosis, softening, perivascular cuffing, colloid, and neuronophagia phenomenon in the brainstem. CONCLUSIONS: Patients with EV-A71 infection showed high complexity of symptoms and onset timing. Death risk may be indicated by autokinetic eyeball, eyeball ataxia, severe coma, respiratory rhythm abnormality, absent pharyngeal reflex, ultrahyperpyrexia, excessive tachycardia, pulmonary edema and/or hemorrhage, and refractory shock and ataxic respiration. Early assessment of these symptoms/signs is important for proper management.

Nipah Virus Transmission from Bats to Humans Associated with Drinking Traditional Liquor Made from Date Palm Sap, Bangladesh, 2011-2014.

Nipah virus (NiV) is a paramyxovirus, and Pteropus spp. bats are the natural reservoir. From December 2010 through March 2014, hospital-based encephalitis surveillance in Bangladesh identified 18 clusters of NiV infection. The source of infection for case-patients in 3 clusters in 2 districts was unknown. A team of epidemiologists and anthropologists investigated these 3 clusters comprising 14 case-patients, 8 of whom died. Among the 14 case-patients, 8 drank fermented date palm sap (tari) regularly before their illness, and 6 provided care to a person infected with NiV. The process of preparing date palm trees for tari production was similar to the process of collecting date palm sap for fresh consumption. Bat excreta was reportedly found inside pots used to make tari. These findings suggest that drinking tari is a potential pathway of NiV transmission. Interventions that prevent bat access to date palm sap might prevent tari-associated NiV infection.

ROLE OF VIRAL PATHOGENS IN INFANTS WITH SYSTEMIC INFECTION AT THE NEWBORN INTENSIVE CARE UNITS IN GEORGIA.

In Georgia, causative agents among infants with systemic infections are generally not identified and "neonatal sepsis" is usually diagnosed and treated without determining the etiology. The objective of this study was to estimate the role of viral pathogens (Herpesviridae and Enteroviruses) among neonates with generalized infections. A cross-sectional study was performed among neonates younger than <8 weeks admitted to a neonatal intensive care unit (NICU) at the two largest pediatric hospitals in Tbilisi, Georgia. Laboratory tests were performed by consensus and then by type-specific PCR methods. A total of 187 infants were recruited from the NICUs; most participants (74.9%) were of normal birth weight at admission to the NICU and half (51.3%) were younger than 7 days of age. Almost all babies (91.4%) were treated with a broad-spectrum antibiotic despite a lack of microbe identification. While the overall mortality rate of infants with a systemic infection was 21.9 %, neonatal outcomes were more favorable when the infection was due to enteroviruses (2.9% mortality rate) compared to a herpesvirus infection (16.1% mortality rate). Multivariate analyses identified independent predictors associated with neonatal mortality. These included etiology of infection, APGAR score and the type of delivery. Our investigation suggests that viral pathogens play a substantial role in systemic infections among NICU infants. Utilizing molecular-based testing in these cases could improve both the clinical management and outcomes of neonates with generalized infections.

Chandipura virus infection causing encephalitis in a tribal population of Odisha in eastern India.

BACKGROUND: The sudden death of 10 children in a tribal village of Kandhamal district, Odisha in eastern India led to this investigation. METHODS: We conducted a door-to-door survey to identify cases. Antibodies for Chandipura, Japanese encephalitis, dengue, chikungunya and West Nile viruses were tested by ELISA in probable cases. Chandipura virus RNA was tested from both human blood samples and sand flies by reverse transcriptase polymerase chain reaction. We conducted vector surveys in domestic and peridomestic areas, and collected sand flies. RESULTS: Entomological investigations revealed the presence of Phlebotomus argentipes and Sergentomiya sp. Thirty-five patients presented with fever, 12 of them had altered sensorium including 4 who had convulsions. The blood samples of 21 patients were tested; four samples revealed Chandipura virusspecific IgM antibody. CONCLUSION: Chandipura virus infection causing encephalitis affected this tribal population in eastern India at 1212 m above sea level.

Type I interferon signaling protects mice from lethal henipavirus infection.

Hendra virus (HeV) and Nipah virus (NiV) are closely related, recently emerged paramyxoviruses that form Henipavirus genus and are capable of causing considerable morbidity and mortality in a number of mammalian species, including humans. However, in contrast to many other species and despite expression of functional virus entry receptors, mice are resistant to henipavirus infection. We report here the susceptibility of mice deleted for the type I interferon receptor (IFNAR-KO) to both HeV and NiV. Intraperitoneally infected mice developed fatal encephalitis, with pathology and immunohistochemical features similar to what was found in humans. Viral RNA was found in the majority of analyzed organs, and sublethally infected animals developed virus-specific neutralizing antibodies. Altogether, these results reveal IFNAR-KO mice as a new small animal model to study HeV and NiV pathogenesis, prophylaxis, and treatment and suggest the critical role of type I interferon signaling in the control of henipavirus infection.

