Ivy leaf dry extract EA 575 for the treatment of acute and chronic cough in pediatric patients: review and expert survey.

OBJECTIVES: EA 575 (Prospan) is a herbal medicine containing a dried extract of ivy leaves (drug extract ratio 5-7.5:1; extraction solvent, 30% ethanol). Although widely used for the treatment of cough, there remains a lack of clarity on the effects of EA 575 in children. This study aimed to evaluate the efficacy and tolerability of EA 575 in pediatric patients with cough, via a literature review and expert survey. METHODS: A MEDLINE/PubMed database search was performed to identify articles evaluating the efficacy and tolerability of EA 575 in pediatric patients with cough. An online survey of international pediatric cough experts was conducted to gather expert opinion regarding the use of EA 575 for pediatric cough. RESULTS: Ten controlled clinical trials and nine observational studies were identified. Controlled trials reported improvements in lung function and subjective cough symptoms with EA 575, while observational studies indicated overall favorable efficacy. EA 575 was generally well tolerated, with a low incidence of adverse events in children of all ages, including those aged <1 year. Survey responses from ten experts aligned with findings from the reviewed studies. Most experts agreed that EA 575 may improve quality of life, and highlighted its potential benefits on sleep. CONCLUSIONS: EA 575 has minimal side effects in pediatric patients with cough, as demonstrated by large, real-world studies. EA 575 may provide clinical benefits in pediatric patients; however, more robust clinical trials are needed to confirm its efficacy.

EA 575 (Prospan) is a medicine containing a dried extract of ivy leaves that is used to treat coughs. The aim of this review was to evaluate the available published information on the health benefits and side effects of EA 575 in children with coughs. We also conducted a survey of doctors who treat children with coughs. We found information from ten research trials that compared EA 575 with another cough medicine or a "dummy medicine". Although these studies included only a small number of children, the results suggested that children's breathing and cough symptoms may improve with EA 575 treatment. We also found nine studies that included children being treated in normal clinical situations and not in a research setting. Most of the children included in these studies and their doctors thought that EA 575 treatment was beneficial. A low number of side effects was reported in children of all ages, including in infants aged <1 year. Survey responses from ten doctors generally agreed with the findings from the research studies. Most of the doctors thought that EA 575 may improve quality of life. Improved sleep was commonly mentioned by doctors. Overall, our findings indicate that EA 575 has minimal side effects in children; we call for more research on the benefits of EA 575 on cough symptoms in children.

Therapeutic principles and unmet needs in the treatment of cough in pediatric patients: review and expert survey.

BACKGROUND: There are evidence gaps in the management of pediatric cough, particularly for acute pediatric cough. This study had two aims: to identify therapeutic principles and unmet needs in the treatment of cough in pediatric patients (internationally), and to consider the evidence required to address these unmet needs. METHODS: A MEDLINE/PubMed database search was performed to identify articles describing therapeutic principles in the treatment of pediatric cough. An online survey of international pediatric cough experts was conducted, with questions on the definitions, diagnosis, treatment, and unmet needs in pediatric cough management. RESULTS: Cough guidelines have differing definitions of pediatric patients (≤12-18 years), acute pediatric cough (< 2-3 weeks), and chronic pediatric cough (> 4-8 weeks). Similarly, among 18 experts surveyed, definitions varied for pediatric patients (≤10-21 years), acute pediatric cough (< 3-5 days to < 6 weeks), and chronic pediatric cough (> 2-8 weeks). Guidelines generally do not recommend over-the-counter or prescription cough medicines in acute pediatric cough, due to lack of evidence. In the expert survey, participants had differing opinions on which medicines were most suitable for treating acute pediatric cough, and noted that effective treatments are lacking for cough-related pain and sleep disruption. Overall, guidelines and experts agreed that chronic pediatric cough requires diagnostic investigations to identify the underlying cough-causing disease and thereby to guide treatment. There are unmet needs for new effective and safe treatments for acute pediatric cough, and for randomized controlled trials of existing treatments. Safety is a particular concern in this vulnerable patient population. There is also a need for better understanding of the causes, phenotypes, and prevalence of pediatric cough, and how this relates to its diagnosis and treatment. CONCLUSIONS: Whereas pediatric cough guidelines largely align with regard to the diagnosis and treatment of chronic cough, there is limited evidence-based guidance for the management of acute cough. There is a need for harmonization of pediatric cough management, and the development of standard guidelines suitable for all regions and patient circumstances.

