You will be shown a paragraph from a biomedical research paper, followed by a question about the paper. Please extract text from the paragraph to answer the question. Do not include any text in your repsonse other than the answer.

Paragraph: Asthma is a complex disease, characterised by chronic airway inflammation, and a history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough . Over time these symptoms can vary in their intensity [20] . Each year over 300 million people worldwide are affected by asthma: approximately 250,000 people die as a result. Many deaths are due to suboptimal long-term medical care and delay in obtaining help during severe exacerbations of the disease [21] . Treatments to prevent worsening of symptoms and other therapies for mild to moderate asthma that avert relapse, i.e., the symptoms worsen again when the treatment stops, are significant unmet medical needs. The human challenge model has been used to investigate the viral pathogenicity [22] [23] [24] [25] [26] and recent publications on the asthma challenge model have focused on how the asthmatic host responds to HRV infection. Work is ongoing as to susceptibility to viral induced asthma worsening [27, 28] innate immune dysregulation [29] and induction of innate, and type 2 responses in nasal and bronchial epithelial secretions [30] . The pathogenesis of rhinoviral infection, along with other ARIs, in exacerbations of airway disease, has been investigated extensively. Impaired host responses to virus infection, a better understanding of the mechanisms of abnormal immune responses and the potential to develop novel therapeutic targets for virus-induced exacerbations have all used the HVC model [12, [31] [32] [33] [34] . Despite previous research work on multiple small molecule antivirals, such as pleconaril which have been tested using both the experimental challenge model and field studies [35] [36] [37] , there is currently no licensed treatment for HRV infections Other compounds have been tested against HRV, such as Vapendavir (BTA798) which prevented the release of viral RNA into the target cell and demonstrated a reduction in peak viral load in the HVC model [38] . A subsequent study in asthmatics was completed and although not published the compound did have a limited effect [39] . Pirodavir an intranasal capsid-binding molecule reached phase 3 clinical trials for HRV prevention and treatment in the 1990s. Although the compound decreased viral replication and shedding, it failed to show a significant reduction in the duration or severity of symptoms [40, 41] . A Protease inhibitor, rupintrivir thats prevents cleavage of viral proteins required for replication was tested in an HRV challenge trial. Rupintrivir was well tolerated and reduced viral loads and respiratory symptoms [36] . However, in studies of natural infection, it did not significantly affect viral loads or symptom severity [42] . Treatments such as zinc-containing products are now widely discredited as demonstrated by the withdrawal of a Cochrane report and JAMA editorial [43] [44] [45] . Current treatment of HRV infections primarily consists of over-the-counter (OTC) medicines to manage symptoms. There is also no licensed vaccine, and while there has been some progress on developing multivalent vaccines [46] , development in this area is hampered by the sheer number of serotypes that need to be covered (at present over 160). Despite HRV being associated with up to 50% of adult asthma exacerbations and up to 80% of childhood exacerbations, there are no HRV-specific asthma therapies [34] . As we better understand the interaction between the virus and the host, new therapies such as the monoclonal antibodies (anti-IgE [omalizumab] and anti-IL-5 [mepolizumab]) along with small molecules carefully targeting specific immune signalling pathways, HRV-specific prophylactic treatment may become practical [47] [48] [49] [50] . In order to prevent exacerbations, the design of new therapeutics could potentially improve efficacy by both directly acting to inhibit viral replication and alleviate the symptoms of asthma and COPD [51] . Influenza virus is a well-known human pathogen and can cause severe morbidity and mortality, particularly in older patients, those with co-morbidities and in the immunocompromised. In 2009, the first pandemic virus of the 21 st century hospitalised 195,000 to 403,000 in the US alone resulting in 8,870 to 18,300 deaths by mid-2010 [52] . A World Health Organization (WHO) global pooled analysis of 70,000 laboratory-confirmed hospitalised H1N1 pandemic patients from 19 countries revealed that of the 9,700 patients admitted to intensive care units, 2,500 died, and that morbid obesity might be a risk factor for hospitalisation and/or death [52] . Obesity was confirmed as a factor associated with a higher likelihood of admission to hospital in influenzainfected patients [53] . The 2009 