Viruses associated with ill health in wild chimpanzees.

Viral infection is a major cause of ill health in wild chimpanzees (Pan troglodytes), but most evidence to date has come from conspicuous disease outbreaks with high morbidity and mortality. To examine the relationship between viral infection and ill health during periods not associated with disease outbreaks, we conducted a longitudinal study of wild eastern chimpanzees (P. t. schweinfurthii) in the Kanyawara and Ngogo communities of Kibale National Park, Uganda. We collected standardized, observational health data for 4 years and then used metagenomics to characterize gastrointestinal viromes (i.e., all viruses recovered from fecal samples) in individual chimpanzees before and during episodes of clinical disease. We restricted our analyses to viruses thought to infect mammals or primarily associated with mammals, discarding viruses associated with nonmammalian hosts. We found 18 viruses (nine of which were previously identified in this population) from at least five viral families. Viral richness (number of viruses per sample) did not vary by health status. By contrast, total viral load (normalized proportion of sequences mapping to viruses) was significantly higher in ill individuals compared with healthy individuals. Furthermore, when ill, Kanyawara chimpanzees exhibited higher viral loads than Ngogo chimpanzees, and males, but not females, exhibited higher infection rates with certain viruses and higher total viral loads as they aged. Post-hoc analyses, including the use of a machine-learning classification method, indicated that one virus, salivirus (Picornaviridae), was the main contributor to health-related and community-level variation in viral loads. Another virus, chimpanzee stool-associated virus (chisavirus; unclassified Picornavirales), was associated with ill health at Ngogo but not at Kanyawara. Chisavirus, chimpanzee adenovirus (Adenoviridae), and bufavirus (Parvoviridae) were also associated with increased age in males. Associations with sex and age are consistent with the hypothesis that nonlethal viral infections cumulatively reflect or contribute to senescence in long-lived species such as chimpanzees.

Simultaneous outbreaks of respiratory disease in wild chimpanzees caused by distinct viruses of human origin.

Respiratory viruses of human origin infect wild apes across Africa, sometimes lethally. Here we report simultaneous outbreaks of two distinct human respiratory viruses, human metapneumovirus (MPV; Pneumoviridae: Metapneumovirus) and human respirovirus 3 (HRV3; Paramyxoviridae; Respirovirus, formerly known as parainfluenza virus 3), in two chimpanzee (Pan troglodytes schweinfurthii) communities in the same forest in Uganda in December 2016 and January 2017. The viruses were absent before the outbreaks, but each was present in ill chimpanzees from one community during the outbreak period. Clinical signs and gross pathologic changes in affected chimpanzees closely mirrored symptoms and pathology commonly observed in humans for each virus. Epidemiologic modelling showed that MPV and HRV3 were similarly transmissible (R0 of 1.27 and 1.48, respectively), but MPV caused 12.2% mortality mainly in infants and older chimpanzees, whereas HRV3 caused no direct mortality. These results are consistent with the higher virulence of MPV than HRV3 in humans, although both MPV and HRV3 cause a significant global disease burden. Both viruses clustered phylogenetically within groups of known human variants, with MPV closely related to a lethal 2009 variant from mountain gorillas (Gorilla beringei beringei), suggesting two independent and simultaneous reverse zoonotic origins, either directly from humans or via intermediary hosts. These findings expand our knowledge of human origin viruses threatening wild chimpanzees and suggest that such viruses might be differentiated by their comparative epidemiological dynamics and pathogenicity in wild apes. Our results also caution against assuming common causation in coincident outbreaks.

Lethal Respiratory Disease Associated with Human Rhinovirus C in Wild Chimpanzees, Uganda, 2013.

We describe a lethal respiratory outbreak among wild chimpanzees in Uganda in 2013 for which molecular and epidemiologic analyses implicate human rhinovirus C as the cause. Postmortem samples from an infant chimpanzee yielded near-complete genome sequences throughout the respiratory tract; other pathogens were absent. Epidemiologic modeling estimated the basic reproductive number (R0) for the epidemic as 1.83, consistent with the common cold in humans. Genotyping of 41 chimpanzees and examination of 24 published chimpanzee genomes from subspecies across Africa showed universal homozygosity for the cadherin-related family member 3 CDHR3-Y529 allele, which increases risk for rhinovirus C infection and asthma in human children. These results indicate that chimpanzees exhibit a species-wide genetic susceptibility to rhinovirus C and that this virus, heretofore considered a uniquely human pathogen, can cross primate species barriers and threatens wild apes. We advocate engineering interventions and prevention strategies for rhinovirus infections for both humans and wild apes.

Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence.

BACKGROUND: Early life rhinovirus (RV) wheezing illnesses and aeroallergen sensitization increase the risk of asthma at school age. Whether these remain risk factors for the persistence of asthma out to adolescence is not established. OBJECTIVE: We sought to define the relationships among specific viral illnesses and the type and timing of aeroallergen sensitization with the persistence of asthma into adolescence. METHODS: A total of 217 children were followed prospectively from birth to age 13 years. The etiology and timing of viral wheezing illnesses during the first 3 years of life were assessed along with patterns of allergen sensitization. The associations between viral wheezing illnesses, presence and pattern of aeroallergen sensitization, and asthma diagnosis at age 13 years were evaluated. RESULTS: When adjusted for all viral etiologies, wheezing with RV (odds ratio = 3.3; 95% CI, 1.5-7.1), but not respiratory syncytial virus (odds ratio = 1.0; 95% CI, 0.4-2.3), was associated with asthma at age 13 years. Age of aeroallergen sensitization also influenced asthma risk; 65% of children sensitized by age 1 year had asthma at age 13 years, compared with 40% of children not sensitized at age 1 year but sensitized by age 5 years, and 17% of children not sensitized at age 5 years. Early life aeroallergen sensitization and RV wheezing had additive effects on asthma risk at adolescence. CONCLUSIONS: In a high-risk birth cohort, the persistence of asthma at age 13 years was most strongly associated with outpatient wheezing illnesses with RV and aeroallergen sensitization in early life.

Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations.

BACKGROUND: Detection of either viral or bacterial pathogens is associated with wheezing in children; however, the influence of both bacteria and viruses on illness symptoms has not been described. OBJECTIVE: We evaluated bacterial detection during the peak rhinovirus season in children with and without asthma to determine whether an association exists between bacterial infection and the severity of rhinovirus-induced illnesses. METHODS: Three hundred eight children (166 with asthma and 142 without asthma) aged 4 to 12 years provided 5 consecutive weekly nasal samples during September and scored cold and asthma symptoms daily. Viral diagnostics and quantitative PCR for Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis were performed on all nasal samples. RESULTS: Detection rates were 53%, 17%, and 11% for H influenzae, S pneumoniae, and M catarrhalis, respectively, with detection of rhinovirus increasing the risk of detecting bacteria within the same sample (odds ratio [OR], 2.0; 95% CI, 1.4-2.7; P < .0001) or the following week (OR, 1.6; 95% CI, 1.1-2.4; P = .02). In the absence of rhinovirus, S pneumoniae was associated with increased cold symptoms (mean, 2.7 [95% CI, 2.0-3.5] vs 1.8 [95% CI, 1.5-2.2]; P = .006) and moderate asthma exacerbations (18% [95% CI, 12% to 27%] vs 9.2% [95% CI, 6.7% to 12%]; P = .006). In the presence of rhinovirus, S pneumoniae was associated with increased moderate asthma exacerbations (22% [95% CI, 16% to 29%] vs 15% [95% CI, 11% to 20%]; P = .01). Furthermore, M catarrhalis detected alongside rhinovirus increased the likelihood of experiencing cold symptoms, asthma symptoms, or both compared with isolated detection of rhinovirus (OR, 2.0 [95% CI, 1.0-4.1]; P = .04). Regardless of rhinovirus status, H influenzae was not associated with respiratory symptoms. CONCLUSION: Rhinovirus infection enhances detection of specific bacterial pathogens in children with and without asthma. Furthermore, these findings suggest that M catarrhalis and S pneumoniae contribute to the severity of respiratory tract illnesses, including asthma exacerbations.

Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life.

RATIONALE: Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood. OBJECTIVE: To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing. METHODS: A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model. MEASUREMENTS AND MAIN RESULTS: Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50-1.1). CONCLUSIONS: Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.

