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1.
Lab Invest ; 100(4): 596-605, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31857694

RESUMO

Enterovirus A71 (EV-A71) infection is primarily responsible for fatal hand, foot, and mouth disease (HFMD) cases. Infants and younger children are more likely to suffer central nervous system damage as a result of EV-A71 infection, but this virus mostly does not affect older children and adults. This study investigated the possible mechanism underlying the age-dependent lethal effect of EV-A71 infection by comparing neonatal and adult mouse models of EV-A71 infection. Although viral proliferation is absent in both neonatal and adult mice, we observed that EV-A71, as a stimulus for astrocytes, elevates the levels of cytokines and monoamine neurotransmitters in neonatal mice. Then, we selected IL-6 and adrenaline as targets in a pharmacological approach to further validate the roles of these factors in mediating the mortality of neonatal mice after EV-A71 infection. Intracerebral injection of IL-6 and adrenaline enhanced the severity of EV-A71 infection, while treatment with an anti-IL-6-neutralizing antibody or the adrenergic-antagonist phenoxybenzamine reversed the lethal effect of EV-A71 in neonatal mice. These results suggest that the central nervous system (CNS) damage in neonatal cases of EV-A71 infection might be caused by an activated fetal cerebral immune response to the virus, including the disruption of brainstem function through increased levels of cytokines and neurotransmitters, rather than the typical cytopathic effect (CPE) of viral infection.


Assuntos
Enterovirus Humano A/patogenicidade , Infecções por Enterovirus , Interações Hospedeiro-Patógeno/fisiologia , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Astrócitos/imunologia , Astrócitos/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/virologia , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/virologia , Feminino , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Carga Viral
2.
Am J Respir Cell Mol Biol ; 62(3): 310-318, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31533004

RESUMO

Rhinovirus (RV) exposure evokes exacerbations of asthma that markedly impact morbidity and mortality worldwide. The mechanisms by which RV induces airway hyperresponsiveness (AHR) or by which specific RV serotypes differentially evoke AHR remain unknown. We posit that RV infection evokes AHR and inflammatory mediator release, which correlate with degrees of RV infection. Furthermore, we posit that rhinovirus C-induced AHR requires paracrine or autocrine mediator release from epithelium that modulates agonist-induced calcium mobilization in human airway smooth muscle. In these studies, we used an ex vivo model to measure bronchoconstriction and mediator release from infected airways in human precision cut lung slices to understand how RV exposure alters airway constriction. We found that rhinovirus C15 (RV-C15) infection augmented carbachol-induced airway narrowing and significantly increased release of IP-10 (IFN-γ-induced protein 10) and MIP-1ß (macrophage inflammatory protein-1ß) but not IL-6. RV-C15 infection of human airway epithelial cells augmented agonist-induced intracellular calcium flux and phosphorylation of myosin light chain in co-cultured human airway smooth muscle to carbachol, but not after histamine stimulation. Our data suggest that RV-C15-induced structural cell inflammatory responses are associated with viral load but that inflammatory responses and alterations in agonist-mediated constriction of human small airways are uncoupled from viral load of the tissue.


Assuntos
Sinalização do Cálcio , Infecções por Enterovirus/fisiopatologia , Enterovirus/fisiologia , Músculo Liso/virologia , Hipersensibilidade Respiratória/etiologia , Asma/virologia , Carbacol/farmacologia , Células Cultivadas , Quimiocina CXCL10/metabolismo , Enterovirus/genética , Enterovirus/isolamento & purificação , Infecções por Enterovirus/virologia , Histamina/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Cadeias Leves de Miosina/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , RNA Viral/análise , Hipersensibilidade Respiratória/virologia , Carga Viral
3.
Folia Med Cracov ; 59(1): 37-47, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31180074

