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1.
BMC Infect Dis ; 20(1): 132, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32050912

RESUMO

BACKGROUND: Community-acquired pneumonia (CAP) is one of the leading worldwide causes of childhood morbidity and mortality. Its disease burden varies by age and etiology and is time dependent. We aimed to investigate the annual and seasonal patterns in etiologies of pediatric CAP requiring hospitalization. METHODS: We conducted a retrospective study in 30,994 children (aged 0-18 years) with CAP between 2010 and 2015 at 23 nationwide hospitals in South Korea. Mycoplasma pneumoniae (MP) pneumonia was clinically classified as macrolide-sensitive MP, macrolide-less effective MP (MLEP), and macrolide-refractory MP (MRMP) based on fever duration after initiation of macrolide treatment, regardless of the results of in vitro macrolide sensitivity tests. RESULTS: MP and respiratory syncytial virus (RSV) were the two most commonly identified pathogens of CAP. With the two epidemics of MP pneumonia (2011 and 2015), the rates of clinical MLEP and MRMP pneumonia showed increasing trends of 36.4% of the total MP pneumonia. In children < 2 years of age, RSV (34.0%) was the most common cause of CAP, followed by MP (9.4%); however, MP was the most common cause of CAP in children aged 2-18 years of age (45.3%). Systemic corticosteroid was most commonly administered for MP pneumonia. The rate of hospitalization in intensive care units was the highest for RSV pneumonia, and ventilator care was most commonly needed in cases of adenovirus pneumonia. CONCLUSIONS: The present study provides fundamental data to establish public health policies to decrease the disease burden due to CAP and improve pediatric health.


Assuntos
Infecções Comunitárias Adquiridas/etiologia , Pneumonia por Mycoplasma/epidemiologia , Pneumonia Viral/epidemiologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Adenoviridae/tratamento farmacológico , Infecções por Adenoviridae/epidemiologia , Infecções por Adenoviridae/etiologia , Adolescente , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/epidemiologia , Feminino , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Macrolídeos/uso terapêutico , Masculino , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/etiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/etiologia , República da Coreia/epidemiologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/etiologia , Vírus Sincicial Respiratório Humano/patogenicidade , Estudos Retrospectivos , Estações do Ano
3.
Internist (Berl) ; 60(11): 1146-1150, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31486858

RESUMO

Respiratory syncytial virus (RSV) is worldwide a very important virus leading to infection of the respiratory system. In particular preterm babies, infants and elderly adults are prone to developing severe diseases such as bronchiolitis or pneumonia, which require intensive care and cause increased mortality. Although RSV is rapidly detected, preventive and therapeutic measures are limited. New antivirals are already in clinical trials.


Assuntos
Antivirais/administração & dosagem , Bronquiolite/diagnóstico , Bronquiolite/prevenção & controle , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Humano/isolamento & purificação , Adulto , Idoso , Antivirais/uso terapêutico , Bronquiolite/tratamento farmacológico , Bronquiolite/virologia , Bronquiolite Viral/diagnóstico , Bronquiolite Viral/virologia , Humanos , Lactente , Recém-Nascido , Pneumonia/diagnóstico , Pneumonia/virologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/imunologia , Fatores de Risco
4.
Mol Biol (Mosk) ; 53(4): 541-560, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397431

RESUMO

The human respiratory syncytial virus (RSV) is one of the most common viral pathogens that affects the lower respiratory tract and could be a reason of bronchiolitis and/or pneumonia. Currently, there are no available effective ways of treating the RSV infection. Attempts to develop preventive vaccine have been unsuccessful. The only therapeutic agent used for RSV treatment is virazole (ribavirin); however, it induces adverse effects. Medications based on neutralizing monoclonal antibodies, such as IGIV (Respigam), palivizumab (Synagis), and MEDI-524 (Numab), are under clinical trials; however, their use will be limited by their high cost. One of the promising approaches for antiviral therapy is the use of natural peptides (defensins and cathelicidins), or their synthetic analogs. The majority of currently described antiviral peptides are developed against the human immunodeficiency virus, the herpes simplex virus, and the influenza virus. At the same time, a body of experimental data evidencing anti-RSV activity of peptides has been accumulated. The main advantages of peptide drugs are their wide spectrum of antiviral activity and low toxicity. However, there are obstacles in implementing peptide-based drugs in clinical practice. Due to their low resistance to the action of serum proteases, most authors consider peptides promising only for local application. Given that RSV affects the epithelium of the respiratory tract, where the protease activity is lower than in the systemic circulation, it is possible to develop locally active peptide drugs, for example, as inhalation forms. Their stability could also be increased by the synthesis of dendrimer peptides and by the development of recombinant peptides as precursor proteins. Anti-RSV peptides can be divided into several groups: (1) attachment and/or fusion blockers; (2) peptides displaying direct virucidal activity, disrupting the viral envelope. Such peptides, which suppress early stages of the viral life cycle, are considered prophylactic agents. However, for several peptides, their immunoregulatory properties have been described, which opens the possibility for therapeutic use. This review summarizes the information on the antiviral properties of such peptides and mechanisms of their action and describes the prospects of the future development of antiviral peptides.


