Children's immune systems are not yet fully developed; in particular, they have lower levels of specific immunity, cellular immunity, and interferon (IFN), making viral diseases common among children. Common respiratory viral infections in children include the common cold, influenza, herpangina, bronchitis, and pneumonia. Pathogenic viruses that are frequently diagnosed include respiratory syncytial virus (RSV), human rhinovirus (HRV), parainfluenza virus (PIV), influenza virus (IV), adenovirus (ADV), human metapneumovirus (HMPV), cytomegalovirus (CMV), and coronavirus (CoV) (1, 2). In pneumonia cases, viruses account for 55% of the primary pathogens (3). Currently, specific therapeutic agents are available for infections caused by influenza A and B viruses, cytomegalovirus, herpes simplex virus, and varicella-zoster virus, but effective treatments are lacking for other viral infections.

Recombinant human interferon α1b (rhIFNα1b) injection is a broad-spectrum antiviral drug, and its indications listed in the prescribing information include the treatment of paediatric RSV pneumonia (4). Additionally, IFN-α injections are widely used clinically for treatment of diseases caused by other respiratory viruses, such as IV, ADV, and CoV, and have demonstrated good efficacy (5–7). Other broad-spectrum antiviral drugs, such as the synthetic nucleoside Ribavirin, are associated with numerous adverse effects, including haemolytic anaemia, decreased haemoglobin levels, anaemia, liver function impairment, and fatigue (8, 9), and are therefore not routinely recommended for the treatment of viral respiratory infections in children.

According to the prescribing information, recombinant human IFN α1b injection is administered via direct intramuscular (im), subcutaneous, or lesion injection. However, in clinical practice, nebulized inhalation (inh) of IFN α1b is frequently used empirically for treating paediatric patients with respiratory viral infections, which means that the indications, patient groups, and administration routes are not within the scope approved by the drug regulatory authorities and that it is considered “off-label use”. Compared with intramuscular injection, nebulized inhalation has distinct advantages (10): (1) aerosolized particle deposition directly in the airways and lungs with increased targeting specificity; (2) rapid distribution, higher concentration, and prolonged retention in lung tissues; (3) improved safety profile, unlike intramuscular injection, which may induce initial flu-like symptoms and, with prolonged use, risks bone marrow suppression or psychiatric disturbances, with nebulized inhalation, in contrast, being generally well tolerated with minimal adverse effects; and (4) ease of administration and higher compliance in paediatric patients, facilitating clinical adoption. Literature reviews indicate that as early as the 1980s, interferon and its inducers, when administered via nebulizer inhalation, demonstrated significant efficacy in treating patients with viral pneumonia ⁽11). In recent years, guidelines and expert consensus have proposed that the clinical use of IFN-α through spray or nebulized inhalation for local treatment can aid in viral clearance, shorten the disease course, alleviate symptoms, and result in a favourable safety profile (12). Nevertheless, systematic studies comparing the efficacy and safety of nebulized inhalation vs. intramuscular injection are lacking.

In our study, a meta-analytic approach was employed to systematically compare the differences in overall efficacy rate and adverse reaction incidence rate between nebulized inhalation and intramuscular injection administration routes. This comparative evaluation aims to assess the clinical efficacy of nebulized interferon therapy for paediatric patients with viral respiratory diseases, with the goal of providing high-quality, evidence-based medical support for clinical use.

Interferons (IFNs) are soluble glycoproteins that have multiple biological functions and are synthesized primarily by monocytes and lymphocytes. These cytokines are classified into three categories on the basis of their receptor specificity: type I (encompassing IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ); type II (IFN-γ); and type III (IFN-λ1, IFN-λ2, and IFN-λ3) (29). Among these classes, type I interferons mediate their biological effects through binding to a heterodimeric cell surface receptor complex known as IFN-α/β receptor (IFNAR) (30). In contrast to the restricted expression profiles of type II and type III interferon receptors, IFNAR subunits are ubiquitously expressed across nearly all immune cell lineages and epithelial tissues (31). This pervasive receptor distribution underscores the broad-spectrum immunomodulatory potential of type I IFNs, enabling them to coordinate pansystemic immune responses and thereby facilitate the rapid mobilization of systemic immune activation.

Innate immunity, also referred to as natural immunity, not only serves as the primary defence barrier against microbial pathogens but also profoundly influences the induction of adaptive immune responses (32). During the initial phase of acute infection, the production of type I interferons (IFN-I) and other inflammatory cytokines constitutes a pivotal event that critically determines the kinetics of viral replication and dissemination (33). Furthermore, IFN-I secretion plays a crucial role in modulating immune homeostasis, demonstrating significant immunoregulatory properties. In clinical scenarios where endogenous interferon production is insufficient to effectively eliminate viral pathogens, the administration of exogenous interferon preparations represents a viable therapeutic strategy to increase antiviral defences and immune competence.

