Severe Lower Respiratory Tract Disease Research Articles

Adenovirus serotype 7 associated with a severe lower respiratory tract disease outbreak in infants in Shaanxi Province, China

BackgroundPneumonia caused by adenovirus infection is usually severe especially with adenovirus serotype 7 commonly associated with lower respiratory tract disease outbreaks. We reported an outbreak of 70 cases of severe pneumonia with one death of infants in Shaanxi Province, China. Sampling showed adenovirus 7 (Ad7) as the primary pathogen with some co-infections.ResultsTwo strains of adenovirus and two strains of enterovirus were isolated, the 21 pharynx swabs showed 14 positive amplifications for adenovirus; three co-infections with respiratory syncytial virus, two positive for rhinovirus, one positive for parainfluenza 3, and four negative. Adenovirus typing showed nine of the nine adenovirus positive samples were HAdV-7, three were HAdV-3 and two were too weak to perform sequencing. The entire hexon gene of adenovirus was sequenced and analyzed for the two adenovirus serotype 7 isolates, showing the nucleic acid homology was 99.8% between the two strains and 99.5% compared to the reference strain HAdV-7 (GenBank accession number AY769946). For the 21 acute phase serum samples from the 21 patients, six samples had positives results for ELISA detection of HAdV IgA, and the neutralization titers of the convalescent-phase samples were four times higher than those of the acute-phase samples in nine pairs.ConclusionsWe concluded adenovirus was the viral pathogen, primarily HAdV-7, with some co-infections responsible for the outbreak. This is the first report of an infant pneumonia outbreak caused by adenovirus serotype 7 in Shaanxi Province, China.

The Role of RSV Infection in Asthma Initiation and Progression: Findings in a Mouse Model

Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract diseases (bronchiolitis and pneumonia) during infancy and early childhood. There is increasing evidence which indicates that severe pulmonary disease caused by RSV infection in infancy is associated with recurrent wheezing and development of asthma later in childhood. However, the underlying mechanisms linking RSV infection to persistent airway hyperresponsiveness and dysfunction are not fully defined. To study these processes in ways which are not available in humans, animal models have been established and have provided valuable insight into the pathophysiology of RSV-induced disease. In this paper, we discuss experimental models of RSV infection in mice and highlight a new investigative approach in which mice are initially infected as neonates and then reinfected later in life. The findings shed light on the mechanisms underlying the association between early severe RSV infection and development of asthma later in childhood.

Decreased Toll-like receptor 8 expression and lower TNF-alpha synthesis in infants with acute RSV infection

BackgroundToll-like receptors (TLRs) are part of the innate immune system, able to recognize pathogen-associated molecular patterns and activate immune system upon pathogen challenge. Respiratory syncytial virus (RSV) is a RNA virus particularly detrimental in infancy. It could cause severe lower respiratory tract disease and recurrent infections related to inadequate development of anti-viral immunity. The reason could be inadequate multiple TLRs engagement, including TLR8 in recognition of single-stranded viral RNA and diminished synthesis of inflammatory mediators due to a lower expression.MethodsIntracellular TLR8 expression in peripheral blood monocytes from RSV-infected infants was profiled and compared to healthy adults and age matched controls. Whether the observed difference in TLR8 expression is a transitory effect, infants in convalescent phase (4-6 weeks later) were retested. Specific TLR8-mediated TNF-α production in monocytes during an acute and convalescent phase was analyzed.ResultsRSV-infected and healthy infants had lower percentage of TLR8-expressing monocytes than healthy adults whereas decreased of TLR8 protein levels were detected only for RSV-infected infant group. Lower protein levels of TLR8 in monocytes from RSV-infected infants, compared to healthy infants, negatively correlated with respiratory frequency and resulted in lower TNF-α synthesis upon a specific TLR8 stimulation. In the convalescent phase, levels of TLR8 increased, accompanied by increased TNF-α synthesis compared to acute infection.ConclusionsLower TLR8 expression observed in monocytes, during an acute RSV infection, might have a dampening impact on early anti-viral cytokine production necessary to control RSV replication, and subsequently initiate an adaptive Th1 type immune response leading to severe disease in infected infants.