Assuntos
Antivirais/farmacologia , Peptídeos/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Antivirais/uso terapêutico , Humanos , Peptídeos/uso terapêutico
5.
Cochrane Database Syst Rev ; 8: CD009417, 2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31446622

RESUMO

BACKGROUND: Millions of children are hospitalised due to respiratory syncytial virus (RSV) infection every year. Treatment is supportive, and current therapies (e.g. inhaled bronchodilators, epinephrine, nebulised hypertonic saline, and corticosteroids) are ineffective or have limited effect. Respiratory syncytial virus immunoglobulin is sometimes used prophylactically to prevent hospital admission from RSV-related illness. It may be considered for the treatment of established severe RSV infection or for treatment in an immunocompromised host, although it is not licenced for this purpose. It is unclear whether immunoglobulins improve outcomes when used as a treatment for established RSV infection in infants and young children admitted to hospital.  OBJECTIVES: To assess the effects of immunoglobulins for the treatment of RSV-proven lower respiratory tract infections in children aged up to three years, admitted to hospital.  SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, Ovid MEDLINE, Embase, CINAHL, and Web of Science (from inception to 6 November 2018) with no restrictions. We searched two trial registries for ongoing trials (to 30 March 2018) and checked the reference lists of reviews and included articles for additional studies. SELECTION CRITERIA: Randomised controlled trials comparing immunoglobulins with placebo in hospitalised infants and children aged up to three years with laboratory-diagnosed RSV lower respiratory tract infection. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias, and extracted data. We assessed evidence quality using GRADE. MAIN RESULTS: We included seven trials involving 486 infants and children aged up to three years. The immunoglobulin preparations used in these trials included anti-RSV immunoglobulin and the monoclonal antibody preparations palivizumab and motavizumab. We assessed the primary outcomes of mortality, length of hospital stay, and adverse events as providing low- or very low-certainty evidence due to risk of bias and imprecision. All trials were conducted at sites in high-income countries (USA, Chile, New Zealand, Australia), with two studies including a site in a middle-income country (Panama). Five of the seven studies were "supported" or "sponsored" by the trial drug manufacturers. We found no evidence of a difference between immunoglobulins and placebo for mortality (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.14 to 5.27; 3 trials; 196 children; 4 deaths; 2 deaths amongst 98 children receiving immunoglobulins, and 2 deaths amongst 98 children receiving placebo. One additional death occurred in a fourth trial, however, the study group of the child was not known and the data were not included in the analysis; very low-certainty evidence), and length of hospitalisation (mean difference -0.70, 95% CI -1.83 to 0.42; 5 trials; 324 children; low-certainty evidence). There was no evidence of a difference between immunoglobulins and placebo in adverse events of any severity or seriousness (reported in five trials) or serious adverse events (four trials) (RR for any severity 1.18, 95% CI 0.78 to 1.78; 340 children; low-certainty evidence, and for serious adverse events 1.08, 95% CI 0.65 to 1.79; 238 children; low-certainty evidence).We found no evidence of a significant difference between immunoglobulins and placebo for any of our secondary outcomes. We identified one ongoing trial. AUTHORS' CONCLUSIONS: We found insufficient evidence of a difference between immunoglobulins and placebo for any review outcomes. We assessed the evidence for the effects of immunoglobulins when used as a treatment for RSV lower respiratory tract infection in hospitalised infants and young children as of low or very low certainty due to risk of bias and imprecision. We are uncertain of the effects of immunoglobulins on these outcomes, and the true effect may be substantially different from the effects reported in this review. All trials were conducted in high-income countries, and data from populations in which the rate of death from RSV infection is higher are lacking.


