Nonimmunocompromised Children With Adenovirus Infection—Clinical Role and Therapeutic Interventions: A Short Systematic Review

Human adenovirus (HAdV) is a common DNA mastadenovirus of the adenoviridae family.1 There are 7 different species and more than 110 known virus types.2 HAdV infections in children and adolescents range from mild to severe diseases,3 and most of the symptoms observed in nonimmunocompromised children are, among others, conjunctivitis, gastrointestinal, urinary or respiratory tract infections (eg, pneumonia).3 In addition, specific HAdV types are associated with distinct clinical symptoms. For example, HAdV-40 and HAdV-41 from species F are frequently associated with acute gastroenteritis in children.1 Depending on the course and the preexisting chronic disorder of the patient, an HAdV infection may lead to hospitalization.4 Consequently, those infections may also contribute to an increased morbidity rate and healthcare resource utilization. Although HAdV is widely recognized, comprehensive systematic analyses focusing on severe diseases caused by HAdV in nonimmunocompromised children have not yet been performed in detail. Furthermore, the risk factors for the requirement of intensive care treatment due to HAdV infection in healthy children are not sufficiently understood.5 The disease burden of HAdV has received additional broad attention following the sudden increase of cases with hepatitis of unknown origin, especially among pediatric patients during the previous SARS-CoV-2/COVID-19 pandemic.6 However, this association has not yet been confirmed.6 Importantly, a thorough overview of the causes and the pathophysiology of HAdV infections in nonimmunocompromised children must be better illustrated and understood to avoid unnecessary diagnostic and therapeutic interventions or even antibiotic use. Respiratory tract infections are the most common diseases caused by HAdV, accounting for 7%–8% of virus-induced respiratory diseases in total, particularly in children under 5 years of age.3 In hospitalized children with acute respiratory infections, the prevalence may increase to as high as 17%.7 The HAdV types commonly detected in respiratory samples mostly belong to species B and C, which exhibit both endemic and epidemic characteristics, particularly in specific patient populations such as pediatric patients. A remarkable increase in the severity of HAdV-induced respiratory tract infections has been reported after the COVID-19 pandemic.8 The prevalence of HAdV in hospitalized children with acute gastroenteritis is approximately 5%.9 However, these numbers may vary depending on the region and the time of year.4 Evidence suggests that HAdV infections may require oxygen support more frequently in children co-infected with other viruses.10 Even the necessity of extracorporeal membrane oxygenation support in nonimmunocompromised children affected by HAdV pneumonia has been described.11 Due to the urgent need to better understand the characteristics of severe HAdV infections in nonimmunocompromised patients, we thus conducted a short systematic review to provide an overview of the clinical characteristics in children with severe HAdV infections published over the last 31 years. MATERIALS AND METHODS This systematic review was conducted following the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020”12 and “PRISMA-S guidelines.”13 This partial evaluation is part of a protocol registered with PROSPERO (PROSPERO 2024 CRD42024559496). An electronic search of the published literature was performed on October 6, 2023, and updated on December 24, 2024, in PubMed, Web of Science Core Collection, and Scopus to identify original/research articles. For details regarding the search, inclusion and exclusion criteria, as well as the PRISMA flow diagram according to Page et al12 are presented in Text, Supplemental Digital Content 1, https://links.lww.com/INF/G334 and Figure 2A and Table 2B, Supplemental Digital Content 2, https://links.lww.com/INF/G335. Abstracts were reviewed by 2 independent reviewers (J.S.W. and C.K.). Articles were excluded if they: (1) were about a different disease entity, (2) referred to HAdV only as a co-infection, (3) related to nonhuman studies, (4) were case reports, (5) case series with less than 20 patients in total, (6) were not related to children, (7) involved immunocompromised patients, (8) reported about newborns, (9) were not suitable to the study question or (10) were in languages other than English or German. In total, 53 full texts of relevant articles were considered for inclusion by 2 independent reviewers (J.S.W. and C.K.). An agreement between both reviewers was required for inclusion or exclusion. Thus, in total, 12 original articles were included in the final analysis. Data were extracted from the original studies following independent inclusion decisions made by 2 reviewers (J.S.W. and A.H.). The critical appraisal was performed using the Joanna Briggs Critical Appraisal Tool.14 Altogether, there was a low to moderate risk of bias. The risk of bias assessment is displayed in Table, Supplemental Digital Content 3A, https://links.lww.com/INF/G336. RESULTS The initial search identified n = 2026 articles. Of which, n = 1221 published manuscripts were screened based on abstracts and titles. A total of 53 articles were evaluated for eligibility, and 12 articles were then included in the final analysis (Figure and Table, Supplemental Digital Content 2, https://links.lww.com/INF/G335). Out of these 12 articles, only data on severe HAdV infections were considered. Severe infections were defined as requiring intensive or intermediate care and/or severe prolonged infections with systemic inflammatory involvement, including lower respiratory tract infections with fever and the need for oxygen supplementation. Importantly, based on the analysis, relevant studies were predominantly conducted in Asia (Fig. 1). Overall, studies reported an increased prevalence rate of severe HAdV infections in children under 5 years. Males were more frequently affected by severe infections, although the overall gender ratio varied within the cohort. Fever, extrapulmonary symptoms (eg, gastrointestinal symptoms, seizures, tachycardia or hypotonia) and respiratory tract infection symptoms were among the most frequently reported clinical manifestations.15–26 Patient characteristics, comorbidities, symptoms and laboratory test results are provided in the Table, Supplemental Digital Content 3B,C, https://links.lww.com/INF/G336.FIGURE 1.: Geographic distribution of included studies, aggregated by country. The displayed median age is weighted by study sample size, where applicable.Higher viral loads in blood correlated with a severe disease course, and viremia was more common in severe cases compared with mild outcomes.15 Further laboratory findings associated with disease severity included co-infections,15,17–19,26 leukocytosis,15,17,23 elevated C-reactive protein,23 and certain HAdV-genotypes (eg, HAdV-B7), in particular in respiratory tract infections.16,20,21 One of the studies specifically identified a co-infection with Mycoplasma pneumoniae related to disease severity in HAdV pneumonia.15 Further studies reported co-infections with Mycoplasma pneumonia, but lacks for statistical correlation.17–19 Other pathogens in relevant co-infections reported included Streptococcus pneumonia,19Streptococcus pyogenes,26Haemophilus influenzae,19 influenza virus17 and respiratory syncytial virus.17 Even if not associated with immunosuppression, any chronic condition, such as neurological, chronic lung, or congenital heart diseases, may lead to a more severe HAdV infection.16,18,21,26 Hospitalization and fever duration were commonly prolonged in severe cases.19,21 The mortality reported in the published studies varied between 3.5%16 and 16.4%.18 Nosocomial infections and liver dysfunction may be key risk factors for mortality in intensive care patients with respiratory tract infection.18 However, not all studies reported deaths in their patient collective. Siew et al16 highlighted pneumonia as a significant predictor of 30-day mortality, which supports the observations of Lim et al20 reporting respiratory complications as an important cause of death.20 Secondary bacterial infections may also contribute to serious outcomes.26 In addition, the long-term effects of severe HAdV infections may include bronchiolitis obliterans, in particular if patients experienced respiratory distress during infection.18,20 Reported management approaches for patients with severe HAdV infections consist of oxygen supplementation18,21 and mechanical ventilation.18,20,21 The role of immunomodulatory treatments such as corticosteroids20,26 and intravenous immunoglobulins16,26 were described in several studies as part of the management strategies for severe cases. The requirement of these treatments is not yet evidence-based and aims to address the inflammatory component of HAdV infections, which can exacerbate disease severity. Last-resort rescue in severe respiratory failure was extracorporeal membrane oxygenation, but the effectiveness and outcomes varied, and the overall impact on survival and recovery was not analyzed in the reports.16,18 Importantly, cidofovir, as an antiviral treatment in severe HAdV infections, was also reported,16,26 although its clinical impact is not yet well established. DISCUSSION AND CONCLUSION HAdV infections in nonimmunocompromised children represent an underrecognized disease clinical condition. They are a significant public health concern due to their high transmissibility. The literature presents a combined mortality rate of 1.4% both for immunocompromised and non-immunocompromised children,4 but the overall burden of disease in nonimmunocompromised children remains insufficiently understood. We therefore aimed to provide an insight into severe HAdV infections in nonimmunocompromised children by performing a short systematic review. Main reported disease symptoms in severe HAdV infection in the included studies are respiratory tract infections15–26 and gastrointestinal symptoms.19,20,22,23,26 Less frequently reported were symptoms that occur in the context of central nervous system affection, such as seizures.21,23 The disease severity in HAdV infection might also be influenced by HAdV type,16,20,21 the comorbidity,16,18,21,26 co-infections,15,17–19,26 gender and age. However, further factors, including host immunity, cannot be quantified through our findings. The total proportion of HAdV infection in hospitalized children might vary by symptoms, season and region. Data from China previously showed that 3.5% of nasopharyngeal swabs and sputum specimens were positive for HAdV in children hospitalized with respiratory tract infections.27 In studies from Singapore and China, the prevalence of HAdV type B7 ranged between 15.2% and 33.6%27 and particularly HAdV B7 seems to be significantly associated with respiratory illnesses. In addition, the odds ratios of 3.7 for severe disease in children and adults (ie, prolonged hospitalization, prolonged fever and intensive care unit admission) have been reported.28 Other HAdV types in the same prospective single-center study demonstrated adjusted odds ratios of 3.2 (HAdV type C2) and 8.5 (HAdV type E4) for severe disease course.28 In contrast, HAdV type B7 seems to be less abundant in the USA, as well as other types predominating during outbreaks.29 Our findings underline the importance of respiratory tract infection due to HAdV in nonimmunocompromised patients, as well as the association of severe HAdV infection with any chronic condition. This aligns with previously published research data as presented above. The variability in clinical outcomes across different studies highlights the complex interplay of factors influencing the severity of HAdV infections. The critical role of co-infections has been reported before10 and might be underscored by our findings. Co-infections may exacerbate disease severity, although it remains uncertain which specific pathogen may be relevant. Understanding the clinical presentation of HAdV infection and its potential to mimic bacterial infections, for example, by presenting as pneumonia with elevated C-reactive protein and leukocytosis, is crucial for precisely identifying affected patients. Since the evidence for antiviral treatment with cidofovir is reduced, a better understanding of patient characteristics that predict benefit from treatment will be necessary for future treatment strategies. The lack of specific antiviral treatments highlights an urgent requirement for clinical trials to evaluate the efficacy of existing drugs, such as cidofovir. The data found in this approach is currently limited due to small reported case numbers and the retrospective origin of most of the included studies. A prospective multi-center population-based approach to assess the clinical burden of HAdV infections in immunocompetent and nonimmunocompetent patients is needed for a better understanding of the disease and potential treatment. Finally, the potential for long-term respiratory sequelae following severe HAdV infections, such as bronchiolitis obliterans, underscores the need for long-term follow-up studies to fully understand the impact of these infections on pediatric populations. The geographic concentration of studies in Asia may indicate a potential regional difference in the epidemiology of severe HAdV infections. However, this could also be based on a reporting bias resulting from lacking research focus on HAdV in other regions. Notably, no study from north-western Europe could be found to the best of our knowledge. Furthermore, the definition of severe disease remains under discussion and may differ between regions, populations, studies, and authors. Our findings rely on the definition of severe disease by the reporting researchers and our inclusion criteria. This may lack precision. The variability of the studies found was extremely high, and a standardized data analysis was only possible with regard to gender and age. As a result, further comprehensive analysis was considered inappropriate, and our findings were therefore presented using descriptive statistics only. ACKNOWLEDGMENTS We acknowledge the invaluable support of Lilli Heinrich for conducting this research. The original dataset will be made available on reasonable request to the corresponding author.