RESUMO

BACKGROUND: Parechovirus and enterovirus belong to a family of Picornaviridae, non- enveloped, small-sized RNA viruses, responsible for multiple human diseases. Recent introduction of molecular tests enabled the identi cation of parechovirus and enterovirus infections. Our aim was a retrospective analysis of signs and symptoms associated with confirmed parechovirus or enterovirus infections among children treated in the Department of Neonatology, St. Louis Regional Children's Hospital in Kraków, Poland. METHODS: Based on laboratory records, we identified all cases of parecho- or enterovirus infections confirmed by identification of viral RNA in nasal swab or cerebrospinal fluid samples. Hospital records and laboratory tests results of selected patients were then analyzed, and selected data were summarized, with emphasis on clinical and laboratory findings at admission. RESULTS: We identified 11 cases of parechovirus and three of enterovirus infections. All cases were neonates admitted to hospital with fever and irritability. Except for leukopenia in 50% of patients, no significant abnormalities were noted in blood counts and serum biochemistry, including low C-reactive protein and procalcitonin. In nine cases, cerebrospinal fluid was collected, the fluid protein concentrations and cell counts were moderately increased. Final diagnosis was meningitis in 12 children, and other viral infections in two. CONCLUSIONS: Viral infection, including parecho- and enteroviruses, should be considered in the etiology of fever and meningitis in neonates. The available molecular tests allow for detection of viral genetic material even in a scant biological specimen collected from neonates.


Assuntos
Infecções por Enterovirus/fisiopatologia , Meningite Viral/fisiopatologia , Infecções por Picornaviridae/fisiopatologia , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/metabolismo , Feminino , Febre , Hospitais Pediátricos , Humanos , Recém-Nascido , Leucopenia , Masculino , Meningite Viral/diagnóstico , Meningite Viral/metabolismo , Cavidade Nasal , Parechovirus , Infecções por Picornaviridae/diagnóstico , Infecções por Picornaviridae/metabolismo , RNA Viral/líquido cefalorraquidiano , RNA Viral/metabolismo , Estudos Retrospectivos
4.
Pediatr Neurol ; 96: 70-73, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30935719

RESUMO

BACKGROUND: Enterovirus-A71 causes outbreaks of brainstem encephalitis, ranging from self-limited disease to acute flaccid paralysis. The aim of this study was to assess the role of cerebrospinal fluid (CSF) neopterin as a biomarker of disease severity in children with enterovirus-related brainstem encephalitis. METHODS: A descriptive, prospective cohort study was conducted from April 2016 to March 2017 in a tertiary hospital. Pediatric patients with a diagnosis of brainstem encephalitis with or without myelitis due to enterovirus infection were enrolled. The final study group comprised a convenience sample including all patients with sufficient CSF volume for neopterin determination. The major variables considered in estimating the severity were the diagnosis of encephalomyelitis, the presence of lesions and extensive lesions on brain and spinal magnetic resonance imaging (MRI), hospital stay length greater than seven days, and sequelae at day 30. RESULTS: Of 60 patients, CSF neopterin could be measured in 36. Median age was 26 months (interquartile range: 19 to 32). Thirty-three were diagnosed with brainstem encephalitis and three with encephalomyelitis. Enterovirus-A71 was the only identified genotype (25 of 25). CSF neopterin levels were elevated (>61 nmol/L) in 33 of 36 (92%), with a median of 347 nmol/L (interquartile range: 204 to 525). CSF neopterin was useful to distinguish patients with lesions on MRI (area under the receiver operating characteristic curve = 0.76; P = 0.02) and extensive lesions (area under the receiver operating characteristic curve = 0.76; P = 0.04). CONCLUSIONS: This study suggests an association between CSF neopterin levels and the presence of inflammatory lesions on MRI.


Assuntos
Tronco Encefálico , Encefalite Viral/líquido cefalorraquidiano , Encefalomielite/líquido cefalorraquidiano , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/líquido cefalorraquidiano , Neopterina/líquido cefalorraquidiano , Tronco Encefálico/patologia , Tronco Encefálico/fisiopatologia , Tronco Encefálico/virologia , Pré-Escolar , Encefalite Viral/patologia , Encefalite Viral/fisiopatologia , Encefalite Viral/virologia , Encefalomielite/patologia , Encefalomielite/fisiopatologia , Encefalomielite/virologia , Infecções por Enterovirus/patologia , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Estudos Prospectivos
5.
Curr Med Sci ; 39(2): 237-242, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31016516

