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Department of Emergency Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, 326 Cambridge Street, Suite 410, Boston, MA 02114, USA
A child who has severe bronchiolitis (eg, an episode requiring hospitalization) is at increased risk for recurrent wheezing of childhood and eventual asthma.
Estimates vary but approximately 80% to 90% of asthma begins before age 6 years, with 70% of children who have asthma having asthmalike symptoms before age 3 years.
this article focuses on the viruses that have been linked to bronchiolitis and how these viruses may predict or contribute to future wheezing and asthma. The article also discusses vitamin D as an emerging risk factor for respiratory infections and wheezing.
Definitions of lower respiratory tract infection
In the United States, lower respiratory tract infections (LRTI) represent almost 60% of infant infectious disease hospitalizations
In 2006, the American Academy of Pediatrics defined bronchiolitis as a child younger than 2 years of age who has “rhinitis, tachypnea, wheezing, cough, crackles, use of accessory muscles, and/or nasal flaring.”
This definition is broad, and when children younger than 2 years of age present to care with symptoms suggestive of an LRTI, they receive various diagnostic labels, such as bronchiolitis, wheezing, cough, reactive airways disease, asthma, or pneumonia.
Variability in the diagnostic labeling of nonbacterial lower respiratory tract infections: a multicenter study of children who presented to the Emergency Department.
As our understanding of LRTI evolves and we identify more clearly the risk factors for children developing recurrent wheezing in preschool years (and asthma as they grow older), we may need to adjust our LRTI definitions. Indeed, based on 259 wheezing hospitalized children aged 3 to 35 months participating in a systemic corticosteroid and wheezing study in Finland, Jartti and colleagues
recently suggested that the diagnosis of bronchiolitis should be restricted either to children younger than 24 months of age who have their first episode of wheezing or to children younger than 12 months of age.
Bronchiolitis epidemiology
With its broad definition, bronchiolitis is the leading cause of hospitalization for infants in the United States
and in a Tennessee Medicaid database there was a 41% increase in bronchiolitis visits at all levels of care (ie, inpatient, emergency department [ED], and outpatient clinic) from 1996 to 2003.
Occurrence of groups A and B of respiratory syncytial virus over 15 years: associated epidemiologic and clinical characteristics in hospitalized and ambulatory children.
Age-specific prevalence of complement-fixing antibodies to sixteen viral antigens: a computer analysis of 58,500 patients covering a period of eight years.
Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection.
Population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children.
Furthermore, there is conflicting literature about the relevance of bacterial coinfection in children who have viral bronchiolitis, especially those children requiring intensive care.
Although myriad infectious causes are associated with bronchiolitis, it remains unclear if the viral cause of a child's bronchiolitis illness is clinically relevant for either the short- or long-term care of the individual child. For short-term care, knowing the infectious cause identifies children who have influenza who may benefit from oseltamivir; it also helps cohort hospitalized children. Otherwise the current consensus is that knowledge of the viral etiology—among those viruses with easily accessible point-of-care testing (eg, RSV and influenza)—does not affect treatment of the individual patient.
As rapid microarray testing becomes less costly and more widely used, however, we are likely to learn much more about the short- and long-term implications of the diverse viruses linked to bronchiolitis. Indeed, these new data could markedly change current understanding and consensus.
Epidemiology of pathogens at different levels of care
Several studies have examined the epidemiology of different viruses associated with LRTI in hospitalized children,
Population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children.
Viral etiology of acute respiratory tract infections in children presenting to hospital: role of polymerase chain reaction and demonstration of multiple infections.
Two-year prospective study of single infections and co-infections by respiratory syncytial virus and viruses identified recently in infants with acute respiratory disease.
but there are fewer studies investigating the epidemiology of viruses linked to bronchiolitis in children presenting to the ED or in outpatient clinics.
In this section, we present one representative study from the three levels of care (inpatient, ED, outpatient clinic) from different regions of the world.
Comparison of human metapneumovirus, respiratory syncytial virus and influenza A virus lower respiratory tract infections in hospitalized young children.
compared the clinical features of RSV, hMPV, influenza A, parainfluenza, and adenovirus in 516 Israeli children younger than 5 years of age who were hospitalized with LRTI over a 1-year period. The investigators detected a virus in 57% of the children tested in this single-center study. Children hospitalized with RSV were younger than those hospitalized with hMPV, but the severity of the respiratory illness caused by RSV and hMPV was similar and higher than that of influenza A.
