Respiratory syncytial virus infection elicits a strong systemic and airway immune response, involving neutrophils, natural killers, dendritic cells (DCs), macrophages and monocytes, eosinophils, T lymphocytes, and inducing the release of several pro-inflammatory cytokines and chemokines (33).

Primarily, RSV targets nasal epithelial cells that release pro-inflammatory mediators and recruit immune cells, such as monocytes-macrophages and DCs (33). Monocytes play two crucial roles: they induce the release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, IL-1, IL-6, IL-8, IL-10, and IL-18; and promote a Th2-impaired immune response with a parallel decrease in lymphocyte maturation and interferon (IFN)-γ production, and a marked release of IL-4 and IL-13 (34). Recent findings suggest that the human innate lymphoid cells (ILCs), especially the type 2 ILCs (ILC2s), promote also the release of IL-4 and IL-13 with a further enhance of the Th2 immune response (33–35). Moreover, the Toll-like receptors (TLRs) present on the membrane of monocytes, trough the interaction with the RSV F protein, induce an enhanced binding of environmental lipopolysaccharides to airway epithelium, a mitogen-activated protein kinase (MAPK) activation, and a further pro-inflammatory cytokine production [(34, 35), Figure 1].

The RSV G protein affects the innate immune response by binding the motif that resembles the CX3C chemokine fractalkine (Fkn). Mutation or deletion of the CX3C-Fkn motif is associated with higher production of IFNs and TNF-α in response to RSV infection (36).

The SH protein is able to activate the inflammasomes which recruit and activate caspase-1, which, in turn, processes pro-IL-1ß and pro-IL-18 to their active forms (37). Moreover, through inhibition of TNF-α signaling, SH protein delays cellular apoptosis (37).

Through NS1/2, RSV blocks the release and acitivity of type I and III IFNs (38). The crucial role of NS1 and NS2 is confirmed by the evidence that the NS genes' deletion significantly reduced RSV replication in IFN-competent cells but not in IFN-deficient cells (39). Moreover, NS1 and NS2 inhibited the IFN-signaling pathway and the formation of “NS-degradasome,” a complex with a protease/proteasomal activity involved in the suppression of IFN signaling (38).

After 4–7 days of infection, the adaptive immune response is activated; however, studies revealed an impairment in T cells response, DCs activity, and T–DC cells interaction, leading to an ineffective memory T cell response to counteract RSV infection (33, 34). Systemic T cell lymphopenia, especially in CD8+ and CD4+, has been reported in patients with early RSV infection compared to convalescence and in uninfected individuals (33, 34). Moreover, an inverse and significant correlation bewteen T cells count and RSV infection severity has also been documented (33, 34).

Given the G and F proteins, RSV elicits the adaptive immune response by inducing the synthesis of RSV-specific antibodies, immunoglobulin (Ig)A and IgG. The RSV-specific IgA are responsible for the defense of the mucosal surfaces, and, moreover, they downregulate the severity of the first infection as well as prevent the reinfection of the upper respiratory tract (40). The RSV-specific IgGs, produced after the first infection, are involved in the viral clearance (41). However, given to the high variability and glycosylation, RSV can change the G protein profile and escape the immune response. By binding the RSV-specific-IgGs, the soluble form of the G protein reduces the serum concentrations of RSV-IgG (42). Moreover, RSV F and G proteins inhibit mitogen-induced T-cell proliferation and decrease T cells functions (39). Lastly, RSV NS1 and NS2 proteins negatively impact the DC maturation into monocyte-derived DCs and affect their ability to interact with T-cell, resulting in a delay in the acquisition of T-cell memory, thus, in a weak adaptive immune response causing susceptibility to reinfection with RSV throughout life (38).

From the upper respiratory tract, the virus moves to the lower airways, where it mainly targets ciliated cells and alveolar type II (ATII) cells.

In response to RSV infection, several changes occur at the airway epithelium. It produces cytokines and chemokines that modulate the influx of inflammatory cells into the infected lung tissue. Higher are the cytokines and chemokines levels in the respiratory tract secretions, and more severe is the RSV infection severity. Moreover, RSV, via the action of NS2 protein, induces epithelial cell shedding, which, in turn, accelerates the clearance of the virus-infected cells from airway mucosa but contributes to acute obstruction of the distal airways (43). Also, following the infection of basal cells, RSV promotes the IFN-mediated formation of epithelium with a profound loss of ciliated cells (44).

Intraepithelial DCs, alveolar type I (ATI) cells, basal epithelial cells of the bronchial epithelium, and airway smooth muscle (ASM) cells can also be infected by the virus (40). The RSV-infected ciliated cells release pro-inflammatory cytokines such as TNF-α, IL-33, and thymic stromal lymphopoietin (TSLP), which, in turn, promote a Th2-mediated inflammatory response and the recruitment of neutrophils and eosinophils (45). The RSV activates the neutrophils expressing specific activation markers, such as CD11b, CD18, and CD54, and induces the release of neutrophil elastase by neutrophils. Moreover, the neutrophil apoptosis and neutrophil extracellular trap (NET) are active during infection, and the peak of these activities coincides with the maximum in the viral load and clinical severity (46). Similarly, eosinophils are activated by the RSV and the high levels of leukotriene C4, eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) detected in the respiratory tract in RSV bronchiolitis support their role during the acute phase of RSV infection (47).

Respiratory syncytial virus may also modulate the human ASM (HASM) function by decreasing the synthesis of cyclic adenosine monophosphate (cAMP) and affecting the ß-2 adrenergic receptor (ß-2AR) functions (48). ß-adrenergic receptors (ß-AR) are transmembrane glycoprotein structures belonging to a major receptor family. They are coupled with guanine nucleotide (GTP) binding proteins (G proteins) and classified in the following three subtypes: ß-1, ß-2, and ß-3 (49). Looking specifically to the ß-2ARs, the latter are coded on chromosome 5 and expressed on epithelial and endothelial cells; eosinophils, lymphocytes, and mast cells; skeletal and uterine muscles; mucous glands, and, predominantly, ATII cells and ASM [(49), Figure 1]. The ß-2AR, existing both in activated and inactivated form, is composed of eight alpha helices; three of which are extracellular, and five intracellular. ß-2 adrenergic receptor is attached to the cellular membrane and transmits the signal intracellularly through heterotrimeric Gs proteins, consisting of alpha, beta, and gamma subunits (49). The catecholamines, such as epinephrine and norepinephrine, are responsible for ß-2ARs stimulation. Additionally, synthetic compounds, known as ß-2AR agonists, and classified in accordance to their duration effects into short-acting, long-acting, and ultra-long-acting drugs, have been tought to stimulate ß-2ARs selectively (50). Following the binding of the agonist ligand to the ß-2AR, the alpha subunit of the Gs protein stimulates the conversion of adenosine triphosphate (ATP) into cAMP, which, in turn, trough the catalytic subunit of protein kinase A enzyme, reduces the intracellular Ca²⁺ concentration, leads to smooth muscle relaxation, and prevents muscle contraction (50). Given their properties, the ß-2AR agonists are part of an effective therapeutic approach to relieve acute airway obstruction, such as during asthma exacerbation; however, they appear less effective when airway obstruction is caused by RSV infection (51). Despite evidence have shown the presence of fully functional ASM also in the early years of life (52, 53) as well as the efficiency of ß-2AR agonists also in newborns and young children (54–56), several clinical trials have failed to demonstrate a clinical benefit of ß-2AR agonists in infants suffering from RSV-mediated bronchiolits (51, 57).

Firstly, Moore et al. (48) investigated the potential influence of RSV on ß-2AR responsiveness by evaluating the isoproterenol (ISO)-cAMP formation, the ß-2AR density, and the Gi expression in HASM cells incubated with RSV. Their findings showed that RSV-infected HASM cells inhibited the ISO-induced cAMP production in a time- and dose-dependent manner and induced a reduction in the ß-2AR density (48). Supporting this evidence, authors showed that RSV could induce an airway insensitivity to ß-2AR-agonists, both directly and indirectly, by inducing heterologous keratinocyte cytokine (KC)/CXCR2-mediated desensitization of epithelial ß-2AR (58, 59). Interestingly, the ß-2AR desensitization occurs in the absence of internalization or degradation of the β2-AR as it results from receptor uncoupling due to phosphorylation by GRK2 (60). More recently, Harford et al. (61) investigated the density and activity of ß-2AR in primary HASM cells derived from pediatric lung tissue with RSV infection compared to non-infected control cells. Their findings showed that RSV induced simultaneously more effects, including a proteasome-mediated cleavage of ß-2AR, a ß-2AR ligand-independent activation of adenylyl-cyclase, and a decrease in cAMP release compared to the control cells, and, lastly, increased intracellular concentrations of Ca2+ resulting in ASM cells contraction (61). Lastly, another explanation for the lack of effectiveness of ß-2AR agonists in infants suffering from RSV infection could be due to the fact that RSV not only induces muscular constriction (bronchospasm) but also impacts the bronchiolar caliber, inducing lymphoid hyperplasia, edema, and mucous plugging, promoting an additional extrinsic compression. Thus, administering ß-2AR agonists did not affect the RSV-mediated airway obstruction (61).

Although human studies are essential to assess or refute data from experimental models, many of RSV's behaviors have been reproduced and replicated in the murine models, as they are highly susceptible to RSV infection, permissive to viral replication, and are strictly reflecting the virus and specific T and B cells interactions. In infected animals, RSV infection causes pulmonary damage similar to that observed in humans, featured by degeneration of nasal epithelial mucosa, peribronchiolitis, interstitial pneumonitis, and perivasculitis (10, 11). Accordingly, several studies in animal model systems, firstly, highlighted the key role of Th2-polarized response in the immunopathogenesis of RSV-induced airway inflammation (10, 11). Later, an “asthma-promoting” effect of the RSV infection, regardless of atopic status, has also been postulated (90). Studies conducted on Balb/C model showed that a population of IFN-γ-secreting CD8+ T cells, potentially attenuating the pathogenic Th2 host response to the RSV G-protein, was involved in the RSV-induced airways inflammation (91).

Authors postulated that the age at first infection determined the type of cytokine production and, consequently, the disease patterns during reinfection (12). To investigate the rechallenge, mice were infected at 1 day or 4 or 8 weeks of age and reinfected at 12 weeks. While neonatal priming produced a more severe inflammatory cell recruitment, such as Th2 and eosinophils, delayed priming led to an increased IFN-γ production and a less severe disease in later life. These results showed the crucial importance of the age at the first infection in determining the outcome of reinfection and suggested that the environment of the neonatal lung is a major determinant of cytokine production and disease patterns in later life (12). In vitro studies have also shown that IFN-γ activates eosinophils, prolongs their survival and promotes the synthesis of leukotrienes from these cells. Considering this evidence, Wedde-Beer et al. postulated that leukotrienes, originating from the interaction between P-containing nerves and mast cells, may be important mediators of RSV-induced airway inflammation (92). Accordingly, rats were inoculated at 2 or 12 weeks of age with RSV or virus-free medium and treated with montelukast or its vehicle starting 1 day before inoculation. The authors reported greater microvascular permeability in the intrapulmonary airways of RSV-infected rats not receiving montelukast treatment compared to the control group. Moreover, a significant increase in 5-lipoxygenase-encoding mRNA and cysteinyl leukotrienes levels and mast cells was detected in the lung tissues of RSV-infected rats, suggesting that the increase in vascular permeability might be promoted by mast cells-derived leukotrienes (92).

The potential effect of the RSV-induced upregulation of NGF must also be considered as a pathogenic mechanism in the onset of non-atopic asthma. Because NGF is released from airway epithelial cells, it increases the release of substance P and other tachykinins from adult sensory neurons and induces sensory hyperinnervation in the airways of transgenic mice. Substance P, in turn, activates mast cells releasing leukotrienes, which further sensitize C-type neurons to release neurotransmitters, thereby reactivating the mast cells and creating a vicious circle contributing to an exaggerated inflammation of the lower respiratory tract (92). In a mouse model, the expression of NGF, trkA, and p75 declined with age, but the RSV increased their levels both in weanling and adult rats. Confirming the role of the NGF and its receptors as major determinants of neurogenic inflammation in RSV infection, authors also reported that exogenous NGF upregulated NK1 receptor expression in the lungs and, on the contrary, the anti-NGF antibody inhibited NK1 receptor and, thereby, the neurogenic inflammation in RSV-infected lungs (86). The evidence that NGF expression was inversely correlated with the age, supported the hypothesis that this neurotrophin is critical for the neuronal plasticity; thereby, variations in its expression can result in permanent changes in sensorineural lung pathways further contributing in airway hyperresponsiveness and asthma susceptibility (93). These findings were confirmed by Piedimonte et al. (79) that showed an increase in NGF and neurotrophin receptor expression in early life during RSV infection and a RSV-related abnormal remodeling of neuronal networks in the respiratory tract, resulting in bronchial hyperreactivity and airway obstruction. Interestingly, the neurogenic inflammation and the bronchial hyperreactivity were long lasting in mice up to 60 days after intranasal inoculation of RSV (94). Confirming these findings, animal data revealed that the RSV-induced airway hyperreactivity was long-lasting for weeks after the inoculation of the virus (95–97). This protracted inflammatory response may be due to the persistence of viral genomic in mouse lung tissue, which has been demonstrated to last for at least 67 days following RSV inoculation (95–98).

New data support the Th17 cell differentiation during RSV infection and Treg airway accumulation during RSV clearance (99). In a mice model, authors found that RSV infection, through activation Notch-1/DLL3, increased the mRNA expression of IL-17A and IL-17A/Foxp3 and Treg levels in the hilar lymph nodes and mesenteric lymph nodes. In contrast, the mRNA expression of IL-4 and other Th2 cytokines was unchanged (100, 101).

Recently, it has been reported that RSV infection contributes to the onset of asthma in later life by inducing High Mobility Group Box-1 (HMGB1), as a result of necroptosis, a programmed cell death of airway epithelial cells (102, 103). The inhibition of necroptosis decreased the severity of bronchiolitis by reducing viral load, prevented the airway epithelial cells remodeling, and the asthma development in later life (102, 103).

In addition to the immune dysfunction and neurogenic inflammation, non-atopic asthma would be the result of an impaired relationship between epithelium and mesenchymal structures. An exaggerated release and responsiveness to trophic factors and a subsequent abnormal growth of smooth muscle, nerves, and blood vessels are considered crucial events in remodeling the airways. The barrier dysfunction could enhance the sampling of luminal antigens by intraepithelial DCs, and facilitate translocation of inhaled particles, allergens, bacterial and viral pathogens through the lung, resulting in an inappropriate immune response and airway inflammation (104, 105).

The integrity of the airway epithelial barrier is regulated by several mechanisms, including the assembly of the epithelial apical junctional complex (AJC), which are composed of apically located tight junctions (TJs) and underlying adherens junctions (AJs), also containing adhesion, scaffolding, signaling, and cytoskeletal proteins (104). The TJs limit the passage of ions and uncharged solutes thanks to their adhesive properties. Three major types of transmembrane proteins are described: (1) members of the claudin family, (2) the TJ-associated MARVEL proteins (TAMP) family, which includes occludin, tricellulin, and Marvel D3, and (3) immunoglobulin-like proteins, which include junctional adhesion molecule A (JAM-A) and coxsackievirus and adenovirus receptor (CAR) proteins (104, 105). The AJs are involved in starting and maintaining of epithelial cell–cell contacts, and enabling TJ assembly. The E-cadherin and nectins are the main transmembrane adhesion proteins involved in forming epithelial AJs, cell–cell adhesion, cell signaling, proliferation, and differentiation. The cytoplasmic side of TJs is organized by multifunctional scaffolding proteins of the zonula occludens (ZO) family, whereas β-catenin, α-catenin, and p120 catenin form a complex with the cytoplasmic domain of E-cadherin (106). C57BL/6 mice, intranasally inoculated with RSV, showed a significant peribronchial inflammation compared with non-infected controls and UV-inactivated RSV-inoculated animals. Moreover, RSV infection increased the permeability of the airway epithelial barrier, decreased the expression of several TJ proteins, and prevented the accumulation of cleaved extracellular fragments of E-cadherin in BAL and tracheal epithelial cells (107). Another study found that RSV infection led to decreased mRNA expression of claudin-1 and occludin in lung samples of wild-type BALB/c mice (108). These studies supported the evidence that RSV induces a AJCs disorganization and dysfunction, and it was likely a result of cortical F-actin cytoskeletal remodeling, which is, in turn, is regulated by Protein kinase D (PKD)-mediated phosphorylation of cortactin, an actin-binding protein that regulates F-actin dynamics between polymerization and depolymerization steps during plasma membrane remodeling (109).

Globally, an abnormal remodeling of the airways substructures, especially involving the mucosal neural network, occurs when the airways are infected during critical developmental windows in early life. However, because these changes seem to be the result of a transient derangement in airway development, these modifications would return to baseline condition when the virus is cleaved, thereby, justifying the evidence that some children with previous RSV infection do not develop asthma. On the other hand, RSV-associated long-term consequences have been reported in neonatal mice, such as persistent mucus production, subepithelial fibrosis, and increased collagen deposition, contributing to promoting and maintaining airway remodeling also in later life (109–111). Moreover, 30 days after inoculation, neither evidence of active RSV infection nor immunostaining and no viral nucleic sequences were detected in a mouse model. In contrast, the substance P in the lung and the capsaicin-induced plasma extravasation were significantly higher in the infected mice compared with pathogen-free rat, supporting the evidence that the sensory innervation of airways remain susceptible to the proinflammatory effects even if RSV infection is disappeared (112). In conclusion, RSV seems to exert a dual influence: in short-term postsynaptic manner, deriving from up-regulation of the substance P, and in long-term presynaptic manner, by remodeling sensory innervation (112).

Similarly to other viruses, RSV shows a close relantionship with the development of wheeze and asthma in later life, regardless atopic status (2, 113). Several birth cohort studies reported that one-third of children with RSV developed recurrent wheezing and asthma, but not allergic sensitization (90, 114, 115). In line with these findings, the Tucson respiratory study reported that children with a previous RSV infection were commonly experiencing wheezing and lower forced expiratory volume at first second (FEV1) by the age 6 years (90). Moreover, the risk decreased significantly with the age and it was not significant by age 13 (90). There was not any significant relationship with atopic status development; as sensitization did not appear as a risk factor for infants suffering from RSV-caused wheezing (90, 116). By enrolling 95,310 children by Carroll et al. (117) and Wu et al. (9), the Tennessee Asthma Bronchiolitis Study (TABS) suggested a causal relationship between severe RSV infection and the onset of asthma by age 5.5 years. They also reported that during the winter months was recorded the greatest number of bronchiolitis-related hospitalizations. Moreover, the authors observed that children born 4 months prior to the annual peak of bronchiolitis-related hospitalizations were 29% more likely to develop asthma compared with infants born 1 year from this time point. This trend was similar troughout the 5-year study although the peak of bronchiolitis-related hospitalizations shifted by up to 6 weeks. Furthermore, if on one side the authors did not state if children were infected with a specific virus, including RSV, on the other hand, up to 70% of severe bronchiolitis were due to RSV infection (118). In accordance with several longitudinal studies, these changes appears to be transient rather than persisting over the time. Pullan et al. (119) showed that children younger than 1 year of age and with severe RSV infections experienced wheezing primarily during the first 4 years of life, while, by age 10 years, no significant difference in incidence are reported compared to the control group. Similar results were observed in the Tucson Children's Respiratory Study of 1,246 children as children, who experienced a severe RSV infection by up to 3 years of life, were at a significantly increased risk of wheezing at ages 6 and 11 years. However, by age 13 years no significant differences were recorded compared to the control group (120). These data were not confirmed by the longitudinal study by Sigurs et al. (121). Authors described a significant increase in asthma by age 13 years; probably, the differential findings reported in the studies above reported are due to several factors involved in the RSV-asthma relationship, including genetic variability among investigated cohorts as well as the difference in pathogenicity of circulating RSV strains (121).

In two controlled, randomized, double-blinded trials performed in preterm infants receiving palivizumab to prevent RSV bronchiolitis, authors reported that the palivizumab administration was protective against recurrent wheeze up to 3 year of life; supporting the evidence that an early-life RSV bronchiolitis can have a continuing causal impact beyond infant infection (122, 123). Confirming these findings, authors demonstrated that RSV prophylaxis in non-atopic children decreased the risk of recurrent wheezing up to 80% and, interestingly, it did not have effects on infants with a positive family history for atopy (124). Later, a Finnish study reported a significant association between RSV infection and self-reported asthma in adolescents aged from 15 to 18 years (125). In a 7 year follow-up study enrolling 127 steroid-naive children, authors reported that the first severe RSV/rhinovirus–negative wheezing episode was a risk factor for developing non-allergic asthma, together with the age of first episode of wheezing <12 months, and exposure to tobacco smoking (113). Despite this increasing body of evidence supporting a relationship between RSV infection and non-atopic asthma, it remains unclear whether the virus contributes really to the onset of asthma or is simple trigger in subjects with asthma susceptibility (126). Authors hypothesized that probably the association between RSV infection and asthma could be also due to a shared genetic predisposition, as reported in a large population of 8,280 twin pairs in Denmark (126). Furthermore, genetic polymorphisms in the gene encoding IkBa, a negative regulator of NF-kB, have been recently associated with RSV and asthma (127). The gain-of-function polymorphisms in the promoter region of IL-8, a chemokine secreted by epithelial cells and macrophages, lead to an increase in RSV infection severity and in developing wheezing and asthma (128–130). Polymorphisms in other chemokines, such CX3CL1, CX3CR1, and CCL5, seem further predispose to asthma onset (131, 132). Mainly, CX3CR1, expressed in human airway epithelial, binds RSV G protein and mediates the viral entry in the host cells; thus, CX3CR1 mutations and/or complete or partial deletion of RSV G protein results in a less efficient viral entry and a decreased virus replication (133).

Gain-of-function polymorphisms in IL-4 and IL-13 cytokine genes as well as deficit in IFN-γ expression have been also associated with developing wheezing during at the age 6 years (134, 135).

Several mechanisms causing RSV-mediated long-term pulmonary effects have also been investigated. The effects of maternal RSV infection on postnatal offspring immunity and neurotrophins release, ASM contractility, and development of wheezing and asthma are still under debate. However, the recent discovery that viral antigens can impact postnatal immunity in vivo model and negatively affect the perinatal period in humans showed the possibility that a challenge in immunity can ocurr after postnatal virus (136, 137). In utero exposure to RSV caused a chronic airway dysfunction by influencing cell-mediated host immunity, local NGF expression, neurotransmitters release and neuronal hyperreactivity, and ASM contractility during RSV-mediated LRTIs in early-life (66, 138–140). Neurotrophin levels and immunoreactivity for neurotrophin-receptor were found to be strongly increased in the BAL fluid of mechanically ventilated infants with severe RSV infection (66). Children with severe RSV-bronchiolitis are reporting an increased bronchial responsiveness and altered epithelial immune response to the viral agents compared with children without bronchiolitis (141). It seems that in subjects with chronic obstructive pulmonary disease, the RSV can persist contributing to the pathogenesis of stable disease (142). Smyth et al. (143) studied the behavior of mediators of lymphocyte activity [IL-4, CD25, and soluble intercellular adhesion molecule 1 (sICAM-1)] in 94 children affected by RSV-mediated bronchiolitis. Authors reported that the serum CD25 levels were elevated during acute infection and they remained raised during convalescence up to 150 days after infection, also in absence of acute infection (143). This finding was in contrast to the rapid decline in serum CD25 levels recorded in children after acute infection mediated by other viral agents, such as measles or dengue fever (143). Thereby, RSV could mediate a persistent inflammatory response in the airway that continues for longer than is generally believed. Similarly, Pala et al. (144) compared the production of cytokines of children 7 years after acute RSV bronchiolitis to healthy children. The post-bronchiolitic children showed a significant response in cells producing IL-4, suggesting the role of this cytokine in the RSV-mediated long-term airway effects (144). Moreover, since RSV induced a strong release of IL-10, IL-11, and prostaglandin E₂ (PGE₂), molecules well-known for their immunosuppressive effects, authors hypothesized that these mediators might be responsible for the delayed protective RSV specific immune response, further contributing to RSV-mediated long-term damage in the airway (145). More recently, Bertrand et al. (146) reported that the cytokine (IL-3, IL-4, IL-10 and IL-13) and chemokine (IL-1β, IL-6, TNF-β, MCP-1/CCL2, MIP-1α/CCL3, and IL-8/CXCL8) levels in the BAL and nasopharyngeal aspirates of children with RSV-mediated bronchiolitis were significantly higher compared to control group, and, moreover, a direct correlation between IL-3 and IL-12p40 levels and development of wheezing later in life was also observed.

Other possible mechanism might include the “hitchhike effect” yet described in patients suffering from chronic bacterial colonization. Specifically, it seems that the neutrophilic airway inflammation following a chronic colonization could contribute to development asthma in the pediatric population (147).

Probably, the development of RSV-induced asthma requires a “two-hit” model (148) featured by the co-existence of at least two among individual (genetic, immune response in the lung environment), developmental (lung remodeling), and environmental (exposure to inhalants) factors (Figure 2). Whether only one factor is present, the patient will not develop chronic airway inflammation and asthma; conversely, whether two factors are coexisting, the patient will report long-term symptoms and/or asthma (148). This might explain why not all children with severe RSV bronchiolitis develop asthma as well as why other children with early wheezing show resolution of their illness by their adolescence (148).