Single mucosal immunization of recombinant adenovirus-based vaccine expressing F1 protein fragment induces protective mucosal immunity against respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infancy and early childhood. Despite its importance as a pathogen, there is no licensed vaccine against RSV. The fusion (F) protein of RSV is a potentially important target for protective antiviral immune responses. Here, we studied the immune responses elicited by recombinant replication-deficient adenovirus (rAd)-based vaccines expressing the soluble F1 fragment of F protein (amino acids 155–524) in murine model. The expression of secreted F1 fragment by rAd was significantly increased by codon optimization. Strong mucosal IgA response was induced by single intranasal immunization of codon-optimized vaccine, rAd/F1co, but not by rAd/F1wt. A single intranasal immunization with rAd/F1co provided potent protection against subsequent RSV challenge. Interestingly, neither serum Ig nor T-cell response directed to F protein was detected in the rAd/F1co-immune mice, suggesting that protective immunity by rAd/F1co is mainly mediated through mucosal IgA induction. Indeed, co-delivery of cholera toxin B subunit significantly enhanced mucosal IgA responses by the optimized vaccine, which correlates with protective efficacy. Taken together, our data demonstrate that a single intranasal administration of rAd/F1co is sufficient for the protection and represents a promising prophylactic vaccination regimen against RSV infection.

Human polyomaviruses, WU and KI in HIV exposed children with acute lower respiratory tract infections in hospitals in South Africa

Background The importance of two recently identified polyomaviruses, WUV and KIV, as respiratory pathogens in populations with a high HIV prevalence needs to be defined, since human polyomaviruses can cause significant morbidity and mortality in patients with immunosuppression. Geographic distribution and disease association of WUV and KIV genotypes are not yet clearly defined. Objectives To investigate the prevalence of WUV and KIV in HIV-positive and HIV-negative patients with respiratory infections in hospitals in South Africa and determine their genotypes. Study design Specimens from patients with acute respiratory infections from hospitals serving Pretoria were screened for WUV and KIV. Positive specimens were sequenced and subjected to phylogenetic analysis. Results WUV was identified in (7%) and KIV in (1%) of mainly pediatric patients. Co-infections were common in WUV- and KIV-infected patients (71% and 66.6%, respectively); 57% of patients with WUV and 33% of patients with KIV were HIV-positive while the HIV prevalence in the respiratory virus patient group screened in this study was 33% WUV and KIV patients presented with moderate to severe lower respiratory tract disease. Four distinct and 2 unique WUV strains were identified clustering into 2 of 4 globally identified genotypes. KIV strains were identical to strains from Sweden. Conclusion WUV is frequently detected in HIV-infected patients with respiratory disease, but its role as respiratory pathogen remains uncertain.

Molecular epidemiological analysis of a nosocomial outbreak of respiratory syncytial virus associated pneumonia in a kangaroo mother care unit in South Africa

Respiratory syncytial virus (RSV) may cause severe lower respiratory tract disease in premature infants. Prolonged viral shedding has been reported in patients with underlying immunosuppressive disorders, such as human immunodeficiency virus 1 (HIV-1) infection. During March to May 2006, 23 preterm pediatric patients developed nosocomial pneumonia in a district hospital in the Gauteng Province of South Africa due to RSV infection. The patients were identified using routine diagnostic testing. All had been admitted with their mothers to a Kangaroo Mother Care (KMC) ward from birth--a low care unit for the management of stable low birth weight infants. The HIV-1 seroprevalence among the mothers to these infants was 52.6%, translating to a 52.6% perinatal exposure. A multiplex nested RT-PCR was used to subtype RSV positive nasopharyngeal aspirates. Sequencing and phylogenetic analysis of part of the G-protein gene was used for molecular epidemiological analysis of the outbreak. In total, 19 of the 23 RSV positive specimens could be PCR amplified and sequenced. The subtype A, GA5 genotype was identified in 14 specimens and the BA genotype, a new subtype B genotype not previously recognized in South Africa, in seven. One patient had an infection with both genotypes. Phylogenetic analysis demonstrated eight separate introductions. Two of the strains identified in this outbreak were identical to strains circulating in a general pediatric ward of this hospital during the preceding month. Inadequate infection control measures by health care providers and mothers to children in KMC units may increase potentially the risk of severe RSV infection in a population group with compounded risk factors.