Nipah virus infection outbreak with nosocomial and corpse-to-human transmission, Bangladesh.

Active Nipah virus encephalitis surveillance identified an encephalitis cluster and sporadic cases in Faridpur, Bangladesh, in January 2010. We identified 16 case-patients; 14 of these patients died. For 1 case-patient, the only known exposure was hugging a deceased patient with a probable case, while another case-patient's exposure involved preparing the same corpse for burial by removing oral secretions and anogenital excreta with a cloth and bare hands. Among 7 persons with confirmed sporadic cases, 6 died, including a physician who had physically examined encephalitis patients without gloves or a mask. Nipah virus-infected patients were more likely than community-based controls to report drinking raw date palm sap and to have had physical contact with an encephalitis patient (29% vs. 4%, matched odds ratio undefined). Efforts to prevent transmission should focus on reducing caregivers' exposure to infected patients' bodily secretions during care and traditional burial practices.

Hexamethonium reverses the lethal cardiopulmonary damages in a rat model of brainstem lesions mimicking fatal enterovirus 71 encephalitis.

OBJECTIVES: Among enterovirus 71 infections, brainstem encephalitis progressing abruptly to cardiac dysfunction and pulmonary edema causes rapid death within several hours. However, no currently known early indicators and treatments can monitor or prevent the unexpectedly fulminant course. We investigate the possible mechanisms and treatment of fatal enterovirus 71 infections to prevent the abrupt progression to cardiac dysfunction and pulmonary edema by using an animal model. DESIGN: Treatment study. SETTING: Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: We microinjected 6-hydroxydopamine or vitamin C into nucleus tractus solitarii of the rat and evaluated the cardiopulmonary changes after treatment with ganglionic blocker. MEASUREMENTS AND MAIN RESULTS: The time course of changes in the heart and lungs of rats with brainstem lesions were investigated. Rats were administered 6-hydroxydopamine to induce brainstem lesions, causing acute hypertension in 10 minutes and acute elevations of catecholamines accompanied by acute cardiac dysfunction and increased strong expressions of connexin 43 gap junction protein in heart and lung specimens by immunohistochemical staining within 3 hours. Severe pulmonary hemorrhagic edema was produced within 6 hours, and the rats expired rapidly within 7 hours. After hexamethonium treatment, it was found that the acute hypertension induced by 6-hydroxydopamine lesions was immediately reversed and the acute high rise of catecholamine serum level was significantly attenuated within 3 hours, accompanied by preserved cardiac output and decreased expressions of connexin 43 in the heart and lungs. No pulmonary edema occurred and the rats survived for more than 14 hours. CONCLUSIONS: Early hexamethonium treatment attenuates acute excessive release of catecholamines to prevent cardiac dysfunction and pulmonary edema for increasing survival rate.

Clinical and pathological manifestations of human henipavirus infection.

The clinicopathological features of human Nipah virus and Hendra virus infections appear to be similar. The clinical manifestations may be mild, but if severe, includes acute encephalitic and pulmonary syndromes with a high mortality. The pathological features in human acute henipavirus infections comprise vasculopathy (vasculitis, endothelial multinucleated syncytia, thrombosis), microinfarcts and parenchymal cell infection in the central nervous system, lung, kidney and other major organs. Viral inclusions, antigens, nucleocapsids and RNA are readily demonstrated in blood vessel wall and numerous types of parenchymal cells. Relapsing henipavirus encephalitis is a rare complication reported in less than 10% of survivors of the acute infection and appears to be distinct from the acute encephalitic syndrome. Pathological evidence suggests viral recrudescence confined to the central nervous system as the cause.

Human herpesvirus-6 encephalitis during hematopoietic stem cell transplantation leads to poor prognosis.

INTRODUCTION: Indications for the application of hematopoietic stem cell transplantation (HSCT) from alternative donors have remarkably broadened in scope; however, the incidence of infections that lead to failure of HSCT, such as human herpesvirus-6 (HHV-6) encephalitis, has also increased. METHODS: We analyzed risk factors for symptomatic HHV-6 reactivation and the development of HHV-6 encephalitis in 140 consecutive adult patients who received allogeneic HSCT at our institution. Stem cell sources for the recipients were as follows: related-donor bone marrow in 40, related-donor peripheral blood in 5, unrelated bone marrow in 67, and unrelated cord blood in 28. RESULTS: Symptomatic HHV-6 reactivation occurred in 22 patients (16%), and 11 patients manifested encephalitis. Multivariate Cox proportional hazards regression analysis identified cord blood cell transplantation (CBT) as an independent predictor of HHV-6 reactivation (P = 0.008). Hyponatremia or hypernatremia at the time of HHV-6 reactivation was detected before the development of HHV-6 encephalitis in 2 or 4 patients, respectively. Two patients died of HHV-6 encephalitis and 6 patients died of relapse of underlying diseases. Survival analysis identified higher risk of the disease (P = 0.021) and HHV-6 encephalitis (P = 0.003) as independent risk factors for reduced overall survival. CONCLUSION: In cases involving CBT or unrelated-donor transplantation, patients should be carefully monitored for the symptomatic reactivation of HHV-6.

