Ricardo Pinto

T helper 1/T helper 2 cytokine imbalance in respiratory syncytial virus infection is associated with increased endogenous plasma cortisol.

OBJECTIVE. Cellular immunity has classically been described as the defense mechanism for viral infections. The development of cellular or humoral immune responses will depend on a repertoire of cytokines produced by numerous cells, including CD4+ and CD8+ 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 γ (IFN-γ), 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-γ 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°C for cortisol assay. In the supernatant of the cultured peripheral blood mononuclear cells (PBMCs), we quantified IL-12, IFN-γ, IL-4, IL-5, and IL-10. Lymphocyte phenotypes and CD4+ and CD8+ T cells with intracellular IL-4, IL-10, and IFN-γ 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-γ production by PBMCs and a fall in the percentage of CD4+ T cells expressing IFN-γ 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-γ 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-γ 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 CD4+ and CD8+ 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-γ 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-γ 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.

Aumento de interleuquinas proinflamatorias y de cortisol plasmático en bronquiolitis por virus respiratorio sincicial: relación con la gravedad de la infección

BACKGROUND An increased inflammatory innate response may play a role in pathogenesis of respiratory syncytial virus (RSV) infection. AIM To quantify pro-inflammatory cytokines (IL-6-IL-8, ÍL-2-P and TNF-a) in nasopharyngeal aspirate (NPA) and plasma, and plasma cortisol in previously healthy infants with RSV bronchiolitis. PATIENTS AND METHODS We studied 49 infants aged less than one year of age with RSV bronchiolitis and 25 healthy controls. Severity was defined using a previously described modified score. We quantified interleukins in NPA and plasma by flow cytometry and plasma cortisol by radioimmunoanalysis. RESULTS Among patients with RSV bronchiolitis, 25 were classified as severe and 24 as moderate or mild. Significantly higher levels of IL-6 and IL-8 in NPA and plasma and IL-lfi in NPA were found in children classified as severe, when compared to those with moderate or mild disease and controls. There was a positive correlation between IL-6 and cortisol in plasma (r = 0,55; p < 0,0001) and both were correlated with the severity of the disease. CONCLUSIONS RSV bronchiolitis severity was associated with higher levéis of inflammatory interleukins and plasma cortisol.

NUEVOS VIRUS RESPIRATORIOS EN PEDIATRÍA

RESUMEN Las infecciones respiratorias continúan siendo la mayor causa de morbimortalidad en pediatría. Los virus constituyen los agentes infecciosos más frecuentes, actualmente con los avances en las técnicas diagnósticas se han sumado “nuevos virus” entre los que destacan Metapneumovirus (MPVh), Bocavirus (BoVh) y Coronavirus (CoVh), que son el objetivo de este artículo. SUMMARY Acute lower respiratory infection is still the leading cause of global morbility and mortality in children. Viruses are the most frequent pathogen, currently the most common viral etiology VRS, although recently due to advances in diagnostic techniques new viruses have been added, that includes Metapneumovirus (hMPV), Bocavirus (hBoV) and Coronavirus (hCoV), which are the purpose of this review.