Viral encephalitis (VE), a widespread infectious disease of the central nervous system, accounts for approximately 20%–50% of encephalitis cases worldwide (Vora et al., 2014). Characterized by high mortality and disability rates, VE represents a major global health burden. It is defined as inflammation of the brain parenchyma caused by neurotropic viruses and presents with diverse clinical manifestations, ranging from mild symptoms to diffuse or focal neurological deficits. Patients may also exhibit nonspecific viral prodromes, including fever, headache, nausea, and vomiting (Venkatesan et al., 2013). Importantly, VE is frequently associated with severe and long-term sequelae such as irreversible neurological damage and cognitive impairment (Mcgrath et al., 1997; Mailles and Stahl, 2009).

The diagnosis of VE requires a comprehensive approach that integrates clinical features, laboratory testing, and epidemiological history. The gold standard for confirmation is the detection of specific viral antigens, antibodies, or nucleic acids in cerebrospinal fluid or brain tissue (Feng et al., 2020). Despite advances in diagnostic techniques, however, the causative virus remains unidentified in 30%–62% of clinically confirmed cases (Yong et al., 2023). A wide range of viruses—including enteroviruses, herpes simplex virus (HSV), epstein–barr virus, human immunodeficiency virus, and other unidentified agents—have been implicated in VE (Vora et al., 2014; George et al., 2014). Among children, HSV encephalitis and enterovirus encephalitis are the most common etiologies (Bloch et al., 2023; Parvez and Ohtsuki, 2022). Pediatric VE imposes a considerable economic burden on both health systems and families (Li et al., 2023).

Supportive care remains the cornerstone of VE management, and approximately 20% of patients require intensive care unit admission (Thakur et al., 2013). Complications such as deep vein thrombosis and epilepsy often demand concurrent treatment (Bradshaw and Venkatesan, 2019; Steiner et al., 2005). Despite the availability of antiviral therapy, patients with HSV encephalitis continue to experience mortality rates of up to 28% and frequently develop severe neurological sequelae (Bradshaw and Venkatesan, 2016). Overall, VE exhibits a mortality rate ranging from 1% to 90% owing to the lack of specific antiviral agents (Ludlow et al., 2016).

In the theoretical framework of traditional Chinese medicine (TCM), VE is not recognized as an independent disease entity. Based on its key clinical manifestations and neurological dysfunction, however, it is classified within the broader category of Warm Disease. The TCM pathogenesis of VE is considered multifactorial, involving disturbances of multiple organ systems, particularly the brain, heart, lungs, liver, and kidneys. This holistic perspective aligns with modern biomedical evidence showing that inadequate viral clearance at the primary infection site can allow dissemination to the central nervous system and other organs, leading to multisystem complications (Yang et al., 2023).

The TCM etiology of VE can be interpreted from two principal perspectives. First, it is attributed to exposure to “epidemic toxins,” a concept closely paralleling the modern biomedical notion of pathogens. Second, it arises from a deficiency of healthy Qi, reflecting an intrinsic weakness in the body’s ability to resist pathogenic invasion. This deficiency, together with an imbalance between Yin and Yang, creates systemic dysfunction that allows pathogenic toxins to ascend and invade the brain orifices, thereby inducing encephalitis (Jia et al., 2016). Emerging evidence supports these concepts: the severity of HSV encephalitis in children is strongly associated with monogenic inborn errors in the Toll-like receptor 3–dependent signaling pathway, which impair the production of key antiviral cytokines such as Interferon-beta and Interferon-lambda—a mechanistic defect analogous to the TCM concept of healthy Qi deficiency (Zhang, 2020). Moreover, neurotropic viruses can disrupt the blood–brain barrier and trigger both adaptive immune responses and trained immunity, culminating in cytokine storm and aggravated neuroinflammation, a process that mirrors the TCM doctrine of Yin–Yang imbalance (Matthews et al., 2025).

TCM provides multiple therapeutic strategies for VE, including herbal decoctions, proprietary Chinese patent medicines, and acupuncture (Wang, 2006). Clinical evidence indicates that formulas such as Changpu Yujin Decoction and Baihu Decoction significantly enhance treatment efficacy in VE (Rao and Han, 2023; Wang et al., 2016). A systematic review of 23 clinical trials demonstrated that Xingnaojing injection combined with conventional therapy improved cure rates, shortened symptom recovery time, and reduced mortality (Cao et al., 2019). Similarly, a meta-analysis of 1,045 cases reported that Angong Niuhuang Pill, when used as an adjunctive therapy, increased the overall effectiveness rate by 17% (Huang et al., 2024). Our previous work also showed that proprietary Chinese medicines effectively improved clinical symptoms and reduced sequelae in pediatric VE (Wang et al., 2024). Acupuncture, used as an adjuvant therapy, has likewise demonstrated clinical benefits; in a rat model of herpes simplex encephalitis, acupuncture improved spatial learning and memory impairments (Jin et al., 2024). Furthermore, the antiviral activities of specific herbal extracts are being increasingly validated. For example, Rhodiola extract disrupts the binding and stability of Japanese encephalitis virus, whereas Artemisia argyi extract damages the integrity of HSV particle membranes, offering new potential therapeutic strategies for viral infections (Lai et al., 2024; Liu et al., 2023).

Xiyanping injection (XYPI), a well-established injectable preparation with a long history of clinical use in China, exhibits broad therapeutic activities, including potent anti-inflammatory, antiviral, and antibacterial effects. XYPI is primarily composed of andrographolide sulfonate (AS). Using high-performance liquid chromatography, Zhan et al. identified four key metabolites of XYPI: andrographolide sulfate ester A, andrographolide sulfate ester B, andrographolide sulfate ester C, and 9-dehydro-17-hydroxyandrographolide (Zhan et al., 2012). Accumulating evidence also indicates that XYPI has additional pharmacological effects, including antitumor and neuroprotective activities. (Lu et al., 2019).

XYPI has been incorporated into the Chinese Pediatric Association guidelines as a first-line therapy for several pediatric infectious diseases, such as viral pneumonia, acute undifferentiated febrile illness, hand-foot-and-mouth disease, and influenza-like illnesses (Wang et al., 2019; Yang et al., 2024). Pharmacokinetic studies in rat models have revealed extensive tissue distribution of XYPI metabolites, with quantifiable concentrations detected in the brain, heart, kidneys, liver, lungs, and spleen (Bera et al., 2014). Moreover, a large-scale real-world clinical study conducted in China demonstrated that XYPI is an effective therapeutic agent for VE, with enhanced efficacy observed when used in combination with conventional chemical drugs (Sheng et al., 2022).

Despite significant advances in neuropharmacological research on XYPI, high-quality clinical evidence supporting its use as an adjuvant therapy for pediatric VE remains scarce. This retrospective study therefore aims to comprehensively assess the benefit–risk profile of XYPI-augmented regimens in the management of pediatric VE, thereby providing an evidence-based foundation for optimizing neuroprotective strategies in this vulnerable population.

VE is a life-threatening neurological disorder that can lead to death or long-term disability, posing a serious threat to the healthy development of children and underscoring the urgent need for effective and well-tolerated therapeutic strategies. A recent prospective study reported that, after a 2-year follow-up, approximately 67% of patients with VE continued to experience cognitive impairment, fatigue, and other debilitating sequelae, regardless of initial disease severity, highlighting the persistent and pervasive impact of VE on long-term health outcomes (Schwitter et al., 2024).

At present, the treatment of VE remains largely empirical, relying mainly on antimicrobial therapy and supportive care. Although these approaches constitute the standard of care, growing evidence indicates that TCM may offer beneficial adjunctive effects in pediatric VE, highlighting the potential value of developing integrative treatment strategies that combine it with conventional medicine (Tunkel et al., 2008; Wang et al., 2024).

The mRS is a comprehensive and objective measure of functional disability, providing a standardized framework that minimizes subjective bias. Widely used in various neurological disorders, including acute stroke and cerebral small vessel disease, it enables clinicians to reliably assess and monitor functional status and disability levels (Hosoya et al., 2024; Clancy et al., 2024). In this study, patients’ prognoses were systematically evaluated and stratified using the mRS. Our findings demonstrated that XYPI administration was an independent protective factor against poor outcomes, significantly reducing the risk of unfavorable prognosis.

The GCS, one of the earliest tools developed to evaluate impaired consciousness, coma depth, and duration, encompasses three core components: motor responsiveness, verbal performance, and eye opening (Teasdale and Jennett, 1974). It remains one of the most universally adopted instruments for assessing the level of consciousness and is widely applied in neurological disorders such as acute intracranial injury and stroke (Easter et al., 2015). Consistent with previous reports, our study revealed a significant association between GCS scores and prognostic outcomes, demonstrating that lower GCS scores are predictive of poor prognosis in