Low to Medium WU-Virus Titers in Young Children with Lower Respiratory Tract Infections

The WU-virus (WUV), a novel polyomavirus, has recently been recovered from respiratory tract samples. Within a study collective of children with severe lower respiratory tract disease, 3% of the patients tested WUV positive. Viral loads ranged from 5 × 10² copies/ml to 1 × 10⁴ copies/ml. The WUV genome-positive patients did not display specific clinical or radiological characteristics to be distinguished from other respiratory tract infections.

Single intranasal immunization with recombinant adenovirus-based vaccine induces protective immunity against respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infancy and early childhood. Despite its importance as a pathogen, there is no licensed vaccine against RSV. The G glycoprotein of RSV, a major attachment protein, is a potentially important target for protective antiviral immune responses. Here, a recombinant replication-deficient adenovirus-based vaccine, rAd/3xG, expressing the soluble core domain of G glycoprotein (amino acids 130 to 230) engineered by codon optimization and tandem repetition for higher-level expression, was constructed and evaluated for its potential as an RSV vaccine in a murine model. A single intranasal immunization with rAd/3xG provided potent protection against RSV challenge which lasted for more than 10 weeks. Strong mucosal immunoglobulin A responses were also induced by a single intranasal immunization but not by intramuscular or oral administration of rAd/3xG. Interestingly, neither gamma interferon- nor interleukin-4-producing CD4 T cells directed to I-E(d)-restricted epitope were detected in the lungs of rAd/3xG-immune mice upon challenge, whereas priming with vaccinia virus expressing RSV G (vvG) elicited strong Th1/Th2 mixed CD4 T-cell responses. Lung eosinophilia and vaccine-induced weight loss were significantly lower in the rAd/3xG-immune group than in the vvG-primed group. Together, our data demonstrate that a single intranasal administration of rAd/3xG elicits beneficial protective immunity and represents a promising vaccine regimen against RSV infection.

Single Intranasal Immunization with Recombinant Adenovirus-Based Vaccine Induces Protective Immunity against Respiratory Syncytial Virus Infection (B192)

Abstract Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infancy and early childhood. Despite its importance as a pathogen, there is no licensed vaccine against RSV. The G glycoprotein of RSV, a major attachment protein, is a potentially important target for protective antiviral immune responses. Here, a recombinant replication-deficient adenovirus-based vaccine, rAd/3×G, expressing the soluble core domain of G glycoprotein spanning amino acids 130 to 230, was engineered by codon optimization and tandem repetition for higher level expression, and evaluated for its potential to be used as an RSV vaccine in murine model. A single intranasal but not intramuscular immunization with rAd/3xG provided potent protection against RSV challenge at an improved level over inoculation of a recombinant vaccinia virus expressing whole G protein (vvG). Strong mucosal secretory IgA responses were induced by single intranasal immunization but not by intramuscular administration or immunization of vvG, while comparable serum IgG responses were observed in each group. Interestingly, rAd/3xG immunization did not induce detectable CD4 T-cell response whereas vvG priming strongly elicited CD4 T-cell response against I-Edrestricted G epitope (amino acids 183 to 195). RSV-induced weight loss was significantly lower in rAd/3xG-immunized group than vvG-immunized group. Thus, our data demonstrate that a single intranasal administration of rAd/3xG elicits beneficial protective immunity and represents a novel vaccine regimen capable of providing mucosal protection against RSV infection.

Peroxisome proliferator‐activated receptor‐γ agonists inhibit respiratory syncytial virus‐induced expression of intercellular adhesion molecule‐1 in human lung epithelial cells