Assuntos
Imunoglobulinas Intravenosas , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Criança , Pré-Escolar , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Tempo de Internação , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções por Vírus Respiratório Sincicial/prevenção & controle
6.
Adv Exp Med Biol ; 1211: 111-119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31165441

RESUMO

This study seeks to define the indications and the economic impact of the use of antibiotics in infants hospitalized due to bronchiolitis during 2010-2017. There were 459 children with bronchiolitis, median age of 2.2 months, 390 infections with respiratory syncytial virus (RSV), and 69 were non-RSV. Twenty two percent of all these children (102/459) required a workup toward urinary tract co-infections (UTI). A control group, consisting of 8,456 children without bronchiolitis, was created to assess UTI frequency in the general population. We found that 16.0% (73/459) children with bronchiolitis received antibiotics; 63 (13.7%) due to respiratory infection and 9 due to UTI. A time-trend analysis showed a decreasing use of antibiotics, from 57.0% in 2010 to 13.7% in 2017, with the lowest value of 6.4% noticed in 2014. Children treated with antibiotics required a 4-day longer hospitalization than those untreated (p < 0.01), but there were no other clinically relevant differences. After excluding the first 2 years with the highest antibiotic ordering, antibiotics, on average, were used in 9.8% of children with bronchiolitis. Frequency of UTI accompanying bronchiolitis was comparable to that in the control group (8.9% vs. 10.9%, respectively). Specificity of urine culture was 71%, with 100% sensitivity assumed, while the positive predicted value of only 41%. The unnecessary costs of urine cultures, if performed in each patient, would have been €2,236, and with additional laboratory tests in each case of a false positive result it would have reached €5,448. We conclude that antibiotics should be used for bronchiolitis only in justified cases, and their use should not exceed 10% of patients. Since UTI is no more frequent in bronchiolitis than in the general children's population, urine cultures should not be performed routinely.


Assuntos
Antibacterianos/uso terapêutico , Bronquiolite/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Coinfecção , Hospitalização , Humanos , Lactente , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico
7.
Pediatrics ; 143(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31040196

RESUMO

CONTEXT: Palivizumab prophylaxis is used as passive immunization for respiratory syncytial virus (RSV). However, because of its high cost, the value of this intervention is unclear. OBJECTIVE: To systematically review the cost-effectiveness of palivizumab prophylaxis compared with no prophylaxis in infants <24 months of age. DATA SOURCES: Medline, Embase, and Cochrane Library up to August 2018. STUDY SELECTION: Two reviewers independently screened results to include economic evaluations conducted between 2000 and 2018 from Organization for Economic Cooperation and Development countries. DATA EXTRACTION: Two reviewers independently extracted outcomes. Quality appraisal was completed by using the Joanna Briggs Institute checklist. Costs were adjusted to 2017 US dollars. RESULTS: We identified 28 economic evaluations (20 cost-utility analyses and 8 cost-effectiveness analyses); most were from the United States (n = 6) and Canada (n = 5). Study quality was high; 23 studies met >80% of the Joanna Briggs Institute criteria. Palivizumab prophylaxis ranged from a dominant strategy to having an incremental cost-effectiveness ratio of $2 526 203 per quality-adjusted life-year (QALY) depending on study perspective and targeted population. From the payer perspective, the incremental cost-effectiveness ratio for preterm infants (29-35 weeks' gestational age) was between $5188 and $791 265 per QALY, with 90% of estimates <$50 000 per QALY. Influential parameters were RSV hospitalization reduction rates, palivizumab cost, and discount rate. LIMITATIONS: Model design heterogeneity, model parameters, and study settings were barriers to definitive conclusions on palivizumab's economic value. CONCLUSIONS: Palivizumab as RSV prophylaxis was considered cost-effective in prematurely born infants, infants with lung complications, and infants from remote communities.


Assuntos
Antivirais/economia , Análise Custo-Benefício/métodos , Palivizumab/economia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/economia , Antivirais/uso terapêutico , Humanos , Palivizumab/uso terapêutico , Vírus Sinciciais Respiratórios
8.
J Ethnopharmacol ; 239: 111901, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31051218

