Human adenoviruses (HAdV), specifically serotypes 3 and 7 (HAdV-3 and HAdV-7), are recognized as significant pathogens in the etiology of lower respiratory tract infections (LRTIs) among children (Lu et al., 2013; Chen et al., 2022). These infections pose substantial health concerns, particularly when they manifest in severe forms such as pneumonia (Jain et al., 2015; Xie et al., 2019). These infections not only lead to high rates of hospital admissions but also present a considerable challenge in terms of management and prevention, due to their rapid transmission, potential to cause large-scale outbreaks, and the absence of effective antiviral drugs or vaccines. The situation is further complicated by the variability in serotypes, clinical presentations and the potential for severe complications, including respiratory failure and death. This severity is notably pronounced in densely populated regions such as China, where frequent outbreaks have been highlighted critical areas for healthcare focus and intervention (Xie et al., 2019; Li et al., 2021; Zou et al., 2021; Wang et al., 2022; Liu et al., 2023a).

While the direct impact of these adenovirus serotypes on the severity of disease has been documented more and more (Lin et al., 2017; Liu et al., 2022; Wang et al., 2023), a critical gap remains in understanding how co-infections and variations in immune response influence the severity of these infections. This gap underscores the need for in-depth research focused on the interplay between co-infecting pathogens and the host’s immune system, which can significantly affect disease outcomes. Infections with HAdV not only result in primary disease manifestations but are also frequently complicated by secondary bacterial or viral infections (Mao et al., 2022; Liu et al., 2023b). These co-infections can exacerbate the severity of the respiratory illness, resulting in more severe symptoms, an increased risk of complications, and prolonged hospital stays (Gao et al., 2020; Chen et al., 2024). Moreover, the immune response to these co-infections, which can vary significantly among individuals, especially in pediatric patients, plays a crucial role in the progression and outcome of the disease. A robust immune response might control the spread of the virus and secondary infections more effectively, while an inadequate or overly aggressive response may lead to worse clinical outcomes (Nazir and Metcalf, 2005).

Currently, the pathogenic distribution of co-infections and the immunological status of patients infected with HAdV-3 or HAdV-7 remains poorly understood. This study aims to elucidate the role of co-infections and immune responses in shaping the clinical severity of HAdV-3 and HAdV-7 infections among hospitalized children with LRTIs. Through this research, we bridge a gap in the literature and lay the groundwork for a comprehensive investigation into the complex dynamics of adenovirus infections compounded by co-infecting organisms and the corresponding immunological responses.

The current analysis highlights significant differences in clinical severity and outcomes between HAdV-7 and HAdV-3 infections, with HAdV-7 patients exhibiting a higher incidence of severe symptoms, including prolonged fever, pneumonia, hypoxia, liver damage, and coagulation disorders. Radiological findings further support the clinical observation of a more severe disease in HAdV-7 infections, evidenced by a higher frequency of alveolar or interstitial infiltrates, consolidation, and pleural effusion compared to those in HAdV-3 infections. This is consistent with the understanding that HAdV-7 can lead to more extensive lung involvement and damage, potentially explaining the increased severity and adverse clinical outcomes observed in these patients. Studies have demonstrated that HAdV-7 can lead to more severe respiratory illnesses, often characterized by higher mortality and requiring increased mechanical ventilation and intensive care unit admissions compared to HAdV-3 (Lin et al., 2017; Dai et al., 2020; Wang et al., 2023). Previous studies have indicated that HAdV-7 exhibits more robust replication and triggers an exacerbated cytokine response compared to HAdV-3, resulting in more severe airway inflammation (Fu et al., 2019; Siew et al., 2020). In the current study, higher frequencies of mechanical ventilation and intensive care unit admissions were observed in the HAdV-3 group; however, mortality remained low across both groups. The investigation in current study revealed a higher incidence of immunoglobulin and glucocorticoid use in treating individuals with HAdV-7 compared to those infected with HAdV-3. Intravenous immunoglobulin and/or glucocorticoid treatments are effective in preventing severe adenovirus pneumonia in children (Oliveira et al., 2020; Cai et al., 2023). Corroborating these observations in this study, Li L et al. (Li et al., 2018) demonstrated that strategic glucocorticoid and immunoglobulin use in adenovirus pneumonia treatment effectively reduces complication risks and enhances recovery prospects.

In this study, co-infection rates were notably higher in patients testing positive for HAdV-7 compared to those with HAdV-3. Furthermore, the current analysis indicated a greater propensity for patients infected with HAdV-3 to present with dual infections, whereas those with HAdV-7 infections were more commonly associated with multiple infections. This discrepancy suggests that HAdV-7 may predispose children to a broader spectrum of secondary infections, potentially owing to differences in pathogenic mechanisms and immune evasion strategies between these adenovirus serotypes. A notable aspect of this investigation is the remarkably high detection rate of MP infection in subjects infected with either HAdV-7 (77.1%) or HAdV-3 (32.6%), identifying MP as a predominant co-infecting agent with adenovirus. These findings underscore the importance of considering HAdV-MP co-infections in the initial empirical treatment strategy for pediatric severe community-acquired pneumonia, aiding in the prognosis of HAdV-infected patients. Previous investigations of Chinese children with LRTIs have noted HAdV-MP co-infection rates ranging from 10% to 16% among all children infected with adenovirus (Lu et al., 2013; Chen et al., 2016). A surge to 58% in co-infection rates has been documented in a recent study by Chen Q et al (Chen et al., 2024). The elevated detection rates of HAdV-7-MP co-infections could stem from the selection of more severe cases, an outbreak of MP and HAdV-7 during the study period enhanced sensitivity of molecular assays (Yang et al., 2021; Cheng et al., 2022), and the prolonged presence of MP nucleic acid in the airway (Liu et al., 2019). These findings in current study align with recent literatures that suggests HAdV-MP co-infections significantly impact the clinical severity and outcomes of patients with LRTIs. Individuals with concurrent HAdV and MP infections exhibit prolonged febrile responses and more acute illness than those afflicted by MP alone (Gao et al., 2020; Zhou et al., 2020; Zhang et al., 2021; Zhou et al., 2022; Chen et al., 2024). Co-infection with MP typically results in prolonged fever, indicating that co-infections may delay pathogen elimination and intensify the host’s immune response due to increased internal and external pyrogens (Gao et al., 2020). Co-infected cases of HAdV-MP exhibited more frequent occurrences of lung consolidation, atelectasis, pleural effusion, and multiple lung lobe lesions, indicating that co-infections can exacerbate pulmonary inflammation in children with adenovirus pneumonia through direct damage or indirect immune responses (Wei et al., 2022). HAdV-7 may prolong pathogen clearance duration and exacerbate the host’s immune response, resulting in prolonged inflammation (Chen et al., 2021). Although the precise mechanisms remain unclear, a potential synergistic interaction between MP and other pathogens is suggested (Cimolai et al., 1995). A study analyzing lung microbiota in BALF revealed that HAdV-MP co-infections increase the diversity within groups while maintaining similar species richness, offering insights into potential mechanisms (Zhou et al., 2022). Future research investigating the mechanisms underlying these observations and their implications for treatment strategies is essential. Addressing the challenges posed by co-infections necessitates a multifaceted approach that combines robust diagnostic strategies, comprehensive treatment regimens, and preventive measures to mitigate the burden of HAdV-associated respiratory diseases in children.

This study highlights the differential impact of HAdV-7 and HAdV-3 infections on the immune system’s cellular components in pediatric patients with LRTIs. Comparative analysis between HAdV-7 and HAdV-3 infected patients revealed a notable, albeit not statistically significant, decrease in total lymphocyte counts in the peripheral blood of HAdV-7 infections. The observed reduction in T cell frequencies in the bloodstream may stem from the demise of T cells engaged in combating HAdV-7 or from virus-induced inhibition of T cell production. This observation supports the hypothesis that viral mechanisms, such as direct lymphocyte destruction, impaired proliferation, or migration to infection sites, contribute to the observed lymphocytopenia (Sun et al., 2023). Regarding T cell subsets, current findings indicate a significant decrease in both CD3+ T cells and CD8+ cytotoxic T cells, as well as marginal decrease in CD4+ helper T cells among HAdV-7 infected patients compared to those with HAdV-3 infections. This disparity suggests a pronounced impact of HAdV-7 on the T cell compartment, potentially leading to an imbalance in T cell subsets and ensuing immune dysregulation. This might reflect a distinct immune response strategy against different adenovirus serotypes and suggest that the primary distinctions in immune response are confined to aspects of cellular immunity. These findings are supported by a broader understanding of adenovirus-specific T cell responses in humans, as detailed by Hutnick NA et al (Hutnick et al., 2010). Adenovirus-specific T cells, both CD4+ and CD8+, exhibit a wide range of functionality and can respond to various adenovirus serotypes due to cross-reactivity against conserved hexon regions. Sun J et al. (Sun et al., 2023) reported a significant decline in the percentages of CD3+ T cells and NK cells in patients with HAdV-7 infection, categorized into upper respiratory infection, common pneumonia, and severe pneumonia groups, with the decline being more pronounced in NK cells and CD4+ T cells, but not in CD8+ T cells. Chen WW et al. (Chen et al., 2014) found that patients with severe HAdV-55 infections exhibited significantly elevated levels of IL-17+CD4+ cells and reduced levels of IL-17+CD8+ cells compared to those with asymptomatic HAdV-55 infections. The notable reduction in T cell subsets, accompanied by increased NK cell percentages in HAdV-7 infections, may have implications for understanding the pathogenesis of these infections and developing targeted therapeutic strategies. Future research should focus on further elucidating the mechanisms behind these observations, potentially exploring the role of adenovirus-specific T cell cross-reactivity in shaping the immune response to different adenovirus infections.

To better understanding the molecular and immunological mechanisms underlying the differences between HAdV-7 and HAdV-3, the following research directions are proposed. First,

further investigation into the viral factors and host cell receptors involved in the differential immune response to these two adenoviruses could provide valuable insights. A comparative study of viral proteins and their interactions with immune cells may reveal key determinants of immune modulation. Second, a comprehensive exploration of the cytokine and chemokine profiles associated with HAdV-7 and HAdV-3 infections is essential, particularly in relation to their roles in driving inflammatory responses and exacerbating disease severity. Such studies will be crucial for elucidating the divergent clinical outcomes. Additionally, leveraging genomic and proteomic approaches to identify host genetic factors and protein interactions that contribute to the severity of HAdV-7 infections will be important. Finally, the development and use of animal models to investigate HAdV-7 and HAdV-3 infections will enable a more detailed examination of in vivo immune responses and the pathophysiological mechanisms contributing to the observed differences.

This study has several limitations. First, its retrospective nature. Second, the relatively small sample size may not fully represent the broader population affected by HAdV-3 and HAdV-7 associated LRTIs. Third, the inability to detect viral load and the presence of HAdV in blood samples limits understanding of the virus’s role in clinical pathogenicity. Particularly in cases of co-infection with other respiratory viruses, the precise contribution of HAdV to disease severity remains unclear. These limitations indicate the need for multicenter, longitudinal studies with larger and more diverse populations to confirm and expand upon these findings.

In conclusion, hospitalized children with HAdV-7-associated LRTIs exhibit greater severity, multiple infections, higher incidence of co-infections with MP, and significant potential for greater cellular immune dysregulation compared to those with HAdV-3 infection, indicating a more severe clinical course and distinct pathogenic profiles. These findings underscore the importance of continuous targeted surveillance, accurate diagnosis, innovative therapeutic interventions, and tailored clinical management strategies to mitigate the impact of these infections on pediatric populations, highlighting the potential for vaccine development to combat the significant health burden posed by HAdV infections. Future research should focus on elucidating the molecular mechanisms underlying the pathogenicity differences between HAdV serotypes and exploring targeted therapeutic interventions to enhance patient outcomes.