Decreased lung function after preschool wheezing rhinovirus illnesses in children at risk to develop asthma.

BACKGROUND: Preschool rhinovirus (RV) wheezing illnesses predict an increased risk of childhood asthma; however, it is not clear how specific viral illnesses in early life relate to lung function later on in childhood. OBJECTIVE: To determine the relationship of virus-specific wheezing illnesses and lung function in a longitudinal cohort of children at risk for asthma. METHODS: Two hundred thirty-eight children were followed prospectively from birth to 8 years of age. Early life viral wheezing respiratory illnesses were assessed by using standard techniques, and lung function was assessed annually by using spirometry and impulse oscillometry. The relationships of these virus-specific wheezing illnesses and lung function were assessed by using mixed-effect linear regression. RESULTS: Children with RV wheezing illness demonstrated significantly decreased spirometry values, FEV(1) (P = .001), FEV(0.5) (P < .001), FEF(25-75) (P < .001), and also had abnormal impulse oscillometry measures--more negative reactance at 5 Hz (P < .001)--compared with those who did not wheeze with RV. Children who wheezed with respiratory syncytial virus or other viral illnesses did not have any significant differences in spirometric or impulse oscillometry indices when compared with children who did not. Children diagnosed with asthma at ages 6 or 8 years had significantly decreased FEF(25-75) (P = .05) compared with children without asthma. CONCLUSION: Among outpatient viral wheezing illnesses in early childhood, those caused by RV infections are the most significant predictors of decreased lung function up to age 8 years in a high-risk birth cohort. Whether low lung function is a cause and/or effect of RV wheezing illnesses is yet to be determined.

Lower airway rhinovirus burden and the seasonal risk of asthma exacerbation.

RATIONALE: Most asthma exacerbations are initiated by viral upper respiratory illnesses. It is unclear whether human rhinovirus (HRV)­induced exacerbations are associated with greater viral replication and neutrophilic inflammation compared with HRV colds. OBJECTIVES: To evaluate viral strain and load in a prospective asthma cohort during a natural cold. METHODS: Adults were enrolled at the first sign of a cold, with daily monitoring of symptoms, medication use, and peak expiratory flow rate until resolution. Serial nasal lavage and induced sputum samples were assessed for viral copy number and inflammatory cell counts. MEASUREMENTS AND MAIN RESULTS: A total of 52 persons with asthma and 14 control subjects without atopy or asthma were studied for over 10 weeks per subject on average; 25 participants developed an asthma exacerbation. Detection of HRVs in the preceding 5 days was the most common attributable exposure related to exacerbation. Compared with other infections, those by a minor group A HRV were 4.4- fold more likely to cause exacerbation (P = 0.038). Overall, sputum neutrophils and the burden of rhinovirus in the lower airway were similar in control subjects without atopy and the asthma group. However, among HRV-infected participants with asthma, exacerbations were associated with greater sputum neutrophil counts (P = 0.005). CONCLUSIONS: HRV infection is a frequent cause of exacerbations in adults with asthma and a cold, and there may be group-specific differences in severity of these events. The absence of large differences in viral burden among groups suggests differential lower airway sensitization to the effects of neutrophilic inflammation in the patients having exacerbations.

Early childhood weight status in relation to asthma development in high-risk children.

BACKGROUND: Obesity has been proposed to be a risk factor for the development of childhood asthma. OBJECTIVE: We sought to examine weight status from birth to age 5 years in relation to the occurrence of asthma at ages 6 and 8 years. METHODS: Two hundred eighty-five full-term high-risk newborns with at least 1 asthmatic/atopic parent enrolled in the Childhood Origin of Asthma project were studied from birth to age 8 years. Overweight was defined by weight-for-length percentiles of greater than the 85th percentile before the age of 2 years and a body mass index percentile of greater than the 85th percentile at ages 2 to 5 years. RESULTS: No significant concurrent association was found between overweight status and wheezing/asthma occurrence at each year of age. In contrast, longitudinal analyses revealed complex relationships between being overweight and asthma. Being overweight at age 1 year was associated with a decreased risk of asthma at age 6 (odds ratio [OR], 0.32; P = .02) and 8 (OR, 0.35; P = .04) years, as well as better lung function. However, being overweight beyond infancy was not associated with asthma occurrence. In fact, only children who were overweight at age 5 years but not at age 1 year had an increased risk of asthma at age 6 years (OR, 5.78; P = .05). CONCLUSION: In children genetically at high risk of asthma, being overweight at age 1 year was associated with a decreased risk of asthma and better lung function at ages 6 and 8 years. However, being overweight beyond infancy did not have any protective effect and even could confer a higher risk for asthma.

