key: cord-0925818-li7pk5xy
authors: Divarathne, Maduja Vyanga Manike; Ahamed, Rukshan Rafeek; Noordeen, Faseeha
title: The Impact of RSV-Associated Respiratory Disease on Children in Asia
date: 2018-04-11
journal: J Pediatr Infect Dis
DOI: 10.1055/s-0038-1637752
sha: f9e8403016965e4c7e7e3265cef147658a3e2668
doc_id: 925818
cord_uid: li7pk5xy

Acute respiratory tract infections (ARTIs) are leading contributors to the global infectious disease burden, which is estimated to be 112,900,000 disability adjusted life years. Viruses contribute to the etiology of ARTIs in a big way compared with other microorganisms. Since the discovery of respiratory syncytial virus (RSV) 61 years ago, the virus has been recognized as a major cause of ARTI and hospitalization in children. The morbidity and mortality attributable to RSV infection appear to be higher in infants < 3 months and in those with known risk factors such as prematurity, chronic lung, and congenital heart diseases. Crowded living conditions, exposure to tobacco smoke, and industrial or other types of air pollution also increase the risk of RSV-associated ARTI. Many epidemiological studies have been conducted in developed countries to understand the seasonal patterns and risk factors associated with RSV infections. Dearth of information on RSV-associated morbidity and mortality in Asian and developing countries indicates the need for regional reviews to evaluate RSV-associated disease burden in these countries. Epidemiological studies including surveillance is the key to track the disease burden including risk factors, seasonality, morbidity, and mortality associated with RSV infection in these countries. These data will contribute to improve the clinical diagnosis and plan preventive strategies in resource-limited developing countries.

chimpanzees with common cold-like illness 21 and this led to the identification of RSV as a causative agent of coryza in chimpanzees. 22 Subsequently, Chanock et al identified the same virus as the cause of LRTI in young infants. 23 The virus was later named as RSV reflecting its ability to form syncytia among infected cells. 24 RSV is an enveloped virus with a nonsegmented negative sense RNA belonging to the genus Orthopneumovirus of the family Pneumoviridae. 25 The virus encodes for 10 genes and 11 proteins. 26 RSV has three surface glycoproteins: the fusion glycoprotein (F), attachment glycoprotein (G), and small hydrophobic (SH) proteins (►Fig. 1). G and F proteins are responsible for the initial phases of viral infection through attachment with the infecting cell. 26 The cell fusion is mediated by F, G, and SH proteins and the latter is believed to change membrane permeability. 27 Based on the structural features of the matrix protein (M) and ribonucleoprotein (RNP), there are three morphological forms (a, b, and c) of RSV particles (►Fig. 2). 28 Transmission of RSV occurs mainly via the nose through infected aerosols. RSV remains infectious on many environmental surfaces suggesting that transmission can occur through contact with hands or inanimate surfaces contaminated with infected nasal secretions. 29 Most of the RSV-associated ARTI are community-acquired, but there have also been reports of hospital-acquired RSV infections. 8, 30 The likelihood of hospital-acquired RSV infection increases with the duration of hospital stay and gaps in the infections control practices. 31 Based on a previous study, RSV detection in children at the time of admission was 39%, which increased to 62% during the hospital stay. 32 RSV alters host cells by initially infecting the epithelial lining of the respiratory airway and nasal passage. The virus influences the expression of genes controlling protein metabolism, inflammation, cell growth, proliferation, nucleic acid regulation, and synthesis. 33 RSV infection causes pneumonia through damaging the respiratory epithelium and bronchociliary apparatus; this results in the collection of fluid in bronchioles and alveoli causing obstruction and collapse of the affected area of the lung. Replication of RSV starts from nasopharynx primarily in the superficial layer of the respiratory epithelium and the virus then descends from the nasopharynx to lower respiratory tract via the respiratory epithelium or inhalation of secretions. 34 RSV-associated bronchiolitis is the most important cause of admission to the hospital during the first year of infancy. 8 Around 50 and 25% hospitalizations of infants are due to RSVassociated bronchiolitis and pneumonia. 34 RSV is responsible for precipitating recurrent wheezes and asthma in susceptible children. 35 Recurrent RSV infections also cause residual parenchymal or airway damage leading to minor abnormalities in lung function in the longer term. The mechanisms involved in RSV-associated recurrent wheeze and asthma are not clear, and whether RSV is directly responsible for asthma or infects children with preexisting broncho-obstructive disease remains unresolved. 36 Recent studies suggest that RSV causes asthma in some infants, but is also capable of attacking infants with a predisposition for wheezing. 36,37 Hospitalized infants aged < 1 year with RSV-associated bronchitis have a tendency to develop asthma and recurrent wheeze for a few years. 38 Here, we review the impact of RSV-associated ARTI on children in Asia including epidemiology, laboratory diagnosis, therapies, and future research priorities.

