Soluble Adhesion Molecules and Cytokines in Children Affected by Recurrent Infections of the Upper Respiratory Tract

Abstract

The objective of this study was to compare plasma levels of soluble adhesion molecules and Th1-Th2 type cytokines in 44 children with frequently recurrent respiratory infections (FRRI) of upper airways, defined as having nine or more episodes per year, and in 34 children without recurrence; all subjects were followed-up for 12 mo. The viral etiology was determined by cultures from nasal, pharyngeal, and ear secretions, using PCR and immunofluorescence. Plasma levels of five soluble adhesion molecules (E-selectin, P-selectin, L-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) and interferon (IFN)-␥, IL-12, IL-4, and IL-10 were measured in patients and in 15 healthy controls using sandwich ELISA. During acute phase, all patients showed significant increase in plasma levels of soluble adhesion molecules; during the followup, the levels were greater in children with FRRI. A difference of cytokine profile was demonstrated between the patients with and without FRRI: an increased IL-4 and IL-10 release with decreased levels of IFN-␥ and IL-12 suggested a skewing into Th2-type response, in patients with FRRI. This pattern persisted during the follow-up. In patients without recurrence, an increased IFN-␥ and IL-12 release, together with decreased levels of IL-4 and IL-10, showed a skewing into Th1-type responses; in the follow-up these cytokines reached normal values. In conclusion, the abnormal levels of all examined parameters in children with FRRI may reflect the persistence of an inflammatory microenvironment in the airways and an activation of the immune system that may contribute to the frequently recurrence of the respiratory disease. Infections of the URTI are the most common cause of viral morbidity in children. They represent the most frequent managed problem in general pediatric practice (1) and are responsible for more than one third of school absences (2). Many different immunologic problems can concur to the development of respiratory infections (3). Disorders of the aspecific humoral and the specific cellular defense are the principal cause of inflammation in the upper respiratory diseases (4). The recruitment and activation of inflammatory cells at the site of infection involve the expression of leukocyte and vascular adhesion molecules and the generation of pro-inflammatory cytokines, which contribute to the injury of lung epithelial and endothelial barriers (5). An important role in the early transient adhesion phases of leukocytes is mediated by the selectin family, which includes three distinct carbohydrate receptors expressed by either endothelial cells (E-selectin), leukocytes (L-selectin), or platelets and endothelial cells (P-selectin) (6). ICAM-1 and VCAM-1 are membrane glycoproteins, belonging to the immunoglobulin superfamily; ICAM-1 are widely expressed on respiratory epithelial cells, monocytes, macrophages, dendritic cells, and, together with VCAM-1, on vascular endothelial cells (7,8). These adhesion molecules, after a proteolytic cleavage, are found as so...

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“…Thirdly, we cannot infer on the relative contribution of upper airway tissues such as tonsils and adenoids to the systemic cytokine levels (44), an issue that clearly merits further investigation. Finally, the levels of IL-10 found herein are somewhat lower than those previously reported (45,46). These differences may simply reflect slightly different methodologies in sample processing or in the assay itself.…”

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“…Increased levels of IFN-γ have also been shown to enhance macrophage function and secretion of IgG2a, thus propagating and sustaining immune modulating signals [22,23]. Reduced plasma levels of IFN-γ have been found in children with recurrent infections of the upper respiratory tract and in animals lacking the transcription factor T-bet, which are known to be highly susceptible to respiratory infections [11,12,24,25]. Release of these cytokines during a respiratory viral infection is also known to affect the duration of the disease.…”

“…These cytokines are thought to comprise one of the principal host defense mechanisms against many intracellular pathogens including respiratory viruses [8][9][10]. Studies on children and adults, and CD4 −/− mouse models have demonstrated that an attenuated production of these cytokines relates with a diminished cell mediated immune response to respiratory virus, loss of cytolytic activity of CD8 + lymphocytes, reactivation of latent infection and consequently recurrence of respiratory viral infections [11][12][13]. In addition, in a study relating stress levels to the frequency of URIs, both low NK cell number and cytotoxicity of NK cells was found to be associated with increased risk of URIs [14].…”

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“…Our findings could therefore be due to a bystander effect of an inflammatory microenvironment created by recurrent or persistent GABHS infection. Indeed, soluble adhesion molecules have been reported as persistently elevated in recurrent paediatric upper respiratory tract infections of viral origin [28], and the possibility of a subclinical GABHS pharyngeal carriage has been thoroughly documented [29]. However, if this was the case, one would expect adhesion molecule titers to correlate with ASOT or anti-DNAse B titers, both highly specific markers of an ongoing immune response to this agent.…”