pandemic was considered mild. However, the classic W shaped age distribution curve of infection for a pandemic virus was observed. That is high mortality in the very young and the old, but an additional spike in death amongst the "young and healthy". The pandemic, as did previous outbreaks, occurred in successive waves, but despite national policies favouring the use of antiviral drugs, few patients received these before admission to hospital, and many were given antibiotics [54] . The lack of real, or perceived, "real world" efficacy of currently available antivirals leads to the overuse of antibiotics and the subsequent problems that may arise [55] [56] [57] . The yearly seasonal morbidity and mortality of influenza results in hospitalisation and death mainly among the high-risk groups. Each year epidemics of seasonal influenza are estimated to result in about 3 to 5 million cases of severe illness, and about 290,000 to 650,000 deaths worldwide [58] . In first world / industrialised countries, most deaths associated with influenza occur among people age 65 or older [59] . Clinics and hospitals, in many countries, can be overwhelmed during peak illness periods, and there can be substantial economic cost [60] . The virus itself has been well characterised, and the two surface proteins, the haemagglutinin (HA) and the neuraminidase (NA) are important in both vaccine and antiviral development [61] . The effects of seasonal influenza epidemics in developing countries are not fully known, but research estimates that 99% of deaths in children under five years of age with influenza-related lower respiratory tract infections are found in developing countries [59, 62] . Currently, vaccines and antivirals exist for the prevention and treatment of influenza, but both have limitations in efficacy due to the rapid evolution of the virus as it mutates on a yearly basis and the sudden unexpected emergence of pandemic influenza strains. The effectiveness of recent annual influenza vaccines (to date mostly based on the HA, and rarely the NA surface glycoproteins) has languished between 37% and 70% over successive influenza seasons. In particular, the failure of the vaccine across the winter season of 2014-2015, where the overall adjusted effectiveness was 23% [95% confidence interval 14, 31] [63] is memorable. In a mismatched year, the mortality rate is increased in the most at-risk populations [64, 65] . The problem of ensuring that the seasonal vaccine is correctly matched to the upcoming circulating strain highlights the need for rapid development of inter-seasonal/universal vaccines and also the need for a way of testing their efficiency rapidly and accurately before the lengthy and expensive mass production is engaged which takes many months [66, 67] . Antiviral drugs exist of which currently the NA inhibitor oseltamivir is most commonly used. This is active against all known NA subtypes of influenza, and one would, therefore, assume against all influenza strains. They may have decreasing effect with the emergence of resistant influenza strains in which NA protein changes preventing efficient oseltamivir binding and thus its ability to inhibit the essential activity of the viral NA. For example, one genetic mutation known as 'H275Y'a substitution of histidine for tyrosine at NA position 275 -confers an evolutionary advantage to the virus including the 2009 H1N1 influenza [68] . During the 2013-2014 influenza season, 59 (1.2%) of 1,811 influenza A(H1N1) pdm09 virus isolates in 20 of 50 US states had the H275Y oseltamivir resistance substitution. No isolates were resistant to zanamivir [69] . Although animal studies have demonstrated limited transmission of mutant viruses [70, 71] , it is thought that the rise of oseltamivir resistance may be due to community transmission [72, 73] rather than the H275Y mutation becoming fixed in the viral genome. Asystematic systematic review and meta-analysis of published data from 2000 onwards concluded that most RSV-associated child deaths occur particularly in preterm infants and in infants up to 1-year of age [62, 74] . An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group [75] . The RSV-specific monoclonal antibody palivizumab is approved for prevention of serious LRI caused by RSV in susceptible infants. Economic benefit in a UK health setting has not been shown due to the high cost and lack of benefit on serious outcomes [76] . A single-centre cohort study of 22 infants showed no difference in treatment outcomes for patients receiving palivizumab when compared to patients only receiving "standard of care" treatment [77] . Despite the lack of evidence for clinical benefit, post-licensure data supports the use of palivizumab for reducing RSV-associated hospitalisations in premature infants under 33 weeks and in children with chronic lung and heart diseases [78] . Importantly, palivizumab resistant mutant virus has rarely