Since the discovery of RSV 61 years ago, the virus has been identified as a major cause of ARTI in infants and the single most common cause of childhood hospitalization. 39 During the past 31 years, RSV has been identified as the cause of severe LRTI in infants and children in developing countries. 39 RSV-associated morbidity and mortality appear to be high in infants < 3 months and children with known risk factors compared with other viral LRTI. Known risk factors for acquiring RSV-associated LRTI include prematurity, chronic lung disease, congenital heart disease, cystic fibrosis, bronchopulmonary dysplasia, down syndrome, compromised immunity, crowded living conditions, and exposure to tobacco or industrial smoke. 9,40 Moreover, RSV-associated ARTI appears to be common in boys than girls; 41 the reason for the male preponderance is believed to be due to immunomodulatory effects of the sex hormones during the early stages of life. 42 Severe RSV-associated respiratory disease has also been recognized as a significant health issue in adult populations, and epidemiological data suggest that the impact of RSV in adults is largely similar to nonpandemic influenza. ARTI due to RSV have been reported in the institutionalized elderly, the immunocompromised, and adults with cardiopulmonary diseases. 43 The Impact of RSV on Global Child Health Globally, RSV is commonly associated with childhood ALRI and related hospital admissions, which results with a substantial burden to the health care systems and economy. Approximately 45% of the hospitalizations and deaths are caused by RSV-associated ARTI in infants < 6 months. In 2015, 33.1 million new episodes of RSV-associated ALRI occurred worldwide in children less than 5 years, with at least 3.2 million hospitalizations and 59,600 in-hospital deaths. 44 Moreover, RSV-associated ALRI caused 1.4 million hospitalizations with 27,300 in-hospital deaths in infants < 6 months. 44 Alaskan native infants have the highest rates of RSV hospitalizations in the world. 42 RSV-associated hospitalization rates for Alaskan native infants, in the rural Yukon-Kuskokwim Delta (YKD) region of Alaska were five times higher than that for the overall United States infant population. 45 From 1993 to 2004 is considered to be the period when the worst RSV outbreaks occurred in the YKD region, and RSV-associated hospitalization rates rose to 38 to 248 per 1,000 during that period. Infants from indigenous Canadian populations, Germany, the United States, New Zealand, and Europe also have high hospitalization rates with RSVassociated ARTI. 46 The Impact of RSV on Child Health in Asia Based on studies conducted in Asia, the most common cause of LRTI in children is RSV (►Table 2). In Hong Kong, RSV-associated hospitalization has been described in children < 5 years. 64 In Japan, RSV-associated LRTI occurred in 31.4% of a sample of 535 children aged < 3 years. 47 In Lanzhou, China, RSV was detected in 40.71% of the children with ARTI. 50 In another study, RSV accounted for 25.0% of the LRTI cases in Harbin, China. 51 In Hong Kong, RSV has been detected in young infants with chronic lung disease, neurodevelopmental conditions, and congenital heart disease; these risk factors significantly increased the risk of RSV infection. 65 Information on the impact of RSV in childhood ARTI in South East Asian countries is scanty. In Malaysia, RSV is the most common respiratory virus identified in children 6 months, accounting for 81.3% of the LRTI cases. 53 Data from Lombok, Indonesia, suggest that 16% of LRTI deaths are caused by RSV. 66 In Vietnam, RSV, influenza A, and rhinoviruses contribute to pneumonia along with multiple viral and coinfections with bacteria. 67 In Bhaktapur, Nepal, RSV infections were detected in 15.1% of the study sample, 58 and in India RSV accounted for 57% of ARTI cases. 64 In Bangladesh, RSV has been identified as the predominant (81%) viral pathogen causing pneumonia in children in rural areas. 60 In urban areas of Bangladesh, the overall incidence of RSVassociated pneumonia is 40/100 child years. 61 In temperate regions of Asia RSV causes outbreaks mostly during the fall or winter; in tropical regions of Asia RSV outbreaks usually peak in hot or rainy seasons, but can occur at any time of the year with genotype shifting. 68 Based on the severe acute respiratory infection (SARI) surveillance in China, RSV has been mostly detected in infants year around with peaks from autumn to winter. 49 In contrast to these findings reported from the mainland China, 58 RSV seasonality has not been noted in winter in Hong Kong. 65 In Japan, cocirculation of different RSV genotypes has been observed every year with shifts in genotypes within a season. 48 In Nepal, the largest peaks of pneumonia occur during RSV peak seasons in rainy and winter periods from July to April. 58, 69 In India, RSV outbreaks occur in the rainy season from August to November. 59 The Impact of RSV on Childhood ARTI in Sri Lanka