Respiratory syncytial virus (RSV) is the major causative agent of severe lower respiratory tract disease and death in infants worldwide. The epithelial cells of the airways are the target cells for RSV infection and the site of the majority of the inflammation associated with the disease. However, despite five decades of intensive RSV research there exist neither an effective active vaccine nor a promising antiviral and anti-inflammatory therapy. Recently, peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has been shown to possess anti-inflammatory properties. Therefore, we hypothesized whether the detrimental increase of intercellular adhesion molecule-1 (ICAM-1) on RSV-infected lung epithelial cells (A549 and primary normal human bronchial epithelial cells (NHBE)) might be modulated by natural and synthetic PPAR-gamma agonists (15d-PGJ2, ciglitazone, troglitazone, Fmoc-Leu). Our data show that all PPAR-gamma agonists under study significantly down-regulated the RSV-induced expression of ICAM-1 on A549- and NHBE cells in a dose-dependent manner resulting in a reduced beta2 integrin-mediated adhesion of monocytic effector cells (U937) to RSV-infected A549 cell monolayers. In contrast, the PPAR-alpha agonist bezafibrate had no impact on the RSV-induced ICAM-1 expression. The reduced ICAM-1 expression was associated with a diminished ICAM-1 mRNA level and binding activity of nuclear factor-kappaB (p65/p50) in A549 cells. These findings suggest that PPARgamma agonists have beneficial effects in the suppression of the inflammatory response during RSV infection and therefore might have clinical efficacy in the course of severe RSV-infection.

High Prevalence of Human Bocavirus Detected in Young Children with Severe Acute Lower Respiratory Tract Disease by Use of a Standard PCR Protocol and a Novel Real-Time PCR Protocol

The human bocavirus (HBoV) was recently isolated from respiratory tract samples. Within a study collective of children with severe lower respiratory tract disease, the patients testing positive for HBoV (12.8%) had a higher rate of underlying cardiopulmonary disease. Viral loads in respiratory tract specimens varied from 10(2) to 10(10) genome equivalents/ml.

H5N1 Virus Attachment to Lower Respiratory Tract

Highly pathogenic avian influenza virus (H5N1) may cause severe lower respiratory tract (LRT) disease in humans. However, the LRT cells to which the virus attaches are unknown for both humans and other mammals. We show here that H5N1 virus attached predominantly to type II pneumocytes, alveolar macrophages, and nonciliated bronchiolar cells in the human LRT, and this pattern was most closely mirrored in cat and ferret tissues. These findings may explain, at least in part, the localization and severity of H5N1 viral pneumonia in humans. They also identify the cat and the ferret as suitable experimental animals based on this criterion.

The Clinical Need for New Antiviral Drugs Directed against Influenza Virus

In this issue of the Journal of Infectious Diseases, Ison et al. present data on the emergence of resistance to the neuraminidase (NA) inhibitor class of influenza antiviral drugs in immunocompromised hosts [1, 2]. Some patients with severe immunosuppression, such as those undergoing bone marrow or solid-organ transplantation, may have prolonged viral replication or severe lower respiratory tract disease. When administered early in the course of disease, antiviral treatment can be effective at preventing progression to pneumonia and reducing mortality in these patients [3]. Antiviral agents targeting the M2 ion channel (amantadine and rimantadine) or the NA enzyme (oseltamivir and zanamivir) can both be used for influenza A virus infections, whereas only the NA inhibitors are useful against influenza B viruses. NA inhibitors have advantages in pharmacokinetics, frequency of adverse effects, and rates of resistance, compared with M2 inhibitors, but are more costly [4]. Prolonged therapy may be necessary to control

Protection against Respiratory Syncytial Virus by a Recombinant Newcastle Disease Virus Vector

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infants and the elderly, but no safe and effective RSV vaccine is yet available. For reasons that are not well understood, RSV is only weakly immunogenic, and reinfection occurs throughout life. This has complicated the search for an effective live attenuated viral vaccine, and past trials with inactivated virus preparations have led to enhanced immunopathology following natural infection. We have tested the hypothesis that weak stimulation of innate immunity by RSV correlates with ineffective adaptive responses by asking whether expression of the fusion glycoprotein of RSV by Newcastle disease virus (NDV) would stimulate a more robust immune response to RSV than primary RSV infection. NDV is a potent inducer of both alpha/beta interferon (IFN-alpha/beta) production and dendritic cell maturation, while RSV is not. When a recombinant NDV expressing the RSV fusion glycoprotein was administered to BALB/c mice, they were protected from RSV challenge, and this protection correlated with a robust anti-F CD8+ T-cell response. The effectiveness of this vaccine construct reflects the differential abilities of NDV and RSV to promote dendritic cell maturation and is retained even in the absence of a functional IFN-alpha/beta receptor.