RESUMO

Few effective treatments for chronic Keshan disease have been available till now. The efficacy of long-term selenium supplementation in the treatment of chronic Keshan disease with congestive heart failure is inconclusive. This study aimed to determine whether selenium supplementation is associated with a decreased risk of cardiac death in chronic Keshan disease with congestive heart failure by ten years of follow-up. A retrospective long-term follow-up analysis was performed on a monitored cohort consisting of 302 chronic Keshan disease patients with a mean age of 40.8±11.4 years. Of the 302 chronic Keshan disease patients, 170 (56.3%) were given selenium supplementation until the end point of follow-up. Cox proportional hazards regression models were used to identify the independent predictors of cardiac events. Our results showed that during the follow-up, there were 101 deaths of patients with chronic Keshan disease in the selenium supplementation group (101/170, 59.4%) and 98 in non-selenium supplementation group (98/132, 74.2%). Multivariate analyses suggested that selenium supplementation was associated with a decreased risk of cardiac death (HR 0.39, 95% CI 0.28-0.53) after adjustment for baseline age, sex, cigarette smoking, family history of Keshan disease, body mass index (BMI), heart rate, electrocardiogram (ECG) abnormalities, blood pressure, initial cardiothoracic ratio, left ventricular ejection fractions (LVEF) and whole-blood selenium concentration. Our ten-year follow-up analysis indicated that selenium supplementation, specifically combined with the use of angiotensin-converting enzyme inhibitor and beta blocker therapy, improved the survival of patients with chronic Keshan disease with congestive heart failure. BMI, selenium deficiency, male, combined ECG abnormalities, LVEF, and fast heart rate increased the risk of cardiac events.


Assuntos
Cardiomiopatias/tratamento farmacológico , Infecções por Enterovirus/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Selênio/administração & dosagem , Adulto , Cardiomiopatias/fisiopatologia , Doença Crônica , Suplementos Nutricionais , Eletrocardiografia/métodos , Infecções por Enterovirus/fisiopatologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos
7.
Artigo em Inglês | MEDLINE | ID: mdl-30631207

RESUMO

AIMS: Enteroviruses (EVs) are the most common agents of aseptic meningitis. Some serotypes can cause serious neuroinfection leading to death. The aim of this study was to determine the representation of EVs in the etiology of aseptic meningitis in children and to analyze the demographic, clinical, laboratory, and epidemiological characteristics of patients with EV meningitis. PATIENTS AND METHODS: This was a prospective study including 147 patients in three groups: EV meningitis, tick-borne encephalitis, and aseptic meningitis with unidentified agent. RESULTS: Boys with EV meningitis predominated over girls. The average patient age was 11 years. Compared to the control group, these patients suffered more from stiff back (P=0.010), vomiting and nausea (P=0.009). They had shorter symptom duration (P<0.001), higher C-reactive protein in blood (P<0.001), higher predominance of polynuclears (P=0.026), and greater lactate (P=0.003) in cerebrospinal fluid (CSF). The serotype seen most frequently (68%) was ECHO virus (ECV) 30. CONCLUSIONS: Enteroviruses play the most important role in the differential diagnosis of aseptic meningitis. Short symptom duration, slightly higher inflammatory parameters in blood, predominance of polynuclears, and elevated CSF lactate have predictive value in diagnosing this disease. ECV 30 (frequently the agent of epidemics in the Czech Republic) was the aseptic meningitis agent most often seen.


Assuntos
Infecções por Enterovirus/genética , Infecções por Enterovirus/fisiopatologia , Enterovirus/genética , Meningite Asséptica/genética , Meningite Asséptica/fisiopatologia , Meningite Viral/genética , Meningite Viral/fisiopatologia , Adolescente , Criança , Pré-Escolar , República Tcheca/epidemiologia , Infecções por Enterovirus/epidemiologia , Feminino , Humanos , Masculino , Meningite Viral/epidemiologia , Estudos Prospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência
10.
Minerva Pediatr ; 71(2): 150-158, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30511561

RESUMO

Enterovirus (EV) and Parechovirus (HPeV) are a frequent cause of infection in children. This review gives an overview of possible causes for differences in clinical presentation. EV and HPeV can cause a meningitis with or without pleocytosis. Different possible mechanisms for meningitis without pleocytosis are given. Little is known about the prognosis and long-term effects of EV and HPeV meningitis in children. Only some studies with a small number of children with EV or HPeV meningitis are reported. The different possible mechanisms involved in the neurological outcome after EV or HPeV meningitis will be discussed.


