Current Respiratory Medicine Reviews - Volume 7, Issue 3, 2011

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Severity of respiratory syncytial virus (RSV) infection is subject to individual variation, and, accordingly, genetic determinants play a role in the risk of developing RSV lower respiratory tract infection (LRTI) in previously healthy infants. A twin study showed that 22% of the individual susceptibility to RSV LRTI is attributable to genetic factors. About half of the infants with RSV LRTI will develop post-bronchiolitis wheeze (PBW). It is unknown whether RSV LRTI and PBW have similar etiology. This systematic review aims to provide insight into the genetic factors influencing susceptibility to RSV LRTI and PBW. Published genetic associations of RSV LRTI with both single nucleotide polymorphisms (SNPs) and haplotypes are shown. Particularly SNPs in innate immunity genes are associated with the pathogenesis of RSV LRTI. However, no genetic variants associated with RSV LRTI have been exactly replicated in other cohorts. A limited number of studies have reported associations between SNPs and PBW, especially in chemokine and Th2 related genes. In conclusion, although RSV LRTI and PBW show similarities in clinical presentation, different genetic factors are important for the development of these diseases in young children.

Rhinovirus is commonly associated with bronchiolitis - only second to RSV during the first year life. The prevalence of HRV-bronchiolitis may be very high in predisposed infants. HRV diagnosis is almost exclusively based on PCR, which detects respiratory infections with or without symptoms. Two immunologic factors, interferon responses and atopy, have been associated with susceptibility to HRV-bronchiolitis in multiple studies. The current data supports the hypothesis that susceptibility to HRV-bronchiolitis is likely to be an early manifestation of biased immune responses, which are linked to both decreased viral defence and atopic airway inflammation. Prospective studies have consistently shown that early wheezing associated with HRV infection is closely associated with recurrent wheezing and the development of asthma in children. Collectively, these studies suggest that HRV infection in wheezing children could serve as a clinically useful marker for early identification of asthma prone children. The findings to date provide the rationale for future studies to incorporate rhinovirus illnesses into asthma risk indices.

Several hypotheses have been proposed regarding the association between RSV infection and asthma but the true nature of their relationship has remained ambiguous. Particularly, it is not clear whether the RSV infection plays a direct causative role in asthma or simply identifies infants at risk for subsequent wheezing resulting from an asthmatic predisposition or pre-existing abnormal lung function. An alternative explanation suggests that severe RSV infection and asthma arise from shared genetic and/or environmental determinants. We review the literature on the relationship between RSV infection and asthma in twins with special emphasis on the population-based twin studies from Denmark. The Danish Twin Registry is one of the oldest and most well-structured twin registries in the world and we show that combining elaborate registry information with paraclinical and clinical data can be used to elucidate how environmental factors interact with the genetics in the development of severe RSV infection and asthma. We conclude that severe infant RSV infection does not seem to cause asthma but rather is an indicator of the genetic predisposition to asthma.

Very premature birth frequently results in chronic respiratory morbidity, particularly if complicated by the development of chronic lung disease, bronchopulmonary dysplasia (BPD). Affected infants may remain oxygen dependent for many months and require hospital readmission in the first two years after birth. Troublesome, recurrent respiratory symptoms requiring treatment are common. The worst affected may remain symptomatic with evidence of airways obstruction even as adults. Infant who are born prematurely and develop BPD are at increased risk of severe respiratory syncytial virus (RSV) infection. RSV infection in prematurely born infants is associated with excess chronic respiratory morbidity, as evidenced by greater frequency of respiratory symptoms, lung function abnormalities and healthcare utilisation. There is some evidence to suggest that prematurely born infants, as those born at term, may be predisposed to symptomatic RSV lower respiratory tract infections by pre-morbid abnormal lung function. Longitudinal studies assessing lung function before and after RSV infection are required to determine whether RSV infection does alter the course of chronic lung disease in prematurely born infants.

Respiratory syncytial virus (RSV) disease is a serious health concern in young children, immunocompromised adults and the elderly. No vaccine or specific treatment is currently available and to develop these, a more thorough understanding of the immune mechanisms of RSV-induced inflammation is required. Studies in mouse models have provided valuable insights and this review aims to provide a concise summary of recent findings on patho-mechanisms at the interface of innate and adaptive immunity. We discuss the role of epithelial cells, macrophages and dendritic cells as well as toll like receptor signalling in RSV-induced airway inflammation and compare data from mouse models with observations from studies in human cells and patients, where available.

Many epidemiologic studies have demonstrated a clear association between viral bronchiolitis early in life and subsequent development of persistent wheezing. Despite that a number of studies have been conducted to reduce post-bronchiolitis wheeze, we do not have consistent evidence of an effective strategy. Two different therapeutic approaches have been evaluated: a) anti-inflammatory and/or immunomodulatory agents; and b) specific anti-viral agents. Corticosteroids have been evaluated by different routes and doses in children with RSV bronchiolitis with disappointing results. Recent data, however, suggest a potential benefit of corticosteroids in reducing the long-term wheezing associated with rhinovirus bronchiolitis. Studies evaluating the anti leukotriene receptor antagonist -montelukast— have showed inconsistent results. Finally, studies in premature infants using agents that specifically target RSV, more specifically anti-RSV antibodies (palivizumab), have provided encouraging results indicating the need to design larger studies in broader patient populations.