Childhood hospitalization due to RSV-associated ARTI is common in Sri Lanka. 70 RSV is recognized as the most common cause of viral ARTI among children in Sri Lanka, as in many other countries. RSV contributes to 90.6% of virusassociated ARTI based on the findings of a small-scale study of children admitted to Kegalle General Hospital with ARTI. 70 This study also described that RSV infections occurred predominantly from July to September. 70 A study based on Gampola and Anuradhapura Teaching Hospitals reported incidences of 31.3 and 28/100,000 person years, respectively, for RSV among infants with ARTI. In Anuradapura (which is located in the dry zone), RSV was detected throughout the year with a peak from May to July in both 2013 and 2014. In Gampola (located in the wet zone), RSV was again detected throughout the year, but peaked during December to January in 2013. 64 Larger studies are needed to fill the gap in understanding the local seasonality, disease burden, and severity of RSV-associated ARTI in Sri Lanka. 64

Data on the incidence and mortality of RSV-associated ARTI in Asian developing countries have not been published and thus the extent of this infection's contribution to mortality remains uncertain. According to the World Health Organization (WHO), almost three-fourths deaths in infants occur due to RSV-associated pneumonia in Southeast Asia and sub-Saharan Africa. 71 The Pneumonia Etiology Research for Child Health (PERCH) project evaluated the etiological agents causing severe pneumonia in children from seven developing counties including two in Asia, Bangladesh and Thailand. This study showed a significant association between hospitalization of children and RSV-associated pneumonia in Bangladesh. 72 Therefore, regional estimates of RSV-associated ARTI burden in Asian developing countries with local seasonal patterns, risk factors, and virus evolution would improve our understanding of RSV epidemiology in these countries.

