Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life

Rationale: The 2009 H1N1 flu appeared to cause more severe cold symptoms during the 2009-2010 flu season. Objectives: We evaluated H1N1 infections during peak viral season in children with and without asthma to determine whether the H1N1 infectivity rate and illness severity were greater in subjects with asthma. Methods: One hundred and eighty children, 4-12 years of age, provided eight consecutive weekly nasal mucus samples from September 5 through October 24, 2009, and scored cold and asthma symptoms daily. Viral diagnostics were performed for all nasal samples. Measurements and Main Results: One hundred and sixty-one children (95 with asthma, 66 without asthma) completed at least 6 of the 8 nasal samples. The incidence of H1N1 infection was significantly higher in children with asthma (41%) than in children without asthma (24%; odds ratio, 4; 95% confidence interval, 1.8-9; P , 0.001), but rates of human rhinovirus infection (90% each) and other viral infections (47 vs. 41%) were similar. In children with asthma, there was a nonsignificant trend for increased loss of asthma control during H1N1 infections compared with human rhinovirus infections (38 vs. 21%; odds ratio, 2.6; 95% confidence interval, 0.9-7.2; P ¼ 0.07). Conclusions: During peak 2009 H1N1 flu season, children with asthma were infected almost twice as often with H1N1 compared with other respiratory viruses. H1N1 infection also caused increased severity of cold symptoms compared with other viral infections. Given the increased susceptibility of children with asthma to infection, these findings reinforce the need for yearly influenza vaccination to prevent infection, and raise new questions about the mechanism for enhanced susceptibility to influenza infection in asthma.Keywords: asthma; viral infection; influenza 2009 H1N1 Flu was first reported in the United States in the spring of 2009, and eventually affected 61 million people (1), one-third of them children. Morbidity was high, with 87,000 children requiring hospitalization. The most common comorbidity for patients hospitalized as a result of H1N1 infection was asthma (2), and the percentage of children with asthma hospitalized because of the 2009 H1N1 virus was two-to fivefold higher than previous reports of hospitalization due to seasonal influenza (3, 4). Despite the observation that subjects with asthma suffer H1N1 illness with increased severity, it remains unclear at what rate they are infected and whether their symptom severity is greater than those of their nonasthmatic counterparts. Previous studies of H1N1 infectivity reflect symptomatic infections with limited reporting of mild or asymptomatic infection (5-7).A study by our group demonstrated that 90% of children with asthma are infected with human rhinoviruses (HRVs) during the month of September, and that the severity of clinical illness varies from no symptoms to severe wheezing illnesses (8). This study provided the foundation on which we designed a larger cohort to prospectively examine the relationship between illness symptom...

Section: Discussionsupporting

confidence: 61%

Increased H1N1 Infection Rate in Children with Asthma

Kloepfer¹,

Olenec²,

Lee³

et al. 2012

“…This relationship between allergic sensitization and HRV wheezing could be explained by a common underlying susceptibility to both conditions or by a causal relationship. In support of a common underlying predisposition, low IFN-g responses during early life have been associated with greater risk of early childhood wheeze and allergy (12)(13)(14). Furthermore, impaired innate immune responses have been associated with allergy and asthma (15,16).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life

Jackson

Evans

Gangnon

et al. 2012

301

270

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.Keywords: virus; wheezing; allergic sensitization; RSV; human rhinovirus Aeroallergen sensitization and virus-induced wheezing episodes during infancy and early childhood are risk factors for subsequent asthma development, and children with both risk factors in early life are at particularly high risk of having asthma at school age (1, 2). Understanding the sequence of events that lead to sensitization and virus-induced wheezing during early life is important to identifying potential causal relationships in the development of atopic asthma. Early allergic sensitization has consistently been identified as a risk factor for asthma development, and plausible mechanisms by which allergic sensitization leads to greater severity of viral respiratory illnesses have also been proposed (3). If allergic sensitization causes subsequent virus-induced wheezing and asthma inception, then preventing or interrupting the development of allergic sensitization would be a potential strategy for asthma prevention.In contrast to this concept, some animal models of early life infection suggest that virus infection could lead to allergic sensitization (4, 5). In clinical studies, S...

“…Particularly in the clinical situation of RSV infection, many studies demonstrated that the Th1/Th2 cytokine balance in the serum of children with severe RSV disease was more skewed toward Th2 cytokines (4). In addition, IFN-g has been determined as a dominant host response factor for RSV clearance clinically and in animal studies (7,50). Therefore, a lack of IFN-g and Th2-skewed cytokine profile in Nrf 2 2/2 mice may explain their delayed viral clearance and support the enhanced RSV susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease

Cho

Imani

Miller-DeGraff

et al. 2009

165

170

Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of significant lower respiratory illness in infants and young children, but its pathogenesis is not fully understood. The transcription factor Nrf 2 protects lungs from oxidative injury and inflammation via antioxidant response element (ARE)-mediated gene induction. Objectives: The current study was designed to determine the role of Nrf 2-mediated cytoprotective mechanisms in murine airway RSV disease. Methods: Nrf 2-deficient (Nrf 2 2/2 ) and wild-type (Nrf 2 1/1 ) mice were intranasally instilled with RSV or vehicle. In a separate study, Nrf 2 1/1 and Nrf 2 2/2 mice were treated orally with sulforaphane (an Nrf 2-ARE inducer) or phosphate-buffered saline before RSV infection. Measurements and Main Results: RSV-induced bronchopulmonary inflammation, epithelial injury, and mucus cell metaplasia as well as nasal epithelial injury were significantly greater in Nrf 2 2/2 mice than in Nrf 2 1/1 mice. Compared with Nrf 2 1/1 mice, significantly attenuated viral clearance and IFN-g, body weight loss, heightened protein/ lipid oxidation, and AP-1/NF-kB activity along with suppressed antioxidant induction was found in Nrf 2 2/2 mice in response to RSV. Sulforaphane pretreatment significantly limited lung RSV replication and virus-induced inflammation in Nrf 2 1/1 but not in Nrf 2 2/2 mice. Conclusions: The results of this study support an association of oxidant stress with RSV pathogenesis and a key role for the Nrf 2-ARE pathway in host defense against RSV.