Treatment of pandemic influenza A (H1N1) 2009-associated encephalopathy in children.

BACKGROUND: The novel pandemic influenza A (H1N1) 2009 virus (influenza A(H1N1)pdm09) caused an epidemic of critical illness, with some patients developing fatal encephalopathy as well as pneumonia. METHODS: To investigate the actual efficacy of treatments, we investigated data from questionnaires regarding 207 cases that occurred between September 2009 and February 2010. RESULTS: The outcomes were recorded in 188 of the 207 cases; 16 of 188 patients died, while 23 had sequelae. Anti-influenza drugs in patients with severe coma (Glasgow coma scale score of ≤ 8) were statistically effective. In 165 out of 199 cases, steroid pulse treatment with methylprednisolone was given at an early stage. Other intensive treatments were mostly administered in serious cases. CONCLUSIONS: Controlled studies are needed to investigate the efficacy of other treatments except for anti-influenza drugs.

Decompressive craniectomy for encephalitis with brain herniation: case report and review of the literature.

BACKGROUND: Decompressive craniectomy (DC) has been sporadically used in cases of infectious encephalitis with brain herniation. Like for other indications of DC, evidence is lacking regarding the beneficial or detrimental effects for this pathology. METHODS: We reviewed all the cases of viral and bacterial encephalitis treated with decompressive craniectomy reported in the literature. We also present one case from our institution. These data were analyzed to determine the relation between clinical and epidemiological variables and outcome in surgically treated patients. RESULTS: Of 48 patients, 39 (81.25 %) had a favorable functional recovery and 9 (18.75 %) had a negative course. Only two patients (4 %) died after surgical treatment. A statistically significant association was found between diagnosis (viral and bacterial encephalitis) and outcome (GOS) in surgically treated patients. Viral encephalitis, usually caused by herpes simplex virus (HSV), has a more favorable outcome (92.3 % with GOS 4 or 5) than bacterial encephalitis (56.2 % with GOS 4 or 5). CONCLUSIONS: Based on this literature review, we consider that, due to the specific characteristics of infectious encephalitis, especially in case of viral infection, decompressive craniectomy is probably an effective treatment when brain stem compression threatens the course of the disease. In patients with viral encephalitis, better prognosis can be expected when surgical decompression is used than when only medical treatment is provided.

The etiological diagnosis and outcome in patients of acute febrile encephalopathy: a prospective observational study at tertiary care center.

BACKGROUND: Acute febrile encephalopathy (AFE) is a clinical term used to an altered mental state that either accompanies or follows a short febrile illness and is characterized by a diffuse and nonspecific brain insult manifested by a combination of coma, seizures, and decerebration. OBJECTIVE: To identify the etiological diagnosis and outcome in adult patients with AFE. SETTINGS AND DESIGN: A prospective observational study was done in patients aged 14 years or above who were admitted with AFE at a tertiary care center in northwest India. MATERIALS AND METHODS: The non-infectious causes of unconsciousness were excluded and then only a diagnosis of AFE was considered. Cerebrospinal fluid (CSF) analysis and imaging of brain was done to determine the possible etiology. Outcome was assessed at 1 month of follow-up after discharge by using modified Rankin Scale (mRS). Data were analyzed and presented as mean, median, and percentages. A P value of <0.05 was considered significant. RESULTS: Of the total 120 patients studied, pyogenic meningitis was the most common cause accounting for 36.7%, followed by acute viral encephalitis (AVE) in 28.33% of the patients (Japanese B encephalitis in 12.5%, herpes simplex virus encephalitis in 3.33%, and other undetermined viral etiology in 12.5%). Cerebral malaria, sepsis associated encephalopathy (SAE), and tuberculous meningitis were diagnosed in 21.7%, 9.17%, and 4.2% of cases, respectively. Of the total, 16 patients died, 6 with AVE, 3 with pyogenic meningitis, 3 with cerebral malaria, and 4 with SAE. mRS at discharge was >3 in 14 patients with AVE (P < 0.001), and in the remaining it was <3. After 1 month, mRS was >3 in six patients with AVE and in the rest it was ≤1 (P < 0.001). CONCLUSIONS: In this study, pyogenic meningitis was the leading cause of AFE, followed by AVE and cerebral malaria. The outcome in cases with AVE can be fatal or more disabling than other etiologies.

Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion.

The development of a tractable small animal model faithfully reproducing human coronavirus disease 2019 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high central nervous system infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model's usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction but did not lead to fatal viral neuroinvasion. When compared with intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition, and a transcriptional signature comparable to that observed in SARS-CoV-2­infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection), and therapeutic interventions.