A few projects have been conducted in developed and developing countries to understand the seasonal patterns of RSV infection compared with other respiratory pathogens and to identify the risk factors for severe respiratory disease. 66 These projects have shown that RSV seasonality depends on the geographic location and altitude of a given country or a region. RSV-associated respiratory disease epidemics tend to occur in clusters during a particular season. Although the occurrence of RSV outbreaks varies among continents, the general pattern is that they start in coastal areas and spread to inland areas. 39 In countries experiencing tropical and semitropical climates and located far from the equator, RSV outbreaks occur in cool dry and cool wet seasons. In regions closer to the equator, RSV outbreaks occur throughout the year with periods of peak activity. 39 RSV outbreaks have been reported year around with a slight increase in the rainy seasons in equatorial islands like Singapore, Fiji, Taiwan, and Hawaii. 40 In countries north of the equator like India, outbreaks have been reported predominantly during the rainy season. 40 RSV peaks have been reported in the winter months in most of the European countries although the infections remain relatively consistent throughout the year. 40 Although there are predictions made on RSV seasonality patterns, the predictions are not reviewed systematically at a global level, in parallel with surveillance data for many other respiratory viruses like influenza in the last decade. RSV diversity is influenced by the physiology of the host, host-virus interactions, social behavior of people, and transmissibility of the virus. The absence of a global picture of RSV seasonal patterns is a hindrance to planning public health strategies to combat RSV outbreaks. An extensive review of the literature, together with proper laboratory surveillance in different geographical areas, remains to be conducted on a global scale.

RSV outbreaks have periodic emergence patterns and the reason for that is not clear. Even though geographic and climatic factors have a clear association with epidemics, the RSV epidemic pattern is also related to human behavior. 39 Due to similarities in risk factors, influenza and RSV epidemics often overlap. 73 In temperate areas, RSV and influenza activities both peak during the winter. However, there is greater diversity in the behavior of the two viruses in tropical countries, where RSV has been reported in 80% of areas, and influenza in 50% of areas, during the same outbreak. 74

Repeated RSV infections are associated with increased prevalence of atopy in children and their families. 34 Some investigations were performed to explore whether there is a connection between RSV-associated bronchiolitis in infancy and subsequent development of allergic sensitization or clinical allergy. 75 These studies confirm the association between recurrent RSV infections and atopy in children. Conversely, children with atopy and recurrent RSV infections also had more siblings and smoking parents. 36 Children with recurrent RSV infections had cardiopulmonary conditions than those with influenza or bacterial infections. Thus, RSV infection in children is associated with asthma, atopy, and other forms of bronchial obstructive diseases. 76 Trials performed in the United States, the United Kingdom, Japan, Canada, and Denmark revealed the significance of crowded living conditions and exposure to tobacco smoke as risk factors for severe RSV disease. 40 Likewise, a study in Sri Lanka found that 31.3% of children with RSV-associated ARTI were from a household with at least one smoker. 64 Also, according to research conducted in Sri Lanka and Kenya, there is a close association between rural inhabitance and hospitalization due to RSV infection suggesting that rural inhabitance may also be a predisposing factor for RSV infection. 64, 71 The time of birth has a significant association with RSV-induced bronchitis, 77 and moreover, birth during the winter virus peak season confers risk for childhood asthma. 78 Immunosuppression is another independent risk factor for RSV infection and the risk of mortality increases with the progression of infection from upper to lower respiratory tract. 77 Among adults, presence of a chronic pulmonary disease, physician-diagnosed congestive heart failure, and functional disability increase the risk of RSVassociated serious ARTI. 79, 80 Moreover, hospitalization is a risk factor for severe RSV infection and mortality attributed to RSV-associated ARTI. 40