Respiratory Syncytial Virus Infections: Old Challenges and New Opportunities

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia among children aged < 1 year. The majority of children hospitalized for RSV infection are younger than 6 months of age. RSV also causes repeated infections including severe lower respiratory tract disease, which may occur at any age, especially among the elderly or those with compromised cardiac, pulmonary, or immune systems. Using the mouse model of RSV infection, this article examines the immunopathogenesis during acute and chronic phases of the disease. This model allows for measurement of basal enhanced pause, which reflects airway obstruction in the acute phase, and the response to methacholine challenge to assess airway hyperresponsiveness during the chronic phase. This article also summarizes some recent studies focusing on novel perspectives and strategies for treatment and prevention of RSV infections. Compared with the lungs of sham-inoculated control mice, mice inoculated with live RSV showed a persistent progression of the severity of pneumonia as determined by an increasing histopathologic score. Mucus production of RSV-infected mice in the acute phase illustrated increased periodic acid-Schiff-positive hypertrophic cells in central and peripheral airways. RSV-infected mice with persistent airway hyperresponsiveness exhibited the presence of abnormal chronic inflammatory changes and mucus overproduction, which likely contributed to long term airway disease induced by RSV infection. These findings provide a histologic correlation to the abnormal pulmonary responses documented by plethysmography. Current trials have demonstrated positive results in continuing to target different alternatives for a new RSV vaccine.

New human coronavirus, HCoV-NL63, associated with severe lower respiratory tract disease in Australia.

A new human coronavirus, HCoV‐NL63, was associated recently with bronchiolitis. The current study aimed to examine retrospectively stored specimens for the presence of HCoV‐NL63 using nested RT‐PCR assays targeting the 1a and 1b genes. The study population was composed of patients with acute respiratory disease warranting presentation to Queensland hospitals. HCoV‐NL63 was detected in the nasopharyngeal aspirates (NPA) of 16 of 840 specimens representing 766 patients (2%). HCoV‐NL63 positive individuals were diagnosed most commonly with lower respiratory tract (LRT) disease (81%). The clinical diagnosis was commonly supported by an abnormal chest X‐ray (56%) together with respiratory distress (50%), wheeze (44%), and râles (25%) on first presentation with HCoV‐NL63 infection. All patients positive for HCoV‐NL63 required admission to hospital. Among 38% of HCoV‐NL63 positive specimens a second pathogen was detected. Sequencing of amplicon from gene 1b revealed more than 99% nucleotide homology with the viral type strains while sequencing amplicon from gene 1a permitted the grouping of viral strains. It was shown that HCoV‐NL63 is associated with severe LRT disease in an Australian hospital setting during the cooler months of the year. We propose that HCoV‐NL63 is a global and seasonal pathogen of both children and adults associated with severe LRT illness. J. Med. Virol. 75:455–462, 2005. © 2005 Wiley‐Liss, Inc.

Respiratory Syncytial Virus Prophylaxis

After completing this article, readers should be able to: 1. Identify risk factors for severe respiratory syncytial virus (RSV) lower respiratory tract disease in children. 2. Identify strategies for prevention of severe RSV disease among high-risk infants and children. 3. Know the recommendations for prophylaxis of RSV disease with palivizumab. RSV is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. Preterm infants and children who have bronchopulmonary dysplasia (BPD) (otherwise known as chronic lung disease of prematurity) or congenital heart disease are at increased risk for severe RSV disease that requires hospitalization (Table 1). | | Hospitalization | PICU Admission | Death | |:-----------:| --------------- | -------------- | ----- | | Prematurity | 8% | 3% | 1% | | BPD (CLD) | 13% | 36% | 5% | | CHD | 10% | 4% | 0.6% | * PICU=pediatric intensive care unit, BPD=bronchopulmonary dysplasia, CLD=chronic lung disease of prematurity, CHD=congenital heart disease. Table 1. Clinical Outcomes of Respiratory Syncytial Virus Infection Among Infants and Children Who Have High-risk Conditions Education of parents and other caregivers about methods to decrease the infant’s exposure to RSV and to factors that may contribute to the severity of the RSV infection must form the basis of any RSV prophylaxis program. Because RSV is transmitted by direct or close contact with contaminated secretions and the virus is known to persist for hours on environmental surfaces and for 30 minutes or longer on hands, emphasis on hand hygiene is crucial. High-risk infants and children should not be exposed to individuals who have respiratory infections, and if at all possible, they should not be in settings (eg, child care centers) where such exposures are likely. Exposure to tobacco smoke must be eliminated because it has been associated with more severe RSV disease. These measures have the added benefit of decreasing transmission of other respiratory pathogens. In addition, all high-risk children older than 6 months of age and their contacts must receive influenza vaccine. Passive immunoprophylaxis of high-risk children with RSV immune globulin intravenous (RSV-IGIV) and palivizumab has been …

Administration of the first dose of palivizumab immunoprophylaxis against respiratory syncytial virus in infants before hospital discharge: What is the evidence for its benefit?