The relationships among immunoglobulin levels, allergic sensitization, and viral respiratory illnesses in early childhood.

IgE plays an essential role in type I allergy, however, there is less information about the relationship between other immunoglobulins (IgA and IgG) and atopic phenotypes in early childhood. We hypothesized that levels of circulating IgA in early childhood would be inversely related to the number of respiratory infections and the risk of becoming sensitized to allergens. Immunoglobulin levels were analyzed (ELISA) in plasma samples (IgG, IgA), and in nasal secretions (IgA) from children participating in a high-risk birth cohort study. Samples were available from 264 children at age 2 yr and 257 children at age 4 yr, and results were compared to rates of respiratory illnesses, allergic sensitization, atopic dermatitis (AD), and asthma. Children who were sensitized to allergens had higher rather than lower levels of circulating IgA. A subgroup analysis showed that IgA levels were increased in relationship to foods sensitization (58 vs. 50 mg/dl, p = 0.003) but not aeroallergen sensitization (52 vs. 53 mg/dl, p = 0.11). IgA levels in the plasma correlated with levels of IgE levels (r(s) =0.19, p = 0.003). Levels of IgE, but not IgG or IgA, were positively correlated with rates of respiratory illnesses, AD, and the risk of developing asthma. Finally, there were no significant relationships between IgA in nasal secretions and infectious outcomes. In conclusion, low-normal concentrations of plasma IgA are associated with a reduced prevalence of allergic sensitization in infancy. Further, levels of IgA and IgG in plasma within the range of normal, and IgA in nasal secretions, do not appear to influence the risk of subsequent respiratory illnesses. Further studies to define relationships between IgA and allergic sensitization are likely to provide new insights into the pathogenesis of allergic diseases in infancy.

Weekly monitoring of children with asthma for infections and illness during common cold seasons.

BACKGROUND: Exacerbations of childhood asthma and rhinovirus infections both peak during the spring and fall, suggesting that viral infections are major contributors to seasonal asthma morbidity. OBJECTIVES: We sought to evaluate rhinovirus infections during peak seasons in children with asthma and to analyze relationships between viral infection and illness severity. METHODS: Fifty-eight children aged 6 to 8 years with asthma provided 5 consecutive weekly nasal lavage samples during September and April; symptoms, medication use, and peak flow were recorded. Rhinoviruses were identified by using multiplex PCR and partial sequencing of viral genomes. RESULTS: Viruses were detected in 36% to 50% of the specimens, and 72% to 99% of the viruses were rhinoviruses. There were 52 different strains (including 16 human rhinovirus C) among the 169 rhinovirus isolates; no strains were found in more than 2 collection periods, and all but 2 children had a respiratory tract infection. Virus-positive weeks were associated with greater cold and asthma symptom severity (P < .0001 and P = .0002, respectively). Furthermore, virus-positive illnesses had increased duration and severity of cold and asthma symptoms and more frequent loss of asthma control (47% vs 22%, P = .008). Although allergen-sensitized versus nonsensitized children had the same number of viral infections, the former had 47% more symptomatic viral illnesses (1.19 vs 0.81 per month, P = .03). CONCLUSIONS: Rhinovirus infections are nearly universal in children with asthma during common cold seasons, likely because of a plethora of new strains appearing each season. Illnesses associated with viruses have greater duration and severity. Finally, atopic asthmatic children experienced more frequent and severe virus-induced illnesses.

Distribution and seasonality of rhinovirus and other respiratory viruses in a cross-section of asthmatic children in Trinidad, West Indies.

