Guerra S, Lohman IC, Halonen M, Martinez FD, Wright AL. Am J Respir Crit Care Med. 2004;169:70–76
Purpose of the Study.
To determine if interferon γ (IFNγ) production and soluble CD14 (sCD14) levels correlate longitudinally with the risk of developing recurrent wheezing in the first year of life. Both environmental risk factors and variation in the maturation of the immune system seem to have a role in the development of asthma. Previous studies have demonstrated reduced IFNγ production in atopic and nonatopic wheezers. IFNγ production correlates positively with endotoxin exposure and with sCD14 levels, and CD14 functions as a receptor for endotoxin. Thus, the investigators reasoned that a CD14-mediated response to endotoxin might play a role in the maturation of IFNγ production, possibly preventing the onset of recurrent wheezing.
Subjects were 238 infants followed prospectively from birth to 12 months as part of the Infant Immune Study in Arizona.
Mothers of enrolled infants completed questionnaires about known environmental risk factors for wheezing before birth and throughout the infant’s first 12 months of life. At 12 months, the mothers were also asked how often their infant’s chest had ever sounded “wheezy” or “whistling” and the age of the first wheezing episode. Frequency of wheezing was quantified, and any response more than “very rarely” was classified as recurrent wheezing. Blood was obtained at birth and 3 months of age for the measurement of sCD14 levels in plasma and IFNγ production from stimulated peripheral blood mononuclear cells.
Wheezing episodes during the first year of life were experienced by 94 infants (39.5%), and 41 experienced recurrent episodes. The mean IFNγ production and sCD14 levels increased from birth to 3 months. Infants in the lowest quartile of IFNγ production at 3 months and of sCD14 levels at birth had up to 4.5 and 3.2 increased odds, respectively, of developing recurrent wheezing compared with children in the medium and high quartiles for these parameters. These relationships persisted after adjusting for demographic and environmental asthma risk factors.
The authors concluded that reduced plasma sCD14 at birth and impaired IFNγ production at 3 months of age increase the risk of recurrent wheezing in the first year of life. Because of the interrelationship of CD14 and IFNγ, a CD14-mediated response to endotoxin may play an important role in enhancing the maturation of IFNγ production and preventing the inception of recurrent wheezing.
The relation of CD14 and IFN with endotoxin exposure lends support for the “hygiene hypothesis,” which postulates that decreased exposure to infectious agents in infancy increases the risk for atopy. From this study, it is impossible to assess whether sCD14 levels at birth and IFNγ production at 3 months of age are simply independent markers that correlate with recurrent wheeze or whether they are truly in the same causal pathway to recurrent wheezing. Additional studies will need to be done to confirm causality. Unfortunately, the design of the study did not allow the investigators to explore whether IFNγ production and sCD14 levels were important in atopic versus nonatopic recurrent wheezing.