In a multicenter ED-based study of 277 United States children who had physician-diagnosed bronchiolitis,
we examined the frequencies of RSV, RV, hMPV, and influenza A/B during one bronchiolitis winter season. We detected a virus in 84% of the samples; RSV was the most common (64%) and RV the second most common (16%).
In a community-based birth cohort sample of Australian children at high risk for atopy (ie, one parent with history of asthma, hay fever, or eczema), Kusel and colleagues
examined the frequency of nine different pathogens in these children during their first year. When the children had acute respiratory infections (either upper or lower) the children had nasopharyngeal samples taken. For upper and lower respiratory tract infections in the first year of life, RV was the most frequent cause (48%) and RSV the second most common (11%).
Most data indicate that RSV and RV are the two most common viruses associated with LRTI in early childhood. RSV is detected more frequently from children in the hospital or ED and RV is detected more frequently from children in the outpatient clinic setting.
Coinfections
When considering the cohorting of inpatients, it is important to realize that the aforementioned infectious agents may cause bronchiolitis in isolation or in combination with other infectious agents. Although older studies report coinfections (eg, detection of two or more viruses from the same biologic sample) in 4.4% to 23.7% of children younger than 3 years of age who had respiratory illnesses,
Viral etiology of acute respiratory tract infections in children presenting to hospital: role of polymerase chain reaction and demonstration of multiple infections.
There is a lack of clear data, however, about the clinical characteristics of children who have coinfections. Some studies have found no increase in the severity of disease from coinfections as measured by hospital length of stay,
Detection of multiple viral agents in nasopharyngeal specimens yielding respiratory syncytial virus (RSV). An assessment of diagnostic strategy and clinical significance.
Other data, however, demonstrate that children infected with multiple pathogens have more severe bronchiolitis as measured by higher hospitalization rates
It is likely that the clinical course of coinfections will differ; some combinations of viruses are more or less deleterious than others. One combination that is believed to increase the severity of illness is RSV and hMPV coinfection.
Comparison of human metapneumovirus, respiratory syncytial virus and influenza A virus lower respiratory tract infections in hospitalized young children.
Differential production of inflammatory cytokines in primary infection with human metapneumovirus and with other common respiratory viruses of infancy.
measured cytokine levels in Buenos Aires infants presenting with upper or lower respiratory tract illness and discovered that the 22 infants who had hMPV were poor inducers of inflammatory cytokines compared with the 46 infants who had RSV. The authors concluded that the viruses elicit disease by different mechanisms and therefore hMPV may augment RSV disease severity. To date, however, studies not only have not had the sample size to answer definitively if coinfection with hMPV and RSV increases bronchiolitis severity but also have been inadequate to determine the clinical implications of the many other pathogen combinations.
In a cooperative agreement with the National Institutes of Health, our research group, the Emergency Medicine Network (EMNet; www.emnet-usa.org), is currently conducting a prospective, multicenter study that will examine the clinical usefulness of testing for the causes of bronchiolitis in 2250 hospitalized children.
Based on the first year of our study, with a sample of 520 hospitalized children, we were able to detect a virus in 93% of the nasopharyngeal samples and found a 27% coinfection rate.
In the first year we have found that coinfection was significantly less likely for hospitalized children who had RSV (33%; 95% CI, 28%–38%) as compared with children who had RV (65%; 95%CI, 56%–73%).
noted a relationship between bronchiolitis and risk for asthma in 100 children in the United States. Over the past 50 years, several research groups have followed small cohorts of children hospitalized with bronchiolitis for the development of recurrent wheezing. For example, Carlsen and colleagues
found that 60% of 51 Norwegian infants hospitalized with bronchiolitis developed recurrent wheezing of childhood (≥3 episodes of bronchial obstruction) by age 2 years compared with 4% of 24 control children. In a retrospective study from Qatar, 31 of 70 (44%) children younger than 12 months hospitalized with RSV bronchiolitis developed recurrent wheezing (≥3 episodes of physician-diagnosed expiratory rhonchi) 2 years after admission, compared with 9 of the 70 controls (12%).
followed a Swedish cohort of 47 infants hospitalized with RSV bronchiolitis and 93 controls up to age 13 years. At a mean age of 3 years, recurrent wheezing was diagnosed in 11 of 47 children (23%) in the RSV group versus 1 of 93 children (1%) in the control group.