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Isatidis, a commonly used traditional Chinese medicine, is also documented in "Dictionary of Chinese Ethnic Medicine" being as an ethnic herb clinically utilized by different nations in China such as Mongol, Uygur, and Dong et al. It has been reported to have a very strong efficacy on respiratory viruses, but to date the mechanism remains unknown. Similarly, it is unclear how different types of effective fractions of Radix Isatidis interact to exert antiviral effects. AIM OF STUDY: To reveal the underlying mechanisms for the inhibitory effects of three active fractions from Radix Isatidis, i.e. total alkaloids, lignans and organic acids, on respiratory syncytial virus when used alone or in combination. In addition, we investigated whether these three parts worked synergistically in vivo and in vitro. MATERIALS AND METHODS: A mouse model of RSV infection was constructed by intranasal infection, and the pathological changes of lung tissues in different parts were observed. The level changes of IFNß and inflammatory cytokines in the mouse alveolar lavage fluid were detected by enzyme-linked immunosorbent assay (ELISA). The anti-RSV effects of different effective fractions were evaluated by the plaque reduction test. The mRNA and protein expressions of RIG-I, MDA-5, MAVS and IRF3 in RAW264.7 cells were detected by RT-PCR and Western blot respectively. RESULTS: HE staining showed that Radix Isatidis extracts alone or in combination relieved virus-induced mouse lung lesions. Compared with individual drugs, the lung lesions were alleviated more significantly after treatment with the three fractions in combination. ELISA demonstrated that the expression levels of IFNß and inflammatory cytokines were maintained balanced between antiviral and proinflammatory effects. The plaque reduction test indicated that the antiviral effect of combination treatment was much stronger than those of individual drugs. RT-qPCR and Western blot suggested that the mRNA and protein expression levels of key signaling molecules in the RIG-I and MDA5 pathways in mouse macrophages were down-regulated by different effective parts alone or in combination. CONCLUSIONS: The three effective fractions of Radix Isatidis have remarkable synergistic anti-RSV effects in vitro and in vivo, and total alkaloids and lignans show multi-target synergistic effects via the RIG-I and MDA5 signaling pathways.


Assuntos
Antivirais/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Antivirais/farmacologia , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Células Hep G2 , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/metabolismo , Lignanas/farmacologia , Lignanas/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Medicina Tradicional Chinesa , Camundongos Endogâmicos BALB C , Projetos Piloto , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/patologia , Transdução de Sinais/efeitos dos fármacos
9.
Br J Hosp Med (Lond) ; 80(5): 278-284, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31059347

RESUMO

Bronchiolitis is an acute respiratory illness that is the leading cause of hospitalization in young children less than 2 years of age in the UK. Respiratory syncytial virus is the most common virus associated with bronchiolitis and has the highest disease severity, mortality and cost. Bronchiolitis is generally a self-limiting condition, but can have serious consequences in infants who are very young, premature, or have underlying comorbidities. Management of bronchiolitis in the UK is guided by the National Institute for Health and Care Excellence (2015) guidance. The mainstays of management are largely supportive, consisting of fluid management and respiratory support. Pharmacological interventions including nebulized bronchodilators, steroids and antibiotics generally have limited or no evidence of efficacy and are not advised by National Institute of Health and Care Excellence. Antiviral therapeutics remain in development. As treatments are limited, there have been extensive efforts to develop vaccines, mainly targeting respiratory syncytial virus. At present, the only licensed product is a monoclonal antibody for passive immunisation. Its cost restricts its use to those at highest risk. Vaccines for active immunisation of pregnant women and young infants are also being developed.


Assuntos
Bronquiolite/terapia , Protocolos Clínicos , Bronquiolite/prevenção & controle , Broncodilatadores/uso terapêutico , Cânula , Hidratação/métodos , Glucocorticoides/uso terapêutico , Humanos , Oxigenoterapia/métodos , Palivizumab/administração & dosagem , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Medicina Estatal , Reino Unido
10.
Transpl Infect Dis ; 21(4): e13105, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31081570

RESUMO

BACKGROUND: Immunocompromised hematologic malignancy (HM) patients experience high mortality after respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI). We measured radiologic severity to determine whether it could improve the performance of 60-day mortality models based only upon immunodeficiency severity. METHODS: We studied 155 HM patients, including 84 hematopoietic cell transplant recipients, who developed RSV LRTI from 2001 to 2013. We measured immunodeficiency using lymphopenia (lymphocyte count <200 cells/mm3 ), Immunodeficiency Severity Index (ISI), and Severe Immunodeficiency (SID) criteria. Radiologic severity was measured by the Radiologic Severity Index (RSI, range 0-72) at time of LRTI (baseline-RSI) and peak severity (peak-RSI). Delta-RSI was defined as the difference between baseline-RSI and peak-RSI. We used logistic regression models to measure the association of immunodeficiency and RSI with 60-day all-cause mortality, and measured model discrimination using areas under the receiver-operating characteristics curves, calibration using Brier scores, and explained variance using pseudo-R2 values. RESULTS: Forty-one patients died within 60 days of RSV LRTI. Severe immunodeficiency was associated with higher mortality. Peak-RSI (odds ratio [OR] 1.06/point, 95% confidence interval [CI] 1.04-1.08), and delta-RSI (OR 1.07/point, 95% CI 1.05-1.10) were associated with 60-day mortality after RSV LRTI, but not baseline-RSI. Addition of peak-RSI or delta-RSI to baseline immunodeficiency improved the discrimination, calibration, and explained variance (P < 0.001) of 60-day mortality models. CONCLUSIONS: Although baseline immunodeficiency in HM patients helps predict 60-day mortality after RSV LRTI, mortality risk estimates can be further refined by also measuring LRTI progression using RSI. RSI is well-suited as a marker of LRTI severity in RSV infection.