Virus evolution contributes to the emergence of new strains of RSV, while old RSV stains disappear under the selective pressures created by the new ones. 81 Pathogenicity and the fitness are strong in emerging RSV stains, which are widespread and cause recurrent infections and outbreaks. 82 The G and F proteins are considered as important antibody targets as changes occur in these areas to avoid the host immune responses. 83 RSV evolution is associated with accumulation of amino acid changes and antigenic variations in the G protein. 84 Even though the sequence variability of RSV is concentrated on the G gene, the rapid pace of infection underlines the contribution of the full genome to virus evolution. 83 According to the sequence variability in the F gene, mutations in the F protein are mostly deleterious, therefore, only a few sites in the F gene are under positive selection pressures. 85 RSV appears to undergo sequential evolution like influenza B, which has evolved through interactions between influenza A and C. It has been shown that multiple lineages of RSV originate from cocirculation of RSV subtypes. 81 RSV subtype B shows significantly faster rate of evolution than the subtype A, with a higher variation in the protein length, stop codon usage, and mechanisms for variation in the G gene. 46 The other explanation for the change of genotypes over time is the rapid distribution of new genotypes as they emerge around the world at the same time. 81 A study conducted in New Zealand on the evolution of the G gene sequence noted the circulation of RSV stains that were related to those circulating in nearby countries during the same period. This finding supports the emergence and spread of RSV stains between closer neighboring regions. 46 A combination of factors including virus persistence in defined areas and continuous reintroductions from different areas are believed to be responsible for RSV epidemics resulting from new subtypes. 86 

Respiratory viruses tend to circulate at the same time making it difficult to identify their individual contributions on the disease burden. 87 Moreover, the chances of detecting viruses in clinical specimens may be constrained by inadequate sample volume or quality, or by the laboratory techniques used. Isolation attempts often fail due to the lability of the virus. 88 However, the laboratory diagnosis should be sensitive and specific to identify viruses causing ARTI. 87 Thus, timely detection of RSV resulting from a rapid and an efficient assay is important. 89 Many laboratory tests are often limited to a single virus, rather than allowing detection of multiple respiratory viruses. Although widely used techniques like viral culture and antigen detection have greater sensitivity over direct antigen testing (►Fig. 3) from respiratory samples, their ability to detect only a single pathogen is a limitation. 90 Molecular techniques (►Fig. 3) are highly effective and have facilitated the identification of previously known and new viruses. 91 Moreover, molecular characterization of different respiratory viruses for epidemiological purposes has been performed using different types of conventional and advanced DNA sequencing methods (►Fig. 3).

Ribavirin is the only licensed antiviral treatment for RSV infections and has shown promising results in placebocontrolled studies with administration at the beginning of the illness to children who are more prone to get lifethreatening complications. 76 However, the drug is less used clinically, at least in part because of a lack of confidence in its efficacy. 92 Factors such as the inconvenience of administration and toxicity also compromise its therapeutic potential in severe RSV infections. 93 Palivizumab (Synagis) is a drug approved for use in selected risk groups, such as infants with chronic lung disease, congenital heart disease, and history of prematurity. 94 It is a monoclonal antibody (mAb) that targets one of the proteins in RSV subtypes A and B. 95 However, palivizumab is only around 40% effective in reducing RSV-associated hospitalization rates in premature infants and high risk children. 96 While this prophylactic treatment may be effective in reducing RSV-associated morbidity in infants, high cost and inconvenience of administration have limited it use. 97 An effective vaccine against RSV has not been available yet, and clinical experience of both inactivated and attenuated test vaccines have not shown great promise. In one trial, RSV-infected children were administrated an inactivated vaccine named "lot 100" and following the vaccination, vaccinees developed severe respiratory disease. Infants aged under 23 months showed a higher incidence of pneumonia (60%) in the vaccinated group compared with the placebo group that had only an 8% incidence of pneumonia.

The vaccine was reported to induce the production of a neutralizing antibody against F and G proteins but the reason for the increased respiratory disease in the vaccinated children was not clear. 34 An RSV live-attenuated vaccine (LAV) with enhanced immunogenicity was tested in cotton rats and this vaccine exhibited thermal stability, efficacy, and immunogenicity. This genetically modified vaccine candidate merits consideration as the next-generation RSV vaccine design for humans. 98 Many other experimental vaccines are being tested on animal models and inactivated vaccines have shown superiority over attenuated vaccines in eliciting humoral and cell-mediated immunity. Recombinant vaccines with the expression of F, G, and N genes are currently under investigation. The common obstacles in the progress of developing a RSV vaccine are the young age group that needs to be protected and the fact that individuals experience continued reinfections with RSV even in the presence of humoral immunity. 34

Poor growth of RSV in vitro, lack of suitable animal models, and instability of RSV in test environments have limited RSV research. More research is needed to address different aspects of RSV structure, function, and infection. The genome structure of the negative strand RNA, three-dimensional structure of the virus, and virion structure should also be evaluated to identify immunogenic proteins as vaccine candidates.