Background: Palivizumab is 1 of 2 agents used to prevent severe lower respiratory tract disease due to respiratory syncytial virus (RSV) infection. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists recommend administering the first dose of RSV immunoprophylaxis to eligible infants before hospital discharge. Unfortunately, third-party payers frequently do not separately reimburse administration of this therapy to hospitalized infants. Objective: Because palivizumab is commonly used to provide RSV immunoprophylaxis, we systematically reviewed all published data on this drug to determine whether the evidence supports the recommendation of administering the first dose before hospital discharge. Methods: MEDLINE was searched for all articles published in English from January 1, 1996, to October 31, 2003, using the search terms palivizumab and Synagis, and the following data were extracted onto a standardized form: author(s), year of publication, study design, patient population, sample size, criteria used for administration of RSV prophylaxis, location of palivizumab prophylaxis (inpatient or outpatient), parental satisfaction with administration of prophylaxis, incidence of RSV infection, and hospitalization rates for RSV. All selected publications were reviewed to determine whether they reported differences in the incidence of RSV infection or hospitalization in patients who received palivizumab before discharge compared with those who received it after discharge. Only those publications that specifically documented administration of the first dose of palivizumab before hospital discharge were included in the final analysis. Results: Six of the 166 studies reviewed met the selection criteria. Although all 6 studies reported reduced RSV hospitalization rates with palivizumab prophylaxis, no study directly compared inpatient and outpatient administration with regard to parental satisfaction or rates of RSV infection or hospitalization. Furthermore, based on the data in these studies, it was not possible to detect any differences in parental satisfaction or rates of RSV infection or hospitalization between the 2 locations of administration. Conclusions: Based on our literature review, there is no evidence to support the recommendation that palivizumab be administered before hospital discharge in every infant who meets the criteria for RSV immunoprophylaxis. Eligible infants may be given the initial dose of RSV prophylaxis as outpatients, reducing the cost to institutions that currently provide palivizumab before hospital discharge.

Do environmental pollutants influence the onset of respiratory syncytial virus epidemics or disease severity?

The trigger for annual epidemics of respiratory syncytial virus (RSV) infections and the factors contributing to the disappearance of RSV infections in late winter remain obscure. Similarly, there is no adequate explanation for the higher morbidity and admission rates in industrialised as compared with rural areas. It has been suggested that a variety of environmental factors such as temperature, daylight and humidity may influence the onset and waning of the epidemics. However, the few studies assessing these variables fail to support such a link. In many tropical countries the annual epidemic occurs in the summer or autumn, arguing against temperature having a direct influence. A number of studies have suggested that indoor pollutants, including cigarette smoke, are associated with an increased likelihood of being admitted to hospital with severe lower respiratory tract disease. One study exploring the potential role of outdoor pollutants on the pattern of RSV related illness in infancy was unable to identify a clear link between a variety of pollutants and the timing of the epidemic. Nitric oxide levels were higher in winter than during the summer and much higher winter peaks of NO were observe in industrialised areas as compared with urban and rural areas. Whether this or other environmental pollutants contribute to the higher incidence of severe disease in industrialised areas is unclear. Further work is required to explore the possible influence of NO and other environmental pollutants on both the timing and severity of epidemics.

Mechanisms of illness during respiratory syncytial virus infection: the lungs, the virus and the immune response

Multiple factors, including cardiopulmonary anatomy, direct viral effects and the immune response can affect the severity of lower respiratory tract disease caused by respiratory syncytial virus (RSV). RSV is the most frequent viral respiratory cause of hospitalization in infants and young children in the world. In this review, we discuss the mechanisms of illness associated with severe RSV lower respiratory tract disease. A better understanding of the factors affecting the course of illness and their interplay should allow development of effective therapies in the future.