SEATTLE—As we learn more about asthma and allergy, one thing is becoming increasingly clear: The seeds of these diseases are sown very early in life. Findings from longitudinal, cross-sectional, and animal studies presented at the annual meeting of the American Thoracic Society in Seattle amply illustrate this.[1]

For example, at least four longitudinal studies suggest that most people with persistent asthma experienced their first symptoms very early in life, reported Fernando D. Martinez, MD. Thus, it appears that early allergic sensitization is a more important risk factor for childhood asthma than is later allergic sensitization. Lung function losses and, possibly, persistent bronchial hyperresponsiveness also appear to begin early; in most patients with chronic asthma, these findings are present by the early school years. Furthermore, patterns of childhood asthma typically persist into adulthood.

“But these are [general] patterns,” noted Dr. Martinez, Director of the Arizona Respiratory Center at the University of Arizona College of Medicine in Tucson. “It does not mean that there are no subjects who develop significant severe bronchial hyperresponsiveness at the age of 40 after a severe viral infection.” The longitudinal data nevertheless have public health relevance, he stressed, because they reflect typical patients with asthma.

Dr. Martinez, who is also the Swift-McNear Professor of Pediatrics at the University of Arizona, suggested that future studies classify asthma into three phenotypes—transient wheezing (this usually resolves by age 3); nonatopic “winter wheezing” (which is less common among adolescents and young adults); and atopic wheezing (which typically develops within the first 11 to 16 years of life). This classification system may help to distinguish chronic asthma from transient or benign forms of the disease, he said.

AIRWAY DEVELOPMENT

“Lung development starts very early after fertilization, and it continues for at least two or three years in humans,” related Charles G. Plopper, PhD, who discussed the role of prenatal and postnatal airway development in the pathogenesis of allergy and asthma.

Although differentiation of the gas exchange area within the lungs begins prenatally, most development of the conducting airways occurs after birth, said Dr. Plopper, who chairs the Department of Anatomy, Physiology, and Cell Biology at the University of California, Davis. Among the processes that develop postnatally are formation and maturation of alveolar areas; differentiation of the airway epithelium, fibroblasts, basement membrane, airway smooth muscle, and establishment of the interaction between them; and integration of the various lung components with the central nervous system.

Because lung development is a lengthy process—it may not cease until as late as age 8 or 9—there is a long time during which children remain susceptible to asthma and allergy. Indeed, allergen-activated immune or inflammatory cells that enter any lung area during the delicate early years may raise the risk of asthma and allergy by altering the dynamics of lung development and growth, Dr. Plopper explained.

IMMUNOLOGIC FACTORS

The fact that rhesus monkeys and humans have a similar postnatal lung maturation process has allowed investigators to gain insight into how chronic allergen exposure affects human lungs postnatally. Often, the first step in the research is to sensitize infant rhesus monkeys to house dust mite allergen via subcutaneous injection, intranasal instillation, or aerosol challenge; the allergen is administered for three hours at a time, three times each week until the monkey is about 6 months of age. The intensive dust mite exposure typically results in markedly increased airway levels of eosinophils and CD1A+ dendritic cells, reflecting a high level of inflammation.

However, “immune cells are differentially distributed throughout the large and small airways in infants and adults,” said Lisa A. Miller, PhD, an Assistant Research Cell Biologist at the University of California, Davis. Infant monkeys exposed to high levels of dust mite allergen have a decreased capacity to express CD25 receptors on circulating lymphocytes, whereas this capacity is increased in similarly exposed adult monkeys. The infant monkeys also seem to underexpress T-helper (Th) cytokines and immunoglobulin E (IgE).

Cross-sectional studies have yielded similar findings in humans, particularly the identification of a phenotype of Th underexpression among children at high risk for allergy. “The level of attenuation was more marked and more prolonged for interferon-gamma, which hinted to us that these children were somewhat more Th2 polarized than the rest of the population,” said Patrick G. Holt, DSc, FRCPath, Deputy Director of the Telethon Institute for Child Health Research at the University of Western Australia in Perth.

The attenuated Th phenotype appears to be present prenatally, suggest unpublished data for about 500 children that Dr. Holt and colleagues have followed for the first six years of life. Furthermore, this phenotype “is associated with increased odds ratios for both wheezing and atopic outcomes at age 6,” stated Dr. Holt. The main source of Th cytokines prenatally is unclear, but it is probably the placenta and not the infant’s own immune system, he speculated.

Large vaccine trials have improved our knowledge about the role of postnatal Th function in the development of allergic disease. These trials have shown that up-regulation of Th1 is usually delayed until about 12 months after birth and that the duration of the delay is probably even longer in atopic infants. Because the immune system is programming its responses to inhaled allergens and committing them to lifelong memory at that time, the result of such a delay may be an increased likelihood that the infant has a predominantly Th2 response, Dr. Holt suggested.

EARLY VERSUS LATE SENSITIZATION

Erwin W. Gelfand, MD, and colleagues have been studying allergen-sensitized mice to get an idea of the effect of the timing of allergen exposure on the degree of allergic disease. “The age at sensitization, not the age of allergen challenge, dictates the extent of the development of airway hyperresponsiveness, airway eosinophilia, Th2 cytokine production, and IgE-specific antibody levels,” reported Dr. Gelfand, Chairman of Pediatrics at the National Jewish Medical and Research Center in Denver.

The mice that were sensitized when they were 8 weeks old had significantly less airway hyperresponsiveness to methacholine challenge four weeks later than did the animals sensitized at age 1 week. Allergen sensitization at 20 to 48 weeks of age produced an even smaller degree of airway hyperresponsiveness.

The effect of delayed allergen challenge persists for long periods. “In fact, we were able to extend these effects for … seven or eight months after sensitization,” said Dr. Gelfand.

Longer delays in allergen challenge did not protect against lung function declines during methacholine challenge. Interestingly, however, T cells derived from younger mice that underwent early allergen sensitization appeared to increase the extent of lung function declines in older mice, but only in those animals that were allergen naive.

The presence of CD4+ T cells and interleukin-4 seems to be necessary for allergen sensitization, whereas airway hyperresponsiveness during methacholine challenge depends on the presence of interleukin-13, noted Dr. Gelfand. “These studies illustrate the importance of defining and developing intervention strategies that go on very early in life if we are going to have effects later in life,” he concluded.

—Timothy Begany