Many of the children who have bronchiolitis who develop recurrent wheezing of childhood also develop childhood asthma. Unfortunately, the respiratory morbidity associated with childhood respiratory infections may be longstanding and influence the development and persistence of adult respiratory conditions.
In the Tucson Children's Respiratory Study prospective birth cohort, having an RSV LRTI before age 3 years was an independent risk factor for wheezing up to age 11 years.
Unlike the Swedish study, nearly all of the Tucson children who had RSV LRTI were not hospitalized and the respiratory outcomes of these two populations (ie, inpatient and outpatient) may be quite different. Indeed, based on a Tennessee Medicaid database there is a dose–response relationship between bronchiolitis severity (as defined by inpatient, ED, and outpatient clinic) and the increased odds of early childhood asthma and asthma-specific morbidity.
Despite the generally strong associations, no one has been able to identify reliably the subset of children hospitalized with bronchiolitis at increased risk for developing recurrent wheezing or if most of this large group of children will ultimately develop asthma.
Occurrence of groups A and B of respiratory syncytial virus over 15 years: associated epidemiologic and clinical characteristics in hospitalized and ambulatory children.
Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection.
One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma.
Relationship of early childhood viral exposures to respiratory symptoms, onset of possible asthma and atopy in high risk children: the Canadian asthma primary prevention study.
The most intriguing virus in studying recurrent wheezing and asthma is RV. Several recent single-center studies have linked RV infection to asthma exacerbations in children and adults,
For example, in the Childhood Origins of ASThma (COAST) birth cohort study, which involves 289 children at high risk for developing asthma, the most significant independent predictor of recurrent wheezing at age 3 years was a moderate to severe RV illness with wheezing during infancy.
Furthermore, a Tennessee study showed that bronchiolitis during RV-predominant months was associated with a 25% increased risk for childhood asthma over bronchiolitis during RSV-predominant months.
Our prospective multicenter data of children younger than 2 years of age presenting to the ED with bronchiolitis found that children who have RV bronchiolitis have similar demographics, medical histories, and ED treatments as older children who have an asthma exacerbation.
Of particular interest, and with potentially large clinical implications, are the results from one small trial of prednisolone for 3 days versus placebo for children hospitalized with their first or second episode of wheezing due to RV. In this trial, Jartti, Lehtinen, and colleagues
found that children who had RV who received prednisolone had reduced relapses during a 2-month period after the hospitalization and reduced recurrent wheezing at 1 year.
Indeed, children who develop wheezing due to RV seem to have a high likelihood of recurrent wheezing of childhood and eventually later developing asthma.
Further investigation is warranted to clarify the potential value of targeting children who have RV bronchiolitis for the primary prevention of asthma.
Although this review focuses on viruses, we want to remind readers that the specific bacteria colonizing an infant's hypopharynx also may play an important role in the risk for recurrent wheezing and childhood asthma.
In other words, a child's long-term outcome probably represents an interaction between the infecting virus, bacterial milieu (colonization or super-infection), and undoubtedly other factors (see Fig. 1).
Fig. 1Respiratory outcomes after severe bronchiolitis. After a child develops severe bronchiolitis (eg, an episode requiring hospitalization), several factors may influence the respiratory outcome. The actual percentages of children who develop each outcome remain unclear.
Vitamin D3 (cholecalciferol) comes from two sources: exposure to sunlight and dietary intake. The major source of vitamin D for most humans is from exposure of skin to the B fraction of ultraviolet light (UVB). In northern latitudes between November and March there are insufficient UVB rays to produce vitamin D, however.
Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin.
Influence of sun exposures during childhood and during adulthood on melanoma risk. EPIMEL and EORTC Melanoma Cooperative Group. European Organisation for Research and Treatment of Cancer.
Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin.
The evidence for the possible link between vitamin D and respiratory disease comes from multiple studies. Two family-based studies demonstrated that gene polymorphisms on the vitamin D receptor were associated with childhood and adult asthma
discovered in a prospective birth cohort in Massachusetts that lower maternal intake of vitamin D during pregnancy is associated with increased risk for recurrent wheezing in the mothers' young children. These findings were replicated in 5-year-old Scottish children.
recently confirmed these novel findings in a separate birth cohort of 922 children from New Zealand (41°–43° S) where low 25-hydroxyvitamin D (25[OH]D) levels in cord blood were associated with increased risk for respiratory infections and childhood wheezing. Moreover, Litonjua and colleagues
recently examined the association between serum 25(OH)D levels and risk for an asthma-related ED visit or hospitalization. Among 1022 children who had asthma in the Childhood Asthma Management Program (CAMP),
those who had low baseline 25(OH)D levels (<75 nmol/L) were more likely to have a severe asthma exacerbation over a 4-month period (OR 1.50; 95%CI, 1.13–1.98). Finally, Brehm and colleagues
recently reported that among 616 children in Costa Rica who had asthma, higher 25(OH)D levels were significantly associated with reduced odds of any hospitalization and reduced use of anti-inflammatory medications.
The pathophysiology of these associations may relate to vitamin D's role in the activity of the innate immune system.
reported in Science a link between Toll-like receptors (TLR), low vitamin D, and the reduced ability to support cathelicidin messenger RNA induction. Wang and colleagues
also have demonstrated that vitamin D is a direct inducer of the cathelicidin gene. Most recently, Janssen and colleagues determined that single nucleotide polymorphisms in four of the innate immunity genes, including the vitamin D receptor, helped predict susceptibility to RSV bronchiolitis.
Taken together, the clinical and mechanistic data support a role for vitamin D as an important factor in the relation between respiratory viruses in bronchiolitis and their link to recurrent wheezing.
Summary
Bronchiolitis is the leading cause of hospitalization for children younger than 1 year of age and these hospitalized children have an increased risk for developing childhood asthma. It remains unclear, however, which children who have severe bronchiolitis (eg, an episode requiring hospitalization) will develop recurrent wheezing or asthma. Two intriguing factors are bronchiolitis due to RV and low levels of vitamin D. Developing a clearer understanding of the complex pathway from bronchiolitis to asthma would help identify the subset of children who have severe bronchiolitis who are at high risk for developing asthma. This understanding would not only help clinicians target follow-up care but also advance bronchiolitis and asthma prevention research by better routing high-risk children into future randomized trials.
References
Glezen W.P.
Loda F.A.
Clyde Jr., W.A.
et al.
Epidemiologic patterns of acute lower respiratory disease of children in a pediatric group practice.
Variability in the diagnostic labeling of nonbacterial lower respiratory tract infections: a multicenter study of children who presented to the Emergency Department.
Occurrence of groups A and B of respiratory syncytial virus over 15 years: associated epidemiologic and clinical characteristics in hospitalized and ambulatory children.
Age-specific prevalence of complement-fixing antibodies to sixteen viral antigens: a computer analysis of 58,500 patients covering a period of eight years.
Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection.
Population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children.
Viral etiology of acute respiratory tract infections in children presenting to hospital: role of polymerase chain reaction and demonstration of multiple infections.
Two-year prospective study of single infections and co-infections by respiratory syncytial virus and viruses identified recently in infants with acute respiratory disease.
Comparison of human metapneumovirus, respiratory syncytial virus and influenza A virus lower respiratory tract infections in hospitalized young children.
Detection of multiple viral agents in nasopharyngeal specimens yielding respiratory syncytial virus (RSV). An assessment of diagnostic strategy and clinical significance.
Differential production of inflammatory cytokines in primary infection with human metapneumovirus and with other common respiratory viruses of infancy.
One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma.
Relationship of early childhood viral exposures to respiratory symptoms, onset of possible asthma and atopy in high risk children: the Canadian asthma primary prevention study.
Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin.
Influence of sun exposures during childhood and during adulthood on melanoma risk. EPIMEL and EORTC Melanoma Cooperative Group. European Organisation for Research and Treatment of Cancer.
This work was supported by grants K23 AI-77801 and U01 AI-67693 from the National Institutes of Health (Bethesda, MD) and the Massachusetts General Hospital Center for D-receptor Activation Research (Boston, MA).
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