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OBJECTIVE. Cellular immunity has classically been described as the defense mechanism for viral infections. The development of cellular or humoral immune re sponses will depend on a repertoire of cytokines produced by numerous cells, including CD[4.sup.+] and CD[8.sup.+] T cells. These lymphocytes can be subdivided into 2 subsets, T helper 1 (Th1) and Th2, on the basis of the cytokine profiles they synthesize. Type 1 T cells produce interferon [gamma] (IFN-[gamma]), an essential cytokine in the viral cell-mediated immune response. Th2 cells selectively produce interleukin 4 (IL-4) and IL-5 that participate in the development of humoral immunity and have a prominent role in immediate-type hypersensitivity. An imbalance in the Th1/Th2 cytokine immune response has been related to pathogenesis of the respiratory syncytial virus (RSV) bronchiolitis and to the severity of the infection. Glucocorticosteroids have a role in inhibiting the IFN-[gamma] response, acting directly on T cells or indirectly through IL-12. In this way, an increase in plasma cortisol would induce a decrease in the Th1 products with the imbalance between Th1/Th2 cytokines and a shift to Th2 response. We hypothesized that there is a relationship among endogenous cortisol response in acute RSV infection, severity of illness, and decreased Th1 cytokine response. METHODS. We studied 42 infants under 12 months of age during an acute RSV infection. Twenty-one infants with a median age of 6 months had a severe illness and required hospitalization, whereas 21 with mild diseases with a median age of 7 months were under ambulatory control. All of them had bronchial obstruction evidenced by wheezing and/or hyperinflation on chest radiograph and positive RSV antigen detected by indirect immunofluorescence in nasopharyngeal aspirates. The control group included 21 infants in good health matched by age and gender with median age of 6 months that required blood tests for minor surgery. They were evaluated during a non-RSV epidemic period. Heparinized blood was collected on enrollment from all participating children at 9 AM for total leukocyte and differential cell count, determination of lymphocyte subsets, and for intracellular detection of cytokines in single cells; mononuclear cells were cultured to determine in the supernatant cytokine production. In addition, 1 mL of plasma was separated and kept frozen at -20[degrees]C for cortisol assay. In the supernatant of the cultured peripheral blood mononuclear cells (PBMCs), we quantified IL-12, IFN-[gamma], IL-4, IL-5, and IL-10. Lymphocyte phenotypes and CD[4.sup.+] and CD[8.sup.+] T cells with intracellular IL-4, IL-10, and IFN-[gamma] were analyzed by triple-color immunofluorescence of single cells on a FACScan flow cytometer. RESULTS. Infants with severe illness had significantly higher plasma cortisol levels than infants with mild disease, and in both groups of infected infants, those were higher than in the control group. A significantly decreased IL-12 and IFN-[gamma] production by PBMCs and a fall in the percentage of CD[4.sup.+] T cells expressing IFN-[gamma] were observed only in the severely affected infants. IL-12 concentrations were 2 pg/mL in severe illness versus 13 pg/mL in mildly infected infants and 12 pg/mL in controls. PBMCs from infants with severe illness produced less IFN-[gamma] than mildly infected infants and than controls when compared with severe illness. No differences between the 3 groups of infants were observed during the acute phase of the disease for IL-4, IL-5, and IL-10. IL-12 and IFN-[gamma] production had an inverse correlation with plasma cortisol levels. During severe RSV bronchiolitis, infants developed lymphopenia, and significantly lower eosinophil counts and percentages and absolute counts of CD[4.sup.+] and CD[8.sup.+] T cells. Eighty days postinfection, all values had returned to normal levels. CONCLUSIONS. In this study, we demonstrate that during the acute phase of RSV infection, there is an increase in the level of plasma cortisol that is parallel to the decrease in IL-12 and IFN-[gamma] production. These findings suggest an association between increased plasma cortisol and a decreased Th1-type response. The increase in plasma cortisol was greater in infants with the more severe symptomatology in association with a lower level of IL-12 and IFN-[gamma] production. The potential causative role of endogenous cortisol in the imbalance of the Th1/Th2 response observed during severe RSV infection requires additional investigation. Our results suggest that the immunologic changes observed in the more severely ill patients may be partially explained by the increased levels of plasma cortisol. This finding should be taken into consideration when systemic steroids are prescribed to infants infected with the RSV because there is still controversy regarding the efficacy of systemic steroid use in severe bronchiolitis. KEY WORDS. cytokines, respiratory syncytial virus, respiratory infectious diseases, lymphocyte markers, glucocorticoids.

Objective. Respiratory syncytial virus (RSV) bronchiolitis is a common cause of hospitalizations in children and has been increasingly identified as a risk factor in the development of asthma. Little is known about what determines the severity of RSV bronchiolitis, which may be helpful in the initial assessment of these children. Design. We evaluated a variety of environmental and host factors that may contribute to the severity of RSV bronchiolitis in the RSV Bronchiolitis in Early Life prospective cohort study. Severity of bronchiolitis was based on the quantization of lowest [O.sub.2] saturation and the length of stay. These factors included the child's and family's demographics, presence of household allergens (dust mite, cat, dog, and cockroach), peripheral blood eosinophil count, immunoglobulin E level, infant feeding, prior illnesses, exposure to intrauterine and postnatal cigarette smoke, and family history of atopy. Patients. We prospectively enrolled 206 hospitalized infants, all under 12 months old (4.0 [+ or -] 3.3 months old), with their first episode of severe RSV bronchiolitis (mean 02 saturation: 91.6 [+ or -] 7.3%; length of stay: 2.5 [+ or -] 2.5 days; presence of radiographic opacities: 75%). Patients were excluded for a variety of reasons including previous wheezing, regular use of bronchodilator or antiinflammatory medications, any preexisting lung disease including asthma, chronic lung disease of prematurity/bronchopulmonary dysplasia, or cystic fibrosis; gastroesophageal reflux disease on medical therapy; or congenital anomalies of the chest or lung. Results. Age was found to be a significant factor in the severity of infection. The younger an infant was, the more severe the infection tended to be as measured by the lowest oxygen ([O.sub.2]) saturation. We also found that infants exposed to postnatal cigarette smoke from the mother had a lower [O.sub.2] saturation than those not exposed. However, there was no significant difference in RSV bronchiolitis severity between infants exposed only to intrauterine smoke and those infants never exposed to cigarette smoke. Infants with a family history of atopy, especially a maternal history of asthma or hay fever, had a higher [O.sub.2] saturation. Although a history of maternal atopy seemed to be protective, there was no association between allergens and bronchiolitis severity, although 25% of households had elevated allergen levels. Black infants demonstrated less severe RSV bronchiolitis than their white counterparts. Multivariate analysis revealed age, race, maternal atopy, and smoking to be associated with severity of RSV bronchiolitis. Conclusion. The severity of RSV bronchiolitis early in life seems modified by postnatal maternal cigarette smoke exposure and atopy and age of the infant, not by levels of allergens in the home environment. Pediatrics 2005;115:e7-e14. URL: www.pediatrics.org/cgi/doi/ 10.1542/peds.2004-0059; RSV, bronchiolitis, asthma.