Assuntos
Infecções por Enterovirus/epidemiologia , Meningite Viral/epidemiologia , Infecções por Picornaviridae/epidemiologia , Criança , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/virologia , Humanos , Leucocitose/epidemiologia , Leucocitose/virologia , Meningite Viral/fisiopatologia , Meningite Viral/virologia , Infecções por Picornaviridae/fisiopatologia , Infecções por Picornaviridae/virologia , Prognóstico
11.
Virology ; 526: 146-154, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30390563

RESUMO

Enterovirus D68 (EV-D68) is unique among enteroviruses because of the ability to cause severe respiratory disease as well as neurological disease. We developed separate models of respiratory and neurological disease following EV-D68 infection in AG129 mice that respond to antiviral treatment with guanidine. In four-week-old mice infected intranasally, EV-D68 replicates to high titers in lung tissue increasing the proinflammatory cytokines MCP-1 and IL-6. The respiratory infection also produces an acute viremia. In 10-day-old mice infected intraperitoneally, EV-D68 causes a neurological disease with weight-loss, paralysis, and mortality. In our respiratory model, treatment with guanidine provides a two-log reduction in lung virus titers, reduces MCP-1 and IL-6, and prevents histological lesions in the lungs. Importantly, viremia is prevented by early treatment with guanidine. In our neurological model, guanidine treatment protects mice from weight-loss, paralysis, and mortality. These results demonstrate the utility of these models for evaluation of antiviral therapies for EV-D68 infection.


Assuntos
Antivirais/uso terapêutico , Modelos Animais de Doenças , Enterovirus Humano D , Infecções por Enterovirus/tratamento farmacológico , Guanidina/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Animais , Citocinas/metabolismo , Infecções por Enterovirus/patologia , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/virologia , Masculino , Camundongos , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/virologia , Infecções Respiratórias/patologia , Infecções Respiratórias/fisiopatologia , Infecções Respiratórias/virologia , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Viremia/prevenção & controle
12.
Am J Epidemiol ; 188(2): 475-483, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30358846

RESUMO

Enterovirus A71 (EV-A71) is responsible for the majority of severe cases of hand, foot, and mouth disease, but little evidence is available on the severity profile of EV-A71 infections. We formulated a hierarchical Bayesian model that synthesized data on diseases/events associated with EV-A71 and EV-A71 antibody responses to infection among unvaccinated children from large clinical trials of EV-A71 vaccination, which were conducted in Jiangsu and Beijing during 2012 and 2013, to reconstruct the severity profile in a unified framework. On average, 15.1% of the children aged 6-35 months were infected by EV-A71 during 1-year follow-up in a mild epidemic season. We estimated that 9.7%, 2.2%, and 0.6% of children infected with EV-A71 were diagnosed with EV-A71-associated diseases, were hospitalized, and showed severe complications, respectively. We estimated on average 1 death per 10,000 EV-A71 infections for children aged 6-35 months. Approximately 70% of children had ≥4-fold rises in antibody titers after infection. Most EV-A71 infections in young children are mild, and overall 2.2% of the infected patients were hospitalized in the 2 trials. There remain several uncertainties about the immune response after infection and the duration of immunity against EV-A71 reinfection.


Assuntos
Teorema de Bayes , Infecções por Enterovirus/epidemiologia , Pré-Escolar , Infecções por Enterovirus/mortalidade , Infecções por Enterovirus/fisiopatologia , Métodos Epidemiológicos , Feminino , Humanos , Lactente , Masculino , Índice de Gravidade de Doença
14.
Medicine (Baltimore) ; 97(43): e12930, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30412100