Respiratory syncytial virus (RSV) is the most common viral cause of seasonal acute respiratory tract illness in very young children worldwide. In addition, life-threatening RSV disease accounts for the most frequent cause of nonelective pediatric intensive care unit admission for mechanical ventilatory support in infants during the winter season. This review article discusses factors associated with a life-threatening course of RSV disease as well as available therapeutic options and mortality rates. Pre-existing medical conditions, direct virus-induced cytopathology and host immunopathology, as well as co-factors such as bacterial and/or viral co-infection, apnea and the syndrome of inappropriate antidiuretic hormone are important features associated with turning a trivial community acquired upper respiratory tract illness into life-threatening disease. Although numerous medical therapies for life-threatening RSV have been suggested, the mainstay of therapy is still primarily supportive. Mortality rates of previously healthy children requiring mechanical ventilation for RSV-associated disease are almost zero, whereas mortality rates in infants with a pre-existent medical condition are up to 10%.

Currently, two birth cohort studies with a focus on on early-life wheezing available have continued until adulthood. At 22 years of age, about a third of early life wheezers had asthma, and another third was in remission though having wheezed at teen age. There are four prospective post-bronchiolitis follow-up studies continued from infancy until teenage or longer, two from Finland and two from Sweden. The prevalence of doctor-diagnosed asthma at 13-15 years of age varied from 13% to 40% in these four studies. The prevalence at 17-20 years of age was surprisingly similar, 41-43%, in those two studies which continued until that age. The Finnish cohort was examined again at 26-29 years of age, and doctor-diagnosed asthma was present in 41% vs 10% in population controls. Parental asthma, sensitization to inhaled allergens, eosinophil activity, passive smoking in infancy and recurrent wheezing at <24 months of age, as well as non- RSV, especially rhinovirus etiology of early-life wheezing, were the significant infantile risk factors for asthma at 13-20 years of age. The post-bronchiolitis lung function studies have offered preliminary evidence that RSV bronchiolitis may be associated with later non-reversible obstructive or even restrictive pulmonary disorder, whereas rhinovirus bronchiolitis was associated with with reversible, obstructive pulmonary disorder.

Background: The cost-effectiveness of palivizumab is subject of vigorous debate. It is recognized that a policy of using palivizumab for all children who meet the licensed indication is not cost-effective, but most clinicians feel that its use is justified in certain subgroups. Objective: To systematically review the literature on the cost-effectiveness of palivizumab prophylaxis in the following subgroups: 1) preterm infants born before 32 weeks gestational age (WGA), 2) preterm infants born between 32 and 35 WGA, 3) children with chronic lung disease, and 4) children with congenital heart disease. Methods: We searched Pubmed, EMBASE and the latest versions of the DARE, NHS EED and HTA databases from inception to February 2010 using the terms cost, cost-effectiveness, respiratory syncytial virus and palivizumab. Results: Seventeen studies evaluating the cost-effectiveness of palivizumab were included. The cost-effectiveness of palivizumab for the subgroups of children born before 32 WGA, children born between 32 and 35 WGA, children with chronic lung disease (CLD), and children with congenital heart disease was studied in 8, 9, 8, and 6 studies, respectively. The incremental cost-effectiveness ratios varied considerably both within and between subgroups. Sensitivity analyses showed that cost-effectiveness was mainly driven by the mortality rate due to RSV infection. Differences in hospitalization rates, industry sponsoring and study year were also associated with differences in cost-effectiveness, but these differences could be attributed to differences in mortality rates. Conclusion: The cost-effectiveness of prophylactic treatment of RSV infection with palivizumab in subgroups varies considerably, and is certainly not always below the threshold. The cost-effectiveness is mainly sensitive to mortality rates of RSV infection. This systematic review indicates that future research should focus on the major uncertainties in costeffectiveness, particularly RSV-related mortality rate.

It has been reported that continuous positive airway pressure therapy introduces negative nasal side-effects including sneezing, itching, nasal dryness, nasal congestion and/or a runny nose. As these symptoms are suggestive of nasal dysfunction, heated humidification is often used to fully saturate and heat the inhaled air to core body temperature. It is expected that this relieves the nasal mucosa from having to supply, or recover, heat and moisture from inspired and expired air. This review summarizes the current in vitro and in vivo knowledge relevant to nasal air-conditioning, and identifies further investigations necessary to improve our understanding the changes that occur during nasal continuous positive airway pressure therapy. Investigations into nasal airway fluid transportation, airflow regulation and heat and fluid supply may lead to a therapy temperature/pressure/humidification algorithm that optimizes these parameters for a prescribed therapy pressure. Optimization could lead to a reduction in titration pressure and improved treatment compliance.

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