Assuntos
Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/virologia , Infecções por Vírus Respiratório Sincicial/mortalidade , Índice de Gravidade de Doença , Adulto , Idoso , Antivirais/uso terapêutico , Feminino , Neoplasias Hematológicas/complicações , Humanos , Hospedeiro Imunocomprometido , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções Respiratórias/virologia , Estudos Retrospectivos , Fatores de Risco
11.
Influenza Other Respir Viruses ; 13(4): 331-338, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30977284

RESUMO

OBJECTIVES: Respiratory syncytial virus (RSV) is an important cause of morbidity and mortality in adults. Existing studies are limited by the number of seasons studied and most have focused on the immunocompromised. METHODS: A retrospective cohort study was conducted on all adults (≥18 years) with a positive RSV molecular test admitted from 2009 to 2015 to one hospital in Chicago, IL. Epidemiologic and outcomes data were collected after IRB approval. RESULTS: Of the 489 eligible patients, 227 had RSV A and 262 had RSV B. Patients had a median age of 61 years and comorbidity (eg, chronic lung disease [40.6%], obesity [37.8%], and cardiac disease [34.3%]). On presentation, most had cough (86.5%), fever (42.4%), and shortness of breath (38.2%). Severe disease was present in 27.6% of patients. Antibiotic was used in 76.3% inpatients and 45.8% at discharged despite few patients (4.7%) having documented bacterial infections. Supplemental oxygen and mechanical ventilation were utilized in 44.6% and 12.3%, respectively, while ICU level care was required in 26.9%. Most patients were discharged home (82.7%). Most deaths (68.4%, 13/19) were attributed to pneumonia or hypoxemia likely from RSV. Most fatal cases were seen in those with recent cancer treatment and older adults. CONCLUSIONS: Respiratory syncytial virus in hospitalized adults is associated with significant morbidity and mortality with 26.9% requiring ICU level care. Antibiotics are commonly prescribed to patients with documented RSV, and antibiotics are frequently continued after diagnosis. Novel antiviral therapies are needed for RSV to improve outcomes and potentially improve antibiotic stewardship in patients without a bacterial infection.


Assuntos
Hospitalização/estatística & dados numéricos , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/mortalidade , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Feminino , Humanos , Hospedeiro Imunocomprometido , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/genética , Estudos Retrospectivos , Ribavirina/uso terapêutico , Adulto Jovem
13.
J Infect Chemother ; 25(7): 514-519, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30885457

RESUMO

INTRODUCTION: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections among infants and young children. The fusion (F) protein of RSV is a major target for monoclonal antibodies and vaccine candidates. We analyzed sequence polymorphisms of the RSV F protein and investigated palivizumab-resistance mutation in clinical isolates from Korean children in post-palivizumab era. METHODS: A review of pediatric patients with RSV infections in Korea from September 2009 to April 2015 was conducted. We performed RSV F gene sequence analysis on positive clinical samples and compared to reference sequences, A2 and 9320. RESULTS: RSV F gene data were obtained from 60 patients (30 RSV-A and 30 RSV-B), of whom 15 (10 RSV-A and 5 RSV-B) received palivizumab. The nucleotide and amino acid identities of the F gene sequence were conserved between RSV isolates and reference strains. There was no significant difference between isolates from patients who received and did not receive palivizumab. One or more amino acid changes were observed in all RSV-A and 26 RSV-B isolates. Twenty-five variations in RSV-A and 17 in RSV-B were noted. One variation within antigenic site II was noted in a RSV-A isolate; D263N with unknown significance was found in a patient without palivizumab prophylaxis. N276S variation adjacent to antigenic site II was observed in 27 RSV-A isolates. However, no known palivizumab-resistant mutations were found in either RSV-A or RSV-B isolates. CONCLUSIONS: The RSV F gene was highly conserved and no known palivizumab-resistant mutants were found in Korean circulating strains.