RESUMO

Enterovirus and human parechovirus (HPeV) are RNA viruses belonging to the family Picornaviridae that frequently infect infants. These infections show a wide variety of clinical manifestations, from mild to severe. However, there are no known early clinical markers for diagnosis and prediction of disease severity. The aim of this study was to examine the clinical utility of urinary beta 2-microglobulin (ß2MG) for the early detection and prognosis of infantile enterovirus and HPeV infections.This retrospective study included 108 full-term infants younger than 60 days of age, including 15 with enterovirus or HPeV-3 (enterovirus/HPeV-3), 22 with respiratory syncytial virus (RSV), and 24 with bacterial infections. Laboratory data and clinical characteristics were compared among these 3 groups. Of the 15 patients with enterovirus/HPeV-3, 6 were treated with intravenous immunoglobulin (IVIG subgroup) because of severe clinical conditions.Urinary ß2MG to creatinine ratio (ß2MG/Cr) was significantly higher in the enterovirus/HPeV-3 group compared to bacterial and RSV infection groups (both P < .001). In the enterovirus/HPeV-3 group, mean peak urinary ß2MG/Cr was observed on day 1 or 2. Urinary ß2MG/Cr values were significantly higher in the IVIG subgroup than the non-IVIG subgroup (P < .001).Increased urinary ß2MG/Cr in early-stage infection may be a useful clinical marker for the detection and prediction of infantile enterovirus and HPeV infection severity.


Assuntos
Infecções por Enterovirus/diagnóstico , Enterovirus/isolamento & purificação , Parechovirus/isolamento & purificação , Infecções por Picornaviridae/diagnóstico , Microglobulina beta-2/urina , Biomarcadores/urina , Creatina/urina , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/urina , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Infecções por Picornaviridae/fisiopatologia , Infecções por Picornaviridae/urina , Estudos Retrospectivos , Índice de Gravidade de Doença
15.
Euro Surveill ; 23(37)2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30229724

RESUMO

BackgroundUnderstanding enterovirus D68 (EV-D68) circulation patterns as well as risk factors for severe respiratory and neurological illness is important for developing preventive strategies. Methods: Between 2010 and 2016, 11,132 respiratory specimens from hospitalised patients in Lyon, France, were screened for EV-D68 by PCR. Phylogenetic relationships of the viral-protein-1 sequences were reconstructed using maximum-likelihood and Bayesian-Markov-Chain-Monte-Carlo approaches. Results: Overall, 171 infections with a biennial pattern were detected, including seven, one, 55, none, 42, one and 65 cases annually during 2010-16. Children (< 16 years-old; n = 150) were mostly affected and 71% (n = 121) of the total patients were under 5 years-old. In 146 patients with medical reviews, 73% (n = 107) presented with acute respiratory distress. Among paediatric patients with medical reviews (n = 133), 55% (n=73) had an asthma/wheezing history, while among adults (n = 13), 11 had underlying diseases. In total, 45 patients had severe infections and 28 patients needed intensive care unit stays. No acute flaccid myelitis (AFM) was detected. We found genotypes A, B1, B2 B3 and D circulating, and no associations between these and clinical presentations. During the study, new genotypes continuously emerged, being replaced over time. We estimated that ancestors of currently circulating genotypes emerged in the late-1990s to 2010. Rises of the EV-D68 effective population size in Lyon coincided with infection upsurges. Phylogenetic analyses showed ongoing diversification of EV-D68 worldwide, coinciding with more infections in recent years and increases of reported AFM paediatric cases. Conclusions: Reinforcement of diagnostic capacities and clinical-based surveillance of EV-D68 infections is needed in Europe to assess the EV-D68 burden.


Assuntos
Enterovirus Humano D/genética , Enterovirus Humano D/isolamento & purificação , Infecções por Enterovirus/virologia , Infecções Respiratórias/virologia , Proteínas Estruturais Virais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Enterovirus Humano D/classificação , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/fisiopatologia , Feminino , França/epidemiologia , Genótipo , Hospitalização , Hospitais Universitários , Humanos , Lactente , Pulmão/virologia , Masculino , Dados de Sequência Molecular , Paralisia/etiologia , Paralisia/virologia , Filogenia , Reação em Cadeia da Polimerase , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/fisiopatologia
16.
Medicine (Baltimore) ; 97(36): e11831, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30200066

RESUMO

RATIONALE: We present the first case of enterovirus (EV) D68, lineage B3 infection, associated with acute flaccid myelitis (AFM) in Taiwan. AFM caused by EV D68 is relatively rare. This report highlights the importance of clinical recognition of the disease and discusses treatments that can benefit such patients. PATIENT CONCERNS: A 5-year-old boy experienced sudden onset of acute flaccid paralysis (AFP) involving left arm after fever and respiratory symptoms for 3 days. DIAGNOSES: Magnetic resonance imaging (MRI) of the spinal cord revealed signal changes over segments C1 to T5 on a T2-weighted image (T2WI), compatible with the diagnosis of AFM. The EV D68 strain, cultured from the throat of the patient was identified. INTERVENTIONS: We administered intravenous immunoglobulin (IVIG, 1g/kg, twice), pulse steroid therapy (methylprednisolone, 30 mg/kg, twice) and oral prednisolone (1mg/kg/day). Rehabilitation was also arranged. OUTCOMES: The patient still had mild muscle atrophy over left arm after following-up for 1 year. LESSONS: Early diagnosis and prompt management are essential for managing this kind of patient. IVIG, pulse therapy, and oral prednisolone may play crucial roles in controlling its clinical course.


Assuntos
Enterovirus Humano D , Infecções por Enterovirus/complicações , Mielite/complicações , Paralisia/complicações , Doença Aguda , Pré-Escolar , Diagnóstico Diferencial , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/terapia , Humanos , Masculino , Mielite/diagnóstico , Mielite/fisiopatologia , Mielite/terapia , Paralisia/diagnóstico , Paralisia/fisiopatologia , Paralisia/terapia , Medula Espinal/diagnóstico por imagem , Extremidade Superior/fisiopatologia
17.
Auris Nasus Larynx ; 45(5): 1093-1097, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29366609

RESUMO

Cluster of acute flaccid paralysis and cranial nerve dysfunction was associated with a 2014 outbreak of enterovirus D68 (EV-D68) respiratory illness in US. We describe a 33 year-old male patient of refractory dysphagia due to EV-D68-induced brainstem encephalitis successfully treated by surgery. Following acute upper respiratory tract infection, he developed dysphagia and bilateral facial paralysis. A coughing reflex was readily produced when the laryngopharyngeal fiberscope touched the epiglottis, however, water infusion induced only very weak and slow swallowing reflex, suggesting that only motor component was impaired but sensory function was preserved during swallowing. Despite eight months-conservative rehabilitations, Food Intake Level Scale (FILS) remained level 4. Therefore, corrective surgeries including cricopharyngeal myotomy, laryngeal suspension, and pharyngeal flap were performed. Thirty-six days after surgery, FILS rapidly and dramatically improved to level 8. This is the first report describing a successful surgical intervention for EV-D68-induced refractory dysphagia. Surgical treatment was suitable for EV-D68-induced dysphagia, perhaps because sensory function was preserved and only motor disturbance was present during the pharyngeal stage of swallowing.


Assuntos
Transtornos de Deglutição/cirurgia , Encefalite/fisiopatologia , Enterovirus Humano D , Infecções por Enterovirus/fisiopatologia , Laringe/cirurgia , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Músculos Faríngeos/cirurgia , Faringe/cirurgia , Adulto , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Encefalite/complicações , Infecções por Enterovirus/complicações , Paralisia Facial/etiologia , Humanos , Masculino , Miotomia/métodos , Retalhos Cirúrgicos
18.
Viruses ; 10(1)2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29329211

RESUMO

Enterovirus D68 (EV-D68) caused a large outbreak in the summer and fall of 2014 in the United States. It causes serious respiratory disease, but causation of associated paralysis is controversial, because the virus is not routinely identified in cerebrospinal fluid. To establish clinical correlates with human disease, we evaluated EV-D68 infection in non-lethal paralysis mouse models. Ten-day-old mice lacking interferon responses were injected intraperitoneally with the virus. Paralysis developed in hindlimbs. After six weeks of paralysis, the motor neurons were depleted due to viral infection. Hindlimb muscles were also infected and degenerating. Even at the earliest stage of paralysis, muscles were still infected and were degenerating, in addition to presence of virus in the spinal cord. To model natural respiratory infection, five-day-old mice were infected intranasally with EV-D68. Two of the four infected mice developed forelimb paralysis. The affected limbs had muscle disease, but no spinal cord infection was detected. The unique contributions of this study are that EV-D68 causes paralysis in mice, and that causation by muscle disease, with or without spinal cord disease, may help to resolve the controversy that the virus can cause paralysis, even if it cannot be identified in cerebrospinal fluid.


Assuntos
Enterovirus Humano D/patogenicidade , Infecções por Enterovirus/fisiopatologia , Mielite/virologia , Miosite/virologia , Paralisia/etiologia , Animais , Infecções por Enterovirus/virologia , Masculino , Camundongos , Neurônios Motores/virologia , Atrofia Muscular/fisiopatologia , Atrofia Muscular/virologia , Mielite/fisiopatologia , Miosite/fisiopatologia , Paralisia/virologia , Receptor de Interferon alfa e beta/deficiência , Receptores de Interferon/deficiência , Medula Espinal/virologia
19.
J Virol ; 91(23)2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28931688

RESUMO

RNA viruses accumulate mutations to rapidly adapt to environmental changes. Enterovirus A71 (EV-A71) causes various clinical manifestations with occasional severe neurological complications. However, the mechanism by which EV-A71 evolves within the human body is unclear. Utilizing deep sequencing and haplotype analyses of viruses from various tissues of an autopsy patient, we sought to define the evolutionary pathway by which enterovirus A71 evolves fitness for invading the central nervous system in humans. Broad mutant spectra with divergent mutations were observed at the initial infection sites in the respiratory and digestive systems. After viral invasion, we identified a haplotype switch and dominant haplotype, with glycine at VP1 residue 31 (VP1-31G) in viral particles disseminated into the integumentary and central nervous systems. In vitro viral growth and fitness analyses indicated that VP1-31G conferred growth and a fitness advantage in human neuronal cells, whereas VP1-31D conferred enhanced replication in human colorectal cells. A higher proportion of VP1-31G was also found among fatal cases, suggesting that it may facilitate central nervous system infection in humans. Our data provide the first glimpse of EV-A71 quasispecies from oral tissues to the central nervous system within humans, showing broad implications for the surveillance and pathogenesis of this reemerging viral pathogen.IMPORTANCE EV-A71 continues to be a worldwide burden to public health. Although EV-A71 is the major etiological agent of hand, foot, and mouth disease, it can also cause neurological pulmonary edema, encephalitis, and even death, especially in children. Understanding selection processes enabling dissemination and accurately estimating EV-A71 diversity during invasion in humans are critical for applications in viral pathogenesis and vaccine studies. Here, we define a selection bottleneck appearing in respiratory and digestive tissues. Glycine substitution at VP1 residue 31 helps viruses break through the bottleneck and invade the central nervous system. This substitution is also advantageous for replication in neuronal cells in vitro Considering that fatal cases contain enhanced glycine substitution at VP1-31, we suggest that the increased prevalence of VP1-31G may alter viral tropism and aid central nervous system invasion. Our findings provide new insights into a dynamic mutant spectral switch active during acute viral infection with emerging viral pathogens.


Assuntos
Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/virologia , Evolução Molecular , Mutação , Quase-Espécies , Substituição de Aminoácidos , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Sistema Nervoso Central/virologia , Criança , Enterovirus Humano A/crescimento & desenvolvimento , Infecções por Enterovirus/fisiopatologia , Trato Gastrointestinal/virologia , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Plasma/virologia , Sistema Respiratório/virologia , Estudos Retrospectivos , Replicação Viral
20.
Virology ; 508: 150-158, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28545002

RESUMO

Enterovirus71 (EV71) is the major causative agent of hand, foot and mouth disease, which threatens the health of infants and young children. The expression of inflammatory cytokines induced by this viral infection aggravate the illness. Here, we describe the anti-EV71 activity of a specific p38 inhibitor that regulates the p38-MAPK signaling pathway. PD169316 was specifically selected from a MAPK compound library due to its significant inhibitory effect on EV71 replication. PD169316 also reduced EV71-induced apoptosis. Animal experiments showed that PD169316 can dampen the replication of EV71, reduce tissue damage and inhibit the release of inflammatory cytokines, thereby alleviating the severe diseases caused by EV71 in suckling mice.


Assuntos
Antivirais/administração & dosagem , Enterovirus Humano A/efeitos dos fármacos , Infecções por Enterovirus/virologia , Inibidores Enzimáticos/administração & dosagem , Imidazóis/administração & dosagem , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Apoptose , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/fisiopatologia , Feminino , Humanos , Masculino , Camundongos , Replicação Viral/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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