BACKGROUND: Childhood asthma in the Caribbean is advancing in prevalence and morbidity. Though viral respiratory tract infections are reported triggers for exacerbations, information on these infections with asthma is sparse in Caribbean territories. We examined the distribution of respiratory viruses and their association with seasons in acute and stable asthmatic children in Trinidad. METHODS: In a cross-sectional study of 70 wheezing children attending the emergency department for nebulisation and 80 stable control subjects (2 to 16 yr of age) in the asthma clinic, nasal specimens were collected during the dry (n = 38, January to May) and rainy (n = 112, June to December) seasons. A multitarget, sensitive, specific high-throughput Respiratory MultiCode assay tested for respiratory-virus sequences for eight distinct groups: human rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, metapneumovirus, adenovirus, coronavirus, and enterovirus. RESULTS: Wheezing children had a higher [chi(2 )= 5.561, p = 0.018] prevalence of respiratory viruses compared with stabilized asthmatics (34.3% (24) versus (vs.) 17.5% (14)). Acute asthmatics were thrice as likely to be infected with a respiratory virus (OR = 2.5, 95% CI = 1.2 - 5.3). The predominant pathogens detected in acute versus stable asthmatics were the rhinovirus (RV) (n = 18, 25.7% vs. n = 7, 8.8%; p = 0.005), respiratory syncytial virus B (RSV B) (n = 2, 2.9% vs. n = 4, 5.0%), and enterovirus (n = 1, 1.4% vs. n = 2, 2.5%). Strong odds for rhinoviral infection were observed among nebulised children compared with stable asthmatics (p = 0.005, OR = 3.6, 95% CI = 1.4 - 9.3,). RV was prevalent throughout the year (Dry, n = 6, 15.8%; Rainy, n = 19, 17.0%) and without seasonal association [chi(2 )= 0.028, p = 0.867]. However it was the most frequently detected virus [Dry = 6/10, (60.0%); Rainy = 19/28, (67.9%)] in both seasons. CONCLUSION: Emergent wheezing illnesses during childhood can be linked to infection with rhinovirus in Trinidad's tropical environment. Viral-induced exacerbations of asthma are independent of seasons in this tropical climate. Further clinical and virology investigations are recommended on the role of infections with the rhinovirus in Caribbean childhood wheeze.

Distribution and seasonality of rhinovirus and other respiratory viruses in a cross-section of asthmatic children in Trinidad, WestIndies

BACKGROUND: Childhood asthma in the Caribbean is advancing in prevalence and morbidity. Though viral respiratory tract infections are reported triggers for exacerbations, information on these infections with asthma is sparse in Caribbean territories. We examined the distribution of respiratory viruses and their association with seasons in acute and stable asthmatic children in Trinidad. METHODS: In a cross-sectional study of 70 wheezing children attending the emergency department for nebulisation and 80 stable control subjects (2 to 16 yr of age) in the asthma clinic, nasal specimens were collected during the dry (n = 38, January to May) and rainy (n = 112, June to December) seasons. Amultitarget, sensitive, specific high-throughput Respiratory MultiCode assay tested for respiratory-virus sequences for eight distinct groups: human rhinovirus, respiratory syncytial virus, parainfluenza virus,influenza virus, metapneumovirus, adenovirus, coronavirus, and enterovirus. RESULTS: Wheezing children had a higher [c2 = 5.561, p = 0.018] prevalence of respiratory viruses compared with stabilized asthmatics (34.3% (24) versus (vs.) 17.5% (14)).... CONCLUSION: Emergent wheezing illnesses during childhood can be linked to infection with rhinovirus in Trinidad's tropical environment. Viral-induced exacerbations of asthma are independent of seasons in this tropical climate. Further clinical and virology investigations are recommended on the role of infections with the rhinovirus in Caribbean childhood wheeze.

Distribution and seasonality of rhinovirus and other respiratory viruses in a cross-section of asthmatic children in Trinidad, West Indies.