Assuntos
Antivirais/farmacologia , Palivizumab/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/genética , Proteínas Virais de Fusão/genética , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Pré-Escolar , Farmacorresistência Viral/genética , Feminino , Humanos , Masculino , Epidemiologia Molecular , Palivizumab/uso terapêutico , Polimorfismo Genético , República da Coreia/epidemiologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/isolamento & purificação , Adulto Jovem
14.
Pediatrics ; 143(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30760509

RESUMO

BACKGROUND: Monoclonal antibody to respiratory syncytial virus (RSV; palivizumab) is recommend for prophylaxis of high-risk infants during bronchiolitis seasons but not for RSV bronchiolitis treatment. Our aim was to determine if palivizumab would be helpful in young infants with acute RSV bronchiolitis. METHODS: Eligible infants ≤3 months old presenting to the pediatric emergency service with RSV-positive bronchiolitis requiring inpatient admission underwent double-blind random assignment to single-dose intravenous palivizumab (15 mg/kg) or placebo. The primary efficacy outcome was the need for inpatient readmission in the 3 weeks after discharge. Secondary outcomes were time to readiness for hospital discharge, need for PICU on the initial admission, and need for revisit not requiring readmission for the same illness during 3-week follow-up. RESULTS: A total of 420 infants (median age 49 days) diagnosed with RSV bronchiolitis were randomly assigned; 417 received treatment, and 413 completed follow-up. Readmission during follow-up was needed for 23 (11%) patients on palivizumab and 19 (9.3%) patients in the placebo group (difference 1.8%; 95% confidence interval -4.4% to 7.7%; P = .51). Geometric mean time to readiness for discharge was 29.5 hours for the palivizumab group and 30.2 hours for the placebo group (ratio 0.98; 95% confidence interval 0.81 to 1.20). No safety issues were reported. CONCLUSIONS: Intravenous palivizumab did not appear to help or harm young infants with acute RSV-positive bronchiolitis.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antivirais/administração & dosagem , Bronquiolite/tratamento farmacológico , Palivizumab/administração & dosagem , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Administração Intravenosa , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Tempo de Internação/tendências , Masculino , Readmissão do Paciente/tendências , Resultado do Tratamento
15.
Eur J Pediatr ; 178(2): 131-138, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30610420

RESUMO

Respiratory syncytial virus (RSV) infection is one of the main causes of infant hospitalization and mortality. The single-stranded RNA virus codes for 11 proteins of which the F protein, a surface epitope responsible for RSV fusion, is the most targeted for developing antiviral medicines and vaccines. The peak of symptoms occurs around day 4 to 6 of illness and the airway obstruction is merely caused by the host immune inflammatory response. Risk factors for severe bronchiolitis are prematurity, comorbidity, and/or being immunocompromised. At present, there are no curative therapies available for RSV infections and treatment is supportive only. Development of new antiviral medicines is however promising. The aim of this review is to give a summary of the most important new antiviral therapies in clinical development for RSV infection and to explain their mode of action. We therefore performed a literature search on this topic.Conclusion: There are currently at least eight antivirals being investigated in clinical trials. They all use different approaches to either focus on preventing viral fusion with host cells or inhibiting virus replication. Some target RSV surface epitopes like the F protein to halt fusion, others aim for RNA chain termination, while small interfering RNAs downregulate viral protein production. What is known: • RSV bronchiolitis is a very important pediatric disease as it is one of the main causes of infant hospitalization and mortality. By the age of 2 years, 95% of all the infants worldwide will have been infected. • The only recommended therapy is supportive since there are no existing curative therapies yet. What this study adds: • This review gives an overview of the current progress in the research field of RSV antivirals with background information on their mode of action.


Assuntos
Antivirais/uso terapêutico , Bronquiolite Viral/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Bronquiolite Viral/virologia , Criança , Pré-Escolar , Humanos , Lactente
16.
Antiviral Res ; 161: 125-133, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503888