been isolated in clinical specimens [79] . The RSV treatment ribavirin is limited due to difficulty with aerosol delivery, cost and potential harm to healthcare workers, despite off-label treatment of immunocompromised patients being reasonably successful. In the immunocompromised, therapy with a concomitant immunoglobulin or palivizumab has had mixed results, probably due to the difficulty of knowing when to initiate treatment [80] . Despite the call for the accelerated development of prevention and treatment strategies for an effective RSV vaccine for children [81] , research has stalled for decades since the death in the 1960s of two subjects in a clinical study. These subjects were infected with a communityacquired RSV infection after receiving the US National Institutes for Health (NIH's) formalin-inactivated, alumprecipitated RSV candidate vaccine. In contrast to influenza for which vaccines to date have shown themselves to be moderately effective but in need of improvement, RSV vaccines require substantially more research. There is currently no licensed vaccine for RSV; the most advanced candidate vaccine recently failed to show efficacy in a field study [82] . Effective treatments are urgently required. RSV is, even amongst healthcare professionals, considered a childhood disease and other confounders have obscured the understanding of the consequences of RSV in adults. RSV is poorly understood as a disease in the elderly [83] , and while the morbidity and mortality in children are of importance, it has been clearly shown that RSV has a comparable health burden to influenza in the elderly [84] . As an example, a recent study was conducted on adult (≥18 years) patients admitted to an emergency department with suspected ARI during 2013-2015 (N = 3743). Multiplex PCR was used to diagnose the cause of the respiratory infection. Eighty-seven patients were identified with RSV. A comparator group with influenza (n=312) was utilised. Based on a 20-day all-cause mortality endpoint, adult patients were less likely to be diagnosed with RSV than with flu (2.3 vs 8.3%, respectively), also they were older, often diagnosed with pneumonia, COPD, hypoxemia, and bacterial co-infection. RSV infection in the elderly was significantly associated with a greater risk of death than seasonal influenza, adjusted for potential confounders and comorbidities. [85] 

The clinical significance of viral/bacterial co-infections has long been a controversial topic. While severe bacterial pneumonia following influenza infection has been well described, associations are less clear among infections caused by viruses common in young children; secondary infections due to other viruses are less well understood and has been reviewed by others [86] . Although assessing the overall contribution of bacteria to disease severity is complicated by the presence of many confounding factors in clinical studies, understanding the role of viral/bacterial co-infections in defining the outcome of paediatric ARI may potentially reveal novel treatment and prevention strategies, improving patient outcomes [33, [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] . A recent (2017) publication considered the role of bacterial colonisation with Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis during symptomatic and asymptomatic viral upper respiratory infection in the nasopharynx of 4 to 7-year-old children during URI and when well. Using a multiplex PCR, virus was detected in about 80% of upper respiratory tract infections (URIs) in children and is also detectable in the nasopharynx of 30% of asymptomatic children. All three bacteria "levels" were higher during acute URI visits compared to asymptomatic surveillance visits by the children. Of note, however, is that even during asymptomatic follow-up visits, if the virus was present, all bacteria were detected at higher levels [96] . It is worth noting that the presence of confounding infections, can mask the importance of the primary aetiology. Taylor et al. [8] report the incidence of HBoV following its identification in 2005 from the respiratory tract samples of children, as an important respiratory pathogen in children. However, the role of this virus on its own as a pathogen of significance was initially unclear, co-infection with other viruses or bacteria was common and confounding. Moesker et al. [97] studied whether HBoV alone could cause acute respiratory infections in children. Using Next Generation Sequencing (NGS), they were able to exclude co-infections amongst those admitted to intensive care unit and studied HBoV viral loads. Of the 990 children who tested positive for a respiratory virus by RT-PCR, HBoV and RSV were detected in 178 and 366 of the children respectively.

Question: What are the clinical characteristics of asthma?
chronic airway inflammation, and a history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough