Atopic children are a special population and atopy is often accompanied by airway hyperresponsiveness. In our study, we compared the clinical characteristics of atopic children with Adv-associated pneumonia to non-atopic children. We found that there was no difference in the duration of fever between the two groups. In atopic children (with Adv or without Adv infection) with pneumonia, the number of cases with severe cough and wheezing were significantly higher compared with those without atopy, and the number of patients with wheezing during hospitalization was significantly different. Therefore, we concluded that, after Adv infection, atopic children are more prone to severe cough and wheezing than non-atopic children. The reason for wheezing in atopic children with Adv pneumonia may be related to the exposure of the damaged airway epithelium neurons and increased airway sensitivity (20). Studies have shown that leukotriene E4 is strongly associated with episodes of acute wheezing in preschool children, and that higher levels of leukotriene E4 are present in the airways of atopic children than in the airways of non-atopic children (21); therefore, atopic children are more prone to wheezing. In contrast, it may also be related to the characteristics of Adv infection. Firstly, damage to the airway mucosa after Adv infection and the release of inflammatory mediators can cause bronchial and bronchioles mucosal edema, congestion, necrosis and shedding, necrotic obstruction of the lumen, and bronchial wall edema and thickening, resulting in vasospasm and muscle contraction. Because airway epithelial cells are damaged, its defence capacity is reduced, resulting in allergens invading the airway more easily (14), indirectly promoting airway inflammation, and further narrowing the airway lumen due to wheezing. On the other hand, toll-like receptors (TLR) and intracellular virus sensors such as protein-catalysed enzymes (protein kinase double-stranded RNA, PKR) in airway epithelial cells (15) induce MUC5AC production, leading to airway epithelial mucus hypersecretion, and blockage of the lumen. After infection, the HAdv can interact with host cells and extensively participate in the functions of host cell proliferation, apoptosis, autophagy, and so on (20). Studies have shown that when HAdv infects respiratory epithelial cells, host cells develop adaptive autophagy, which enables immune evasion (21), leading to autophagy dysregulation in host cells. Adv can induce the activation of CD8+T cells through the autophagy pathway, leading to microenvironmental changes in the lung tissue (22). Activated CD8+T cells lead to death of airway structural cells, repeated damage, and repair of the airway tissue, by releasing cytotoxic particles such as perforin and granzyme, and inflammatory mediators such as IFN-γ, IL-10, and TNF-α, and inducing FAS/FASL expression to promote apoptosis. In the airways of atopic children, damaged neurons in the airway epithelia are exposed, increasing the airway sensitivity (23), and leading to more serious epithelial injury, thus making patients more susceptible to wheezing.
The changes caused by Adv pneumonia on the chest CT include lung consolidation, patchy shadows, flocculent shadows, cluster shadows, air bronchograms, and lymph node enlargement. Its effects on the small airways include uneven inflation, mosaic sign, bronchial thickening, and bronchiectasis (22). In the current study, we compared atopic and non-atopic children with Adv pneumonia and found that the percentage of atopic children with small airway lesions was greater than that of non-atopic children. We also compared the baseline characteristics and symptoms of children with pneumonia with and without small airway diseases. We found that in the small airway disease group the number of patients with atopy, severe infection, and family or personal history of asthma were significantly higher than those without small airway diseases. Family history of asthma, personal history of asthma, atopic, severe infection, and Adv infection were independent factors associated with the development of small airway disease on the chest HRCT scan.
Uneven inflation of the lungs is always found on the chest CT of atopic children, and children often experience coughing or wheezing which requires treatment after discharge. The changes in the lung parenchyma, such as lung consolidation, usually recover slowly after discharge and most small airway lesions require atomisation to recover; however, we observed that, even after 1 month, some atopic children had small airway lesions on the chest CT. Some children were still intolerant to sports activities, had post-activity wheezing, and progressed to obliterative bronchitis.
The small airway refers to the airway with an inner diameter ≤ 2 mm, and is one of the smallest visible areas of the lungs. Most of the airways are referred to as bronchioles, belonging to the 12th ~ 23rd branch of the airway (23). There are direct and indirect manifestations of small airway diseases on the HRCT. The direct signs are caused by thickening of the bronchial wall or bronchiectasis, including central lobular nodules, tree bud signs, and bronchiectasis (25). Indirect signs are caused by obstruction of bronchioles, and include mosaic sign and gas trapping (25). In recent years, with advancements in imaging and medical instruments, the rate of small airway lesion detection has increased, especially with the widespread use of HRCT. HRCT imaging of small airway lesions can detect the following: thickening of the bronchiole wall; tree bud sign; mosaic characteristics; and air retention. The mechanism for development of small airway lesions in atopic children may be eosinophilia and an abundance of CD4+T lymphocytes in the small airways compared to larger airways, which results in small airway inflammation (26). Small airway inflammation, airway remodelling, and matrix deposition eventually leads to increased airway resistance, similar to the pathophysiologic changes that occur in the small airways of asthmatic patients (27). In contrast, small airway lesions are also associated with persistent latent infection of the Adv E1A genes. The adenovirus genome is linear double-stranded DNA, containing five early transcription units, namely E1A, E1B, E2, E3, and E4. The viral genome translocates to the host nucleus, and its transcription and expression initiates and facilitates viral replication. E1A is the earliest transcribed gene (28). Studies have demonstrated that the adenoviral E1A DNA and proteins persist in the lung tissue after viral replication stops in the acute infection phase and enables the long-term expression of proteins without the need for replication of the entire virus. The main target cells are bronchial epithelial cells, alveolar epithelial cells, and submucosal cells (29). Studies have shown that enhanced expression of E1A genes can activate the mitogen-activated protein kinase (MAPK) signalling pathway, allowing HAdv to proliferate continuously in respiratory epithelial cells (26). Persistent latent infection of the lung tissue by E1A genes may lead to airway remodelling (30).
There are many limitations to our study. We only considered the influence of atopy on the clinical symptoms of children, and other confounding factors that may also affect the prognosis of children, such as co-infection with respiratory syncytial virus (30), mycoplasma, influenza (31), or influenza mixed infections were not considered. In some patients with wheezing, the use of glucocorticoids to suppress immune responses may have also affected the prognosis of pneumonia, which was not considered in this study. The difference in the timing of treatment for some severe pneumonia patients may also affect their prognosis, which was not considered in this study (32) and warrants further investigation. In addition, we only analysed patients with small airway disease 1 month after discharge, and more research conducted over a longer period of time is warranted.