RESUMO

Human respiratory syncytial virus (HRSV) infection is a significant cause of morbidity and mortality, particularly among the children and the elderly. Despite extensive efforts, there is currently no formally approved vaccine and effective antiviral options against HRSV infection are limited. The development of vaccines and antiviral strategies for HRSV was partly hampered by the lack of an efficient lethal mouse model to evaluate the efficacy of the candidate vaccines or antivirals. In this study, we established a lethal HRSV mouse model by consecutively passaging a clinical HRSV isolate, GZ08-0. GZ08-18 was isolated from mouse bronchioalveolar lavage fluids at the 50th passage of GZ08-0. Importantly, all GZ08-18-inoculated mice succumbed to the infection by day 7 post infection, whereas all GZ08-0-inoculated mice recovered from the infection. Subsequent investigations demonstrated that GZ08-18 replicated to a higher titer in mouse lungs, induced more prominent lung pathology, and resulted in higher expression levels of a number of key pro-inflammatory cytokines including IFN-γ, MIP-1α, and TNF-α in comparison to that of GZ08-0. The cyclophosphamide pretreatment rendered the mice more susceptible to a lethal outcome with less rounds of virus inoculation. Full genome sequencing revealed 17 mutations in GZ08-18, some of which might account for the dramatically increased pathogenicity over GZ08-0. In addition, by using ribavirin as a positive control, we demonstrated the potential application of this lethal mouse model as a tool in HRSV investigations. Overall, we have successfully established a practical lethal mouse model for HRSV with a mouse-adapted virus, which may facilitate future in vivo studies on the evaluation of candidate vaccines and drugs against HRSV.


Assuntos
Envelhecimento , Modelos Animais de Doenças , Infecções por Vírus Respiratório Sincicial/mortalidade , Vírus Sincicial Respiratório Humano/patogenicidade , Animais , Antivirais/uso terapêutico , Linhagem Celular , Ciclofosfamida/farmacologia , Genoma Viral , Humanos , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/fisiologia , Ribavirina/uso terapêutico , Replicação Viral
17.
Eur J Clin Microbiol Infect Dis ; 38(1): 171-176, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30374685

RESUMO

Children with medical complexity (CMC) are vulnerable to respiratory illness hospitalization (RIH) and respiratory syncytial virus (RSV)-related hospitalization (RSVH) due to multisystem disorders and compromised airways. It is unknown whether RSV prophylaxis is effective, or if RSVH is associated with significant morbidities in CMC. The study objectives were to (1) determine the incidence of RSV-related infection in prophylaxed CMC during the first 3 years of life and (2) assess the burden of illness following RSVH. A single tertiary center, retrospective study, was conducted of CMC who received palivizumab during the 2012-2016 RSV seasons. Fifty-four subjects were enrolled; most received one (38.9%, n = 21) or two (57.4%, n = 31) seasons of prophylaxis (mean = 4.2 [SD = 1.24], palivizumab doses per season). The cohort comprised children with multiple medical conditions (n = 22, 40.8%), tracheostomy (n = 18, 33.3%), and invasive (n = 10, 18.5%) or non-invasive (n = 4, 7.4%) ventilation. Of the CMC, 24 were hospitalized 47 times for a viral-related respiratory illness. RSV incidence in the first 3 years of life was 7.4%. Viral-related RIH and RSVH rates were 44.4% (n = 24/54) and 1.9% (n = 1/54), respectively. Of the four RSV-positive children, one was ventilated for 9 days, two acquired nosocomial RSV that was managed on the ward, and one was discharged home under close complex care supervision. All four RSV-positive cases required additional oxygen during their illness. CMC experience a high viral-related RIH rate and palivizumab likely minimizes RSV-related events and associated morbidities. The efficacy of palivizumab in CMC, especially in those ≤ 3 years, should be prospectively evaluated.


Assuntos
Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sincicial Respiratório Humano , Antibioticoprofilaxia , Antivirais/uso terapêutico , Pré-Escolar , Comorbidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Palivizumab/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Estudos Retrospectivos , Resultado do Tratamento
18.
J Med Chem ; 62(7): 3206-3227, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30411898

RESUMO

Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle. A number of approaches to DAAs have produced landmark clinical studies over the past few years, notably in fusion and nucleoside inhibitors, and an update of the clinical status of these compounds is provided. Non-nucleoside inhibitors of replication are reviewed in addition to inhibitors of other mechanisms, notably the RSV N and G proteins. This article will provide an informative perspective of the current status of drug discovery targeted at providing an effective therapy for RSV infection.


Assuntos
Antivirais/química , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/química , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/metabolismo , Palivizumab/imunologia , Palivizumab/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/imunologia , Vírus Sincicial Respiratório Humano/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Proteínas Virais de Fusão/química , Proteínas Virais de Fusão/metabolismo
19.
J Virol ; 93(4)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30541831

RESUMO

Respiratory syncytial virus (RSV) is a leading cause of hospitalization of infants and young children, causing considerable respiratory disease and repeat infections that may lead to chronic respiratory conditions such as asthma, wheezing, and bronchitis. RSV causes ∼34 million new episodes of lower respiratory tract illness (LRTI) in children younger than 5 years of age, with >3 million hospitalizations due to severe RSV-associated LRTI. The standard of care is limited to symptomatic relief as there are no approved vaccines and few effective antiviral drugs; thus, a safe and efficacious RSV therapeutic is needed. Therapeutic targeting of host proteins hijacked by RSV to facilitate replication is a promising antiviral strategy as targeting the host reduces the likelihood of developing drug resistance. The nuclear export of the RSV M protein, mediated by the nuclear export protein exportin 1 (XPO1), is crucial for RSV assembly and budding. Inhibition of RSV M protein export by leptomycin B correlated with reduced RSV replication in vitro In this study, we evaluated the anti-RSV efficacy of Verdinexor (KPT-335), a small molecule designed to reversibly inhibit XPO1-mediated nuclear export. KPT-335 inhibited XPO1-mediated transport and reduced RSV replication in vitro KPT-335 was effective against RSV A and B strains and reduced viral replication following prophylactic or therapeutic administration. Inhibition of RSV replication by KPT-335 was due to a combined effect of reduced XPO1 expression, disruption of the nuclear export of RSV M protein, and inactivation of the NF-κB signaling pathway.IMPORTANCE RSV is an important cause of LRTI in infants and young children for which there are no suitable antiviral drugs offered. We evaluated the efficacy of KPT-335 as an anti-RSV drug and show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and reduction in RSV levels. KPT-335 treatment also resulted in inhibition of proinflammatory pathways, which has important implications for its effectiveness in vivo.


Assuntos
Acrilamidas/farmacologia , Hidrazinas/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Células A549 , Acrilamidas/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Glicoproteínas/imunologia , Humanos , Hidrazinas/metabolismo , Carioferinas/efeitos dos fármacos , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Células Vero
20.
J Ethnopharmacol ; 242: 111575, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30391397

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lophatherum gracile, an important medicinal plant, is used traditionally in the treatment of cough associated with lung heat and inflammation. In this study, an ethanol extract of L. gracile (DZY) was shown to inhibit respiratory syncytial virus (RSV) infection and RSV-induced inflammation in vitro and in vivo. These findings provide a strong and powerful support for the traditional use of L. gracile in the treatment of RSV-related diseases. AIM OF THE STUDY: To determine the anti-RSV activities of DZY and its ingredients, and explore the relationship between RSV infection and inflammation. MATERIALS AND METHODS: DZY was extracted from L. gracile and its major ingredients were determined by high-performance liquid chromatography (HPLC). RSV-infected HEp-2 and RAW264.7 cell models were established to assess the inhibitory effect of DZY on RSV replication and nitric oxide (NO) production in vitro. Three-week-old BALB/c mice challenged intranasally with RSV were used to establish RSV-infected animal mode. The mice were respectively administered DZY at high-, middle-, and low-dose in different groups. The anti-RSV activity of DZY was evaluated by detecting viral load, lung lesion, CD4+ and CD8+ T cell population, and interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ expression in the lung tissue. RESULTS: In HEp-2 cell line, DZY effectively inhibited RSV infection in a dose-dependent manner with IC50 values of 20 µg/mL against RSV (Long strain) and IC50 values of 25 µg/mL against RSV (A2 strain). The anti-RSV activity of DZY was mainly determined by isoorientin, swertiajaponin, 3, 5-di-caffeoylquinic acid, and 3, 4-di-caffeoylquinic acid. Moreover, DZY suppressed NO production induced by RSV in vitro. In vivo, oral administration of DZY significantly reduced the viral load and ameliorated lesions in the lung tissue. A probable antiviral mechanism was mediated by slightly improving the ratio of CD4+/CD8+ T cells and inhibiting the mRNA and protein expression of IL-1ß, TNF-α, and IFN-γ. CONCLUSIONS: (1) DZY exhibits anti-RSV activities both in vitro and in vivo. (2) RSV infection can trigger a series of inflammatory reactions; thus, ameliorating inflammation is helpful to control the course of disease caused by RSV. These findings provide the rationale and scientific evidence behind the extensive use of L. gracile in traditional medicine for the treatment of diseases potentially caused by RSV.


Assuntos
Antivirais/uso terapêutico , Extratos Vegetais/uso terapêutico , Poaceae , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Animais , Antivirais/química , Antivirais/toxicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Citocinas/imunologia , Etanol/química , Humanos , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Folhas de Planta , Caules de Planta , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Solventes/química , Carga Viral/efeitos dos fármacos
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