Due to limited therapeutic options to treat RSV-associated respiratory disease, the development of effective novel therapies must be high priority too. Currently, the effect of administering RSV neutralizing antibodies is being studied. These studies have also progressed to evaluating the effectiveness of combination therapy with these antibodies and antivirals like ribavirin. 99 Combinations of intravenous palivizumab and ribavirin have also been studied in high-risk RSV disease in children; such combination therapy has been reported to be effective, and associated with reduced mortality rates. 100 The combination of two mAbs (130-6D and 131-2G), which are reactive to the central conserved region (CCR) of RSV G protein, has also shown promising results in reducing the pulmonary inflammation caused by RSV compared with the effect of these antibodies alone in reducing the inflammation. 99 Finally, mucolytic agents such as recombinant human deoxyribonuclease (rhDNase) have shown promising results based on the improvements shown on chest X-rays, 78 but more work is needed to evaluate the effectiveness of these drugs.

As the immune responses elicited by viruses are specific despite their structural and pathogenic similarities, work is needed to identify the fundamental aspects of the immune response in RSV infections. For instance, very little information is available on the mechanisms of mucin (MUC) expression in human epithelial cells during an RSV infection and its Fig. 3 Laboratory diagnosis of RSV infection using NPA. When NPA is not available nasal swabs can be used but the chances of viral antigen or nucleic acid detection in the nasal swab is low when compared with that in the NPA. (a) Immunofluorescence assay has been used in many diagnostic laboratories to detect RSV antigen. (b) Real-time PCR has been used in well-equipped laboratories to detect RSV nucleic acid and is the gold standard test. However, other types of PCRs have also been used to detect RSV nucleic acid depending on the availability. (c) Sequencing is done to understand the local, regional, and global epidemiology of different RSV types. PCR, polymerase chain reaction; NPA, nasopharyngeal aspirate; RSV, respiratory syncytial virus. contribution to immune response. As MUC is recognized as an important component of the immune response, further research on this would bring a better understanding on the role of MUC in rendering protection in RSV infections. Moreover, research on the immune response in primary, secondary, homotypic, and heterotypic RSV infections would help to design immunoprophylactic strategies. Conversely, identifying the role of the respiratory microbiome in severe RSV infections will help to understand the impact of microbiome in disease severity as well as in protection.

The evolution of RSV around the globe is not fully understood, and thus sequence analysis of the stains will provide knowledge about the ancestry of the RSV and its evolution. Studies should also be performed to gather information on seasonality patterns and transmission dynamics according to regional differences in RSV seasonality data with climatic and population data. 82 Better understanding of the epidemiology of ARTI in developing countries would provide options for preventive measures in a timely manner as use of respiratory precautions and health education can be undertaken in different target populations.

Respiratory syncytial virus has a worldwide distribution and it contributes to significant morbidity and mortality in infants compared with other respiratory pathogens. Regional seasonality of RSV infections is pronounced. In equatorial countries, RSV is seen year-round, but there is an association with the rainy season in tropical and semitropical countries north of the equator, and with the dry season south of the equator. Changes in temperature and humidity correspond with the spread of the disease. Many host and environmental risk factors contribute to RSV-associated ARTI and hospitalizations including prematurity, overcrowded living conditions, passive exposure to tobacco smoke, and bronchopulmonary dysplasia/chronic lung disease. Detecting RSV-associated ARTI in resource-limited countries will contribute to minimizing irrational antibiotic use. Research is needed to develop effective vaccines and antiviral agents to tackle the increasing RSV-associated ARTI burden. 

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None declared.