Functional characterization of 5' untranslated region (UTR) secondary RNA structures in the replication of tick-borne encephalitis virus in mammalian cells.

Tick-borne Encephalitis Virus (TBEV) is an emerging flavivirus that causes neurological disorders including viral encephalitis of varying severity. Whilst secondary RNA structures within the 5' untranslated regions (UTRs) of many flaviviruses determine both virus replication and pathogenic outcomes in humans, these elements have not been systematically investigated for TBEV. In this study, we investigated the role of predicted RNA secondary elements of the first 107 nucleotides (nts) of the viral genome forming the stem-loop A (SLA). Experiments were performed in replicons and infectious TBEV system. This region comprises three distinct structures: 5' stem 0 (S0), stem-loop 1 (SL1) and stem-loop 2 (SL2). S0 was found to be essential for virus infection as mutations in the lower stem of this region significantly reduced virus replication. Point mutations in SL1 that preserved the Y-shape confirmation delayed viral RNA replication but did not abolish virus infectivity. Deletion of SL2 did not abolish infectivity but had a negligible effect on virus propagation. No correlation was observed between in vitro translation efficiency and virus infectivity, suggesting that the 5'UTR functions independently to virus translation. Together, these findings reveal distinct RNA elements within the 5'UTR that are essential for the stability and replication of viral RNA. We further identify changes in RNA folding that lead to altered TBEV infectivity and pathogenesis.

Identification of Host Factors Differentially Induced by Clinically Diverse Strains of Tick-Borne Encephalitis Virus.

Tick-borne encephalitis virus (TBEV) is an important human arthropod-borne virus that causes tick-borne encephalitis (TBE) in humans. TBEV acutely infects the central nervous system (CNS), leading to neurological symptoms of various severity. No therapeutics are currently available for TBEV-associated disease. Virus strains of various pathogenicity have been described, although the basis of their diverse clinical outcome remains undefined. Work with infectious TBEV requires high-level biocontainment, meaning model systems that can recapitulate the virus life cycle are highly sought. Here, we report the generation of a self-replicating, noninfectious TBEV replicon used to study properties of high (Hypr) and low (Vs) pathogenic TBEV isolates. Using a Spinach2 RNA aptamer and luciferase reporter system, we perform the first direct comparison of Hypr and Vs in cell culture. Infectious wild-type (WT) viruses and chimeras of the nonstructural proteins 3 (NS3) and 5 (NS5) were investigated in parallel to validate the replicon data. We show that Hypr replicates to higher levels than Vs in mammalian cells, but not in arthropod cells, and that the basis of these differences map to the NS5 region, encoding the methyltransferase and RNA polymerase. For both Hypr and Vs strains, NS5 and the viral genome localized to intracellular structures typical of positive-strand RNA viruses. Hypr was associated with significant activation of IRF-3, caspase-3, and caspase-8, while Vs activated Akt, affording protection against caspase-mediated apoptosis. Higher activation of stress-granule proteins TIAR and G3BPI were an additional early feature of Vs but not for Hypr. These findings highlight novel host cell responses driven by NS5 that may dictate the differential clinical characteristics of TBEV strains. This highlights the utility of the TBEV replicons for further virological characterization and antiviral drug screening. IMPORTANCE Tick-borne encephalitis virus (TBEV) is an emerging virus of the flavivirus family that is spread by ticks and causes neurological disease of various severity. No specific therapeutic treatments are available for TBE, and control in areas of endemicity is limited to vaccination. The pathology of TBEV ranges from mild to fatal, depending on the virus genotype. Characterization of TBEV isolates is challenging due to the requirement for high-containment facilities. Here, we described the construction of novel TBEV replicons that permit a molecular comparison of TBEV isolates of high and low pathogenicity.