BACKGROUND: Childhood asthma in the Caribbean is advancing in prevalence and morbidity. Though viral respiratory tract infections are reported triggers for exacerbations, information on these infections with asthma is sparse in Caribbean territories. We examined the distribution of respiratory viruses and their association with seasons in acute and stable asthmatic children in Trinidad. METHODS: In a cross-sectional study of 70 wheezing children attending the emergency department for nebulisation and 80 stable control subjects (2 to 16 yr of age) in the asthma clinic, nasal specimens were collected during the dry (n=38, January to May) and rainy (n=112, June to December) seasons. A multitarget, sensitive, specific high-throughput Respiratory MultiCode assay tested for respiratory-virus sequences for eight distinct groups: human rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, metapneumovirus, adenovirus, coronavirus, and enterovirus. RESULTS: Wheezing children had a higher [chi square =5.561, p=0.018] prevalence of respiratory viruses compared with stabilized asthmatics (34.3 per cent (24) versus (vs.) 17.5 per cent (14)). Acute asthmatics were thrice as likely to be infected with a respiratory virus (OR = 2.5, 95 per cent CI = 1.2 - 5.3). The predominant pathogens detected in acute versus stable asthmatics were the rhinovirus (RV) (n=18, 25.7 per cent vs. n=7, 8.8 per cent; p=0.005), respiratory syncytial virus B (RSV B) (n=2, 2.9 per cent vs. n=4, 5.0 per cent), and enterovirus (n=1, 1.4 per cent vs. n=2, 2.5 per cent). Strong odds for rhinovirus infection were observed among nebulised children compared with stable asthmatics (p=0.005, OR = 3.6, 95 per cent CI = 1.4 - 9.3,). RV was prevalent throughout the year (Dry, n=6, 15.8 per cent; Rainy, n=19, 17.0 per cent) and without seasonal association [chi square =0.028, p=0.867]...

Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.

RATIONALE: Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood. OBJECTIVES: To define the relationship between specific viral illnesses and early childhood asthma development. METHODS: A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed. MEASUREMENTS AND MAIN RESULTS: Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR , 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age. CONCLUSIONS: Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.

Viral infections, cytokine dysregulation and the origins of childhood asthma and allergic diseases.

BACKGROUND: The origins of asthma and allergic disease begin in early life for many individuals. It is vital to understand the factors and/or events leading to their development. METHODS: The Childhood Origins of Asthma project evaluated children at high risk for asthma to study the relationships among viral infections, environmental factors, immune dysregulation, genetic factors, and the development of atopic diseases. Consequently wheezing illnesses, viral respiratory pathogen identification, and in vitro cytokine response profiles were comprehensively evaluated from birth to 3 years of age, and associations of the observed phenotypes with genetic polymorphisms were investigated. RESULTS: For the entire cohort, cytokine responses did not develop according to a strict T helper cell 1 or T helper cell 2 polarization pattern during infancy. Increased cord blood mononuclear cell phytohemagglutin-induced interferon-gamma responses of mononuclear cells were associated with decreased numbers of moderate to severe viral infections during infancy, especially among subjects with the greatest exposure to other children. In support of the hygiene hypothesis, an increased frequency of viral infections in infancy resulted in increased mitogen-induced interferon-gamma responses at 1 year of age. First year wheezing illnesses caused by respiratory viral infection were the strongest predictor of subsequent third year wheezing. Also, genotypic variation interacting with environmental factors, including day care, was associated with clinical and immunologic phenotypes that may precede the development of asthma. CONCLUSIONS: Associations between clinical wheezing, viral identification, specific cytokine responses and genetic variation provide insight into the immunopathogenesis of childhood asthma and allergic diseases.

Rhinovirus illnesses during infancy predict subsequent childhood wheezing.

BACKGROUND: The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/or allergic diseases in early childhood is not established. OBJECTIVE: To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases. METHODS: By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed. RESULTS: Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR]=2.1), older siblings (OR=2.5), allergic sensitization to foods at age 1 year (OR=2.0), any moderate to severe respiratory illness without wheezing during infancy (OR=3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR=3.0), rhinovirus (OR=10) and/or non-rhinovirus/RSV pathogens (OR=3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR=6.6; P < .0001). Moreover, 63% of infants who wheezed during rhinovirus seasons continued to wheeze in the 3rd year of life, compared with only 20% of all other infants (OR=6.6; P < .0001). CONCLUSION: In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature.