Adenovirus pneumonia is a pulmonary infectious disease commonly occurring in children[4, 23]. Most patients have mild disease and recover from adenovirus pneumonia, but severe adenovirus pneumonia can result in considerable morbidity and mortality in immunocompetent pediatric patients[3]. HAdV-7 is known to be associated with serious pneumonia in children and is more prone to be followed by the PIBO development [24]. However, the standard therapy for the management of severe adenovirus pneumonia is not yet established to date, and efficacy data evaluating possible treatment options were not systematically studied in non-immunocompromised pediatric patients. In this retrospective study of 202 patients treated with intravenous immunoglobulin (IVIg) for severe adenovirus pneumonia at our hospital, we preliminarily assessed the potential efficacy and safety of the treatment in pediatric patients.
IVIg was used for non-immunocompromised children with severe adenovirus pneumonia when they combined serious complications[23]. The principal components of IVIg are natural antibodies (NAbs) of the IgG isotype. NAbs can enhance the recruitment of virus into lymphoid organs where they are present to T and B cells, thereby eliciting an active immune response[25]. The protective effect of IVIg against infections has been attributed to the ability of specific antibodies to neutralize pathogens[26]. Indeed, research has found that commercial IVIg preparations possess anti-adenovirus activity in vitro, suggesting a potential role for adjuvant IVIg in adenovirus infectious diseases[14]. In this retrospective study, IVIg was administered as supplementary therapy to suppress viral replication through neutralization by viral antibodies. The stratification analysis by illness duration according to IVIg administration showed that later presenters were more associated with lower hemoglobin and albumin levels and higher LDH levels, and more importantly, fungal coinfections were more prevalent in these patients. These results indicate that later presenters have been more complicated and serious. Based on the analysis results, early administration of IVIg was important to decrease the use of mechanical ventilation and shorten the fever duration. For the long-term outcome, early treatment was also crucial to lowering the incidence rate of bronchiectasis. In particular, early presenters had lower mortality than later presenters had, although the difference was not statistically significant. Therefore, the study confirmed the importance of early IVIg administration in non-immunocompromised children with severe adenovirus pneumonia.
The following step toward the therapeutic utilization of IVIg for pediatric severe adenovirus pneumonia would be the fine-tuning the dose regimen in a clinical study. In this study, patients were categorized into two groups based on their IVIg treatment regimens during each hospitalization: high-dosage group underwent IVIg treatment with 1 g/kg for 2 days, whereas low-dosage group were treated with 0.4–0.5 g/kg for 3–5 days. At high doses, IVIg inhibits the function of different arms of the immune system, including inhibition of the maturation and function of dendritic cells, attenuation of T-cell proliferation, and production of proinflammatory cytokines[26]. A previous study demonstrated that a high-dose regimen might not be appropriate for the treatment of infectious diseases. However, recent research has found that activation of the immune system and generation of numerous chemokines and cytokines could play a major role in the pathogenesis of adenovirus tissue damage[27]. In our study, no significant differences were observed between low- and high-dose groups in clinical end-points of early presenters. Nevertheless, for later presenters, the high-dosage group can reduce the fever duration and ECMO usage, although different dosages of IVIg administration had little impact on the prognosis of later presenters. In other words, later presenters with severe adenovirus pneumonia could benefit from a high-dose of regimen IVIg during hospitalization.
The intravenous immunoglobulin level in this study was well tolerated, and no serious adverse events were found to be attributed to IVIg. Currently, most viewpoints are that majority of adverse effects are associated with high IVIg dosage[16]. Moreover, the incidence was 6.62% during infusion with IVIg in this study. Furthermore, the IVIg dosage was not related with the incidence of adverse events in the two study groups. Thus, different dosages to guarantee the efficacy of therapy and minimize adverse effects were observed in our study.
Limitations of our study were mainly due to its retrospective file review design, with all associated disadvantages of this study type (e.g., missing information, poor documentation, etc.). However, this study is the first to explore the timing and dosage of IVIg administration in non-immunocompromised pediatric patients with severe adenovirus pneumonia and to evaluate the correlation between different dosages and the incidence of adverse events.