Bronchiolitis needs a revisit: Distinguishing between virus entities and their treatments

Jartti, Tuomas; Smits, Hermelijn H.; Bønnelykke, Klaus; Bircan, Ozlem; Elenius, Varpu; Konradsen, Jon R.; Maggina, Paraskevi; Makrinioti, Heidi; Stokholm, Jakob; Hedlin, Gunilla; Papadopoulos, Nikolaos; Ruszczynski, Marek; Ryczaj, Klaudia; Schaub, Bianca; Schwarze, Jürgen; Skevaki, Chrysanthi; Stenberg-Hammar, Katarina; Feleszko, Wojciech

suppressing IRF-1 through EGRF activation. [44] [45] [46] [47] While severe RSV bronchiolitis is associated with weaker antiviral innate interferon responses, data on the association between virus genome load and illness severity are discrepant. 47, 48 Furthermore, ineffective inflammatory and adaptive immune responses are important factors that contribute to severe RSV disease. As at birth the immune system is still immature and needs to develop, it depends mostly on the innate immune system in response to toll-like receptor (TLR) ligation and maternal-derived antibodies. At the same time, pro-inflammatory innate immune responses are not very prominent as anti-inflammatory cytokines, such as interleukin (IL)-10 and transforming growth factor (TGF)-beta, prevail since during pregnancy mother's immune system protects the fetus. 49 As a consequence, T helper 1 (Th1) cell skewing cytokines such as IL-12 seem to develop rather slowly in young infants, even in the presence of TLR-ligating viruses and increased type I interferon production. 50, 51 Interestingly, the cytokines IL-6 and IL-23, both potent inducers of IL-17-producing T cells, were found to be increased in TLR-stimulated neonatal cells and neonates were shown to have increased numbers of Th 17 cells ( Figure 4A ). 52 As enhanced pathology following RSV infections is often associated with increased IL-17 production and this cytokine is more prominent in neonates, the presence of this cytokine may contribute to a more severe disease state. 53, 54 In addition, studies in neonatal mice have shown that there is a spontaneous early wave of innate cytokines such as IL-33, a Th 2 skewing cytokine, and a recruitment of innate lymphoid cells (ILC)-2 into the lungs that reach the maximum at day 14 after birth. 55, 56 Therefore, age-specific events in neonatal lungs seem to naturally support the initial development of Th 2 immune responses that combined with a yet ineffective activation of innate immunity and IL-17 being upregulated in young infants, drive mucus hyperproduction and the promotion of severe pathology during early RSV infections. 57 In addition, B-cell function is not yet developed in very young infants (<6 months of age) and it takes more time to generate a sufficient and sustained antibody production. As at very early phase, babies still rely on maternal antibodies, babies born from a mother with high circulating neutralizing antibodies are better protected from severe diseases. 58 This notion has led to the idea of developing a vaccine for RSV that targets pregnant mothers instead of young children. Thus, through vaccinating the mothers, the children would be provided with an increased transfer of protective maternal antibodies against RSV. 59,60