Currently, the most widely used type I interferon in clinical practice in China is IFN-α, which primarily includes IFN α1b and IFN α2b. This systematic analysis focuses on IFN α1b as the investigational agent. Recombinant human IFN α1b is a broad-spectrum therapeutic agent with antiviral, antitumour, and immunomodulatory properties. In accordance with its prescribing information, the approved indications include the treatment of certain malignant neoplasms (such as chronic myeloid leukaemia, hairy cell leukaemia, melanoma, and lymphoma) as well as viral diseases (including chronic hepatitis B and C, herpes zoster, condyloma acuminatum, and epidemic haemorrhagic fever). In paediatric practice, IFN α1b has demonstrated confirmed therapeutic efficacy and broad clinical potential in the treatment of viral pneumonia, viral hepatitis, bronchiolitis, herpangina, hand-foot-and-mouth disease, and certain malignancies. In clinical practice in China, IFN α1b injection is used for nebulization because of the lack of a dedicated inhalation agent. Encouragingly, regulatory-compliant, specifically formulated nebulizable interferon solutions have now entered phase III clinical trials (34), and the first human IFN α1b inhalation solution, GB05, was developed in compliance with FDA guidelines (35).

Many studies have confirmed that the inhalation of IFN α1b is safe and effective for treating paediatric patients with viral respiratory diseases (compared with normal saline control) (36, 37). According to the “Guidelines for the rational use of antiviral drugs in children with respiratory viral infectious diseases” (38), IFN-α can be used for acute upper and lower respiratory tract infections caused by viruses in children. Inhalation of IFN-α can be used for acute lower respiratory tract viral infections in children. In medical institutions without inhalation equipment, children with bronchiolitis or viral pneumonia can be treated with IFN-α by intramuscular injection as appropriate. The “Expert consensus on inhalation therapy for common respiratory diseases in children” (39) and the “Guidelines for standardized management of children's inhalation centers” (40) indicate that IFN-α is a commonly used antiviral drug and has a history of clinical application. The “Chinese pediatric guideline for the diagnosis, treatment, and prevention of respiratory syncytial virus infection” (41) proposes that recombinant human IFN-α inhalation is safe and effective for RSV-related lower respiratory tract infections and recommends its use. The “Guidelines for the management of community-acquired pneumonia in children (2024 revision)” (12) state that interferon has a broad-spectrum antiviral effect and can be used to treat viral pneumonia. The “Expert consensus on the rational application of interferon alpha in pediatrics” (42) mentions that subcutaneous or intramuscular injection of IFN-α drugs can be distributed throughout the body and is used in clinical practice to treat various viral infections and haematological diseases in children. Inhalation of IFN-α drugs leads to distribution mainly in the respiratory tract and is used to treat various respiratory viral infections. The “Diagnosis, treatment and prevention of severe acute respiratory syndrome coronavirus 2 infection in children: experts’ consensus statement (Fourth Edition)” (43) suggests that IFN-α inhalation can be used for children with pneumonia and other lower respiratory tract infections. Beyond the recommendations in guidelines and consensuses, preclinical and clinical data have been published on the advantages, but there is still a lack of systematic reviews to determine whether it has significant advantages over intramuscular injection.

In our study, the overall efficacy rate of nebulized inhalation of IFN α1b in the treatment of paediatric patients with viral respiratory diseases was significantly greater than that of intramuscular injection. Subgroup analyses revealed that nebulized inhalation was more effective for both herpangina and bronchiolitis patients. In terms of the incidence of adverse reactions, nebulized inhalation resulted in a significantly lower incidence than intramuscular injection did. The types of adverse reactions during intramuscular injection were more diverse and included nausea, vomiting, fever, chills, local redness at the injection site, rash, headache, listlessness, and granulocytopenia. The adverse reactions to nebulized inhalation of IFN α1b mainly included rash, listlessness, fever, nausea, and vomiting. However, in the subgroup analysis, there was no significant difference between the herpangina and bronchiolitis groups (Supplementary Figure S1), which might be due to the reduced sample size in the subgroups, leading to a decrease in statistical power.

This study has several limitations: (1) the quality assessment scores of the included studies were not high, largely because of the inability to implement blinding in the administration methods; (2) most of the included studies were single-centre studies, which might have a certain influence on the universality of the final conclusion; (3) owing to the numerous viral respiratory diseases in children and the large number of outcome indicators in various studies that are difficult to unify, only the overall efficacy rate is adopted as the effectiveness indicator; and (4) the heterogeneity of efficacy criteria in different diseases might influence the generalizability of the efficacy findings and limit the comparability and interpretability of the pooled efficacy estimate, despite the statistical homogeneity (low I²).

In summary, the current evidence demonstrates that nebulized inhalation of recombinant human interferon α1b (injection form) is safer and more effective than intramuscular injection in the treatment of paediatric patients with viral respiratory diseases, providing substantial support for this off-label clinical application. However, we strongly recommend that future multicentre, large-scale randomized controlled trials be conducted to further validate the comparative efficacy and safety of these two administration routes.

Although our findings suggest favourable safety outcomes with nebulized administration, strict adherence to standardized nebulization protocols and relevant clinical guidelines remains imperative. This includes proper administration techniques, rigorous monitoring for potential adverse reactions, and the implementation of appropriate preventive measures against treatment-related complications. In the future, we anticipate the development and approval of dedicated nebulized formulations.