Abstracts

Abstract

Increase in Alveolar Nitric Oxide in the Presence of Symptoms in Childhood Asthma; Mahut, B., Delacourt, C., Zerah-Lancner, F., et al. Chest 2004; 125:1012–1018.

Background. Asthma is defined as an inflammation encompassing both the proximal and distal pulmonary airways. Exhaled nitric oxide is regarded as a non-invasive surrogate of airway inflammation. There is evidence of cellular inflammation in the very small airways and alveoli that result in an increase in nitric oxide (Q_no) output. There is documentation using bronchial alveolar lavage of cytokine expression, eosinophil presence, and nitric oxide synthetase expression in the distal airways. The authors hypothesized that increased nitric oxide output could result from distal airways and/or alveoli in asthmatic individuals.

Objective. The objective was to assess the contributions of alveolar and proximal airway compartments in exhaled nitric oxide (NO) output (Q_no) in children with asthma and to determine their correlation with mild symptoms of bronchial obstruction.

Methods. The subjects in this study included 15 children with asthma with recent onset of mild symptoms, 30 asymptomatic asthmatic children and 15 healthy children. The investigators measured exhaled nitric oxide concentration at multiple expiratory flow rates (V) allowing the determination of alveolar and proximal airway contributions in Q_no. Spirometric measurements and flow volume curves were obtained, as well.

Results. The asymptomatic and recently symptomatic individuals were not significantly different with regard to spirometry measurements. The maximal airway nitric oxide output was more elevated in recently symptomatic versus asymptomatic asthmatics, and in asymptomatic asthmatics versus healthy children. Variables that impacted airway nitric oxide output were symptoms and distal airway obstruction as assessed by MEF (25-75). The nitric oxide determination from the distal airways was significantly higher in individuals with MEF (25-75) less than 50% of predicted as compared with children whose MEF (25-75) was greater than 50% of predicted. Alveolar nitric oxide was significantly elevated in recently symptomatic children as compared with children who were asymptomatic, whereas it was not significantly different between asymptomatic and healthy children.

Conclusions. An increase in alveolar nitric oxide concentration was observed in correlation with increased symptoms of asthma and proximal airway nitric oxide was correlated with distal obstruction during asthma.

Reviewer's Comment. This is a useful prospective study, having healthy children as control subjects, which indicates the increased sensitivity and specificity of nitric oxide determination in the assessment of airway inflammation and correlating with the results of pulmonary function tests. It further extends our knowledge of airway inflammation to include the smallest airways and alveoli and indicates that even with mild or no symptoms, airway inflammation can be present distally as detected by nitric oxide, although it is not detected by conventional pulmonary function testing. It would be of interest to determine the correlation of nitric oxide with increasing levels of symptoms to provide parameters that might parallel the NHLBI Guidelines for mild, moderate, and severe asthma. Nitric oxide determination, particularly of the distal airway, may be useful as a marker of recent symptoms and of increasing loss of asthma control.

Christopher Randolph, M.D.

Waterbury, CT

Abstract

Early Infant Multivitamin Supplementation Is Associated with Increased Risk for Food Allergy in Asthma; Milner, J.D., Stein, D.M., McCarter R. Pediatrics 2004; 114:27–32.

Objective. Recent studies indicate that formula feeding and early exposure to food may predispose to an increased likelihood for asthma and allergy. Greater than 50% of all toddlers currently take some sort of vitamin, and recent American Academy of Pediatric recommendations include vitamin D supplementation for all breast-fed infants. This will likely result in an augmentation in early multivitamin utilization. The objective of the authors was to determine if infant exposure to immunomodulating vitamins has an impact on subsequent risk for food allergy and asthma.

Methods. Data analyzed in this study included the National Center for Health Statistics, 1998, and the National Maternal Infant Health Survey, which followed pregnant women and their newborns. Individuals were stratified by race and breast-feeding characteristics. Factors associated with alteration of the risk for asthma or food allergies were identified using a univariant logistical regression. A multivariant logistic regression model was then utilized to further analyze these factors. Early vitamin supplementation was characterized by vitamin use within the first 6 months by the authors.

Results. There were greater than 8,000 total patients in the investigation. The overall incidence of asthma was 10.5%, and food allergy 4.9%. By univariant analysis, male gender, smoker in the household, child care, prematurity (less than 37 weeks), black race, absence of history of breast feeding, lower income, and lower education were associated with a higher risk for asthma. A higher risk for food allergies was conferred by childcare, higher levels of education, income, and a history of breast-feeding. Early vitamin use was associated with a higher risk for food allergies in the exclusively formula-fed population. Vitamin use at 3 years of age was also associated with augmented probability of food allergies but not asthma. Finally, the history of vitamin use in the first 6 months of life was associated with a higher risk of asthma in the black infant.

Conclusions. The conclusions of the authors are that early vitamin introduction is related to increased likelihood for asthma in black children and food allergies in the exclusively formula-fed child.

Reviewer's Comment. It is not clear if the findings are associational or causal. The mechanism for the association of multivitamin supplementation and increased incidence of asthma and allergy relates to in vitro and animal data, which would enable naïve T cells to differentiate to TH1 or TH2 phenotypes and may increase the allergic and the asthma response. The formula-fed infants may be at greatest risk for effects of multivitamin supplementation because of population selection, predisposition to hypersensitivity from formula, and possibly because of a dose response, given that the formula contains significantly higher amounts of vitamin D than breast milk. There are several limitations to this study, as indicated by the authors. The diagnosis of food allergy and asthma were made by 3 years of age and relied on parental self-report of a physician diagnosis. It is also possible that the parent with a child with more significant disease may be more likely to be provided multivitamin supplements for their children.

Christopher Randolph, M.D.

Waterbury, CT

Abstract

A Prospective Study of Fel d1 and Der p1 Exposure in Infancy and Childhood Wheezing; Polk, S., Sumyer, J., Munoz-Ortiz, L., et al. American Journal of Respiratory and Critical Care Medicine 2004; 170:273–278.

Background. European researchers developed the Asthma Multi-Center Infants Cohort Study to evaluate the impact of atopy, which affects approximately 25% of European children, on asthma, which affects approximately 1 in 7 children. The authors evaluate the impact of early allergen exposure in the first year of life via Der p1 and Fel d1 and wheezing in early childhood with modifications of this interaction by respiratory irritants including hydrogen dioxide, cigarette smoke, and susceptibility factors, including parental allergy or asthma.

Objective. The objective of the authors was to assess the impact of domestic exposure to cat allergen and house dust mite on wheezing from birth to 4 years of age in a multi-center prospective birth cohort.

Methods. The clinical population included 1,611 mothers who were recruited before delivery in Ashford, England and Barcelona and Majorca, Spain. Exposure information was derived from questionnaires and by dust collection. The collection was done in the same standard procedure in three centers and analysis performed by a single laboratory in the United Kingdom. Prick skin test to inhalants was performed, but only 60% of fathers underwent skin prick testing, so maternal atopy alone was used as a surrogate for allergic vulnerability of the child. Variables, including number of siblings, pet ownership, paternal smoking, self-reported paternal asthma, antibiotic use, and lower respiratory tract infection were evaluated.

Results. The clinical findings of the study were that the incidence of wheeze decreased with each additional year in two of the Centers, Ashford, UK, and Majorca, Spain, but Barcelona, which is the only center with a hospital, experienced as much wheeze in the fourth year as the first (27% vs. 28%). Der p1 levels were higher in the homes of non-wheezers, particularly at 3 to 4 years of age. Families provided completed outcome data and wheezing status in all 4 years for 1,289 children. Forty-seven percent of the children never wheezed during the first 4 years of life. Der p1 levels did not correlate with any type of wheezing prognosis. Fel d1, however, significantly enhanced the risk of wheezing in 3- and 4-year-olds in comparison with 1-year olds, particularly when combined with maternal asthma.

Conclusions. The author's conclusion is that the house dust mite did not impact incidence of wheeze at any age, whereas the cat allergen impacted at age 3 to 4 years. They speculate that the cat allergen may be a surrogate for another biologically relevant exposure, although they cannot rule out that there is a causal relationship between the outcomes, based on their data.

Reviewer's Comment. The literature on the subject of cat allergen exposure and wheezing is controversial. Findings in one American study of 1- to 5-year-old American children with at least one atopic parent noted that exposures greater than 8 μg per gram of cat allergen at 2 to 3 months was associated with decreased risk of wheezing from age 1 to 5 years, unless the child's mother had asthma, in which case there was an increased risk of wheezing at and beyond 3 years of age. The odds ratio was higher for maternal asthma compared to paternal asthma. Other studies have reported similar findings in cohorts of children. Since asthma is genetically heterogeneous with polygenic inheritance, this would explain the influence of parental asthma on wheezing. Greater cat and allergen exposure may increase the risk of wheezing at later ages, as the risk of wheezing and response to lower response to lower respiratory tract infection declines.

In conclusion, the authors demonstrate that aeroallergens Der p1 and Fel d1 play little role in the development of wheeze in the first 4 years of life. Fel d1 has a small impact that varied according to age and maternal asthma.

Christopher Randolph, M.D.

Waterbury, CT

Abstract

The Relationship Between Infant Airway Function, Childhood Airway Responsiveness, and Asthma; Turner, S.W., Palmer, L.J., Rye, P.J., et al. The American Journal of Respiratory and Critical Care Medicine 2004; 169:921–927.

Background. Recurrent childhood wheezing is common in early life and may persist. Factors associated with persistent wheezing include male sex, a history of maternal asthma or smoking, atopy, and increased airway responsiveness. Abnormalities in pulmonary function have also been associated with increased wheeze that persists into adult life. Reduced pulmonary function demonstrated by a reduced VmaxFRC before the onset of respiratory symptoms may also place the child at risk for persistent wheezing as a later complication of bronchiolitiis and pneumonia.

Objective. The objective of the authors was to assess VmaxFRC in infants to determine if reduced VmaxFRC soon after birth would be associated with persistent wheezing at 11 years of age, independent of atopy and elevated airway responsiveness in childhood.

Methods. The clinical population was a cohort enrolled before birth and selected from a white population attending an antenatal clinic between June 1987 and November 1990. Infant pulmonary function was assessed at 1 month of age. Monthly questionnaires were completed by parents in the first year and annually at the child's second, third, fourth, and fifth birthdays to assess the history of recent wheeze or physician diagnosed asthma. At age 6 and 11 years, children were assessed by questionnaire, spirometry, airway hyperresponsiveness, and histamine skin prick test.

Results. The authors found that recent wheeze reported at 11 years of age was clearly related to a reduced VmaxFRC at one year of age compared to a report of no recent wheeze. Wheeze between 4 and 6 years of age that persisted at 11 years (persistent wheezing) was highly correlated with reduced VmaxFRC at one month, as was atopy and increased airway responsiveness at age 11 years.

Conclusions. Reduced airway function in early infancy is independently associated with persistent wheezing at 11 years of age.

Reviewer's Comment. This study demonstrates that reduced VmaxFRC at one month is clearly associated with persistent wheezing at 11 years. The mechanism for persistent wheezing in children may involve both an intrinsic abnormality from birth and later onset of elevated airway responsiveness associated with atopy. The data may explain why asthma does not develop in all atopic children and why early childhood wheeze does not necessarily persist in all individuals. Further study of the mechanisms of infantile and persistent wheezing are necessary.

Christopher Randolph, M.D.

Waterbury, CT

Abstract

Inhaled Corticosteroids and the Risk of Fractures in Children and Adolescents; Schlienger, R.G., Jick, S.S., Meier, C.R. Pediatrics 2004; 114:469–473.

Background. Current therapeutic guidelines recommend inhaled corticosteroids as first line therapy for children and adults with mild, moderate, and severe persistent asthma. Inhaled corticosteroids are known to be deposited in the oropharynx and subsequently swallowed and absorbed, making them bioavailable via the gastrointestinal tract to the systemic circulation. The causal relationship between oral steroids and osteoporosis and increased fracture risk has been demonstrated. However, it is not as clear that being on inhaled corticosteroids is associated with suppression of bone formation or has a negative impact on bone mineral density.

Objective. The objective of the authors was to ascertain whether children or adolescents exposed to inhaled steroids, which included beclomethasone, budesonide, and fluticasone, were at increased risk for bone fracture, compared with nonexposed controls.

Methods. The clinical populations included three groups:

1. Individuals 5 to 79 years of age with a diagnosis of asthma or chronic obstructive pulmonary disease (COPD) with at least one prescription for inhaled steroids or oral corticosteroids.

2. Group 2 included individuals 5 to 79 years of age with asthma or COPD with no exposure to inhaled or oral corticosteroids.

3. Group 3 was a random sample of 50,000 individuals who were 5 to 79 years of age who had neither a diagnosis of asthma or COPD nor had a prescription for inhaled or oral corticosteroids.

There were six control subjects identified for each child or adolescent with a fracture diagnosis and cases were matched by age, gender, general practice, calendar time, and years of history in the research database. The use of inhaled corticosteroid before the index date between fracture cases and control cases was compared.

Results. There were 3,744 cases and 21,757 matched control individuals. There was no increased fracture risk associated with current exposure to inhaled steroids when compared with non-users, even in individuals with current longer-term exposure (20 or more prescriptions).

Conclusions. The conclusion of the authors was that exposure to inhaled steroids does not substantially enhance the fracture risk in children and adolescents when compared with non-exposed individuals.

Reviewer's Comment. This excellent study verifies general consensus in the literature that inhaled corticosteroids used in recommended doses do not impact on fracture risk in children or adolescents when compared with controls. There are some limitations to this study admitted by the authors in their discussion. These include lack of clear data regarding smoking status of the individuals, the level of physical activity, the actual use of the drug by the patient, socioeconomic status, and dietary factors. In addition, the majority of the children were on beclomethasone, which is not as potent as other inhaled corticosteroid agents. This study is useful in verifying that inhaled corticosteroids, using recommended dosage guidelines over the long-term will not affect fracture risk in children and adolescents.

Christopher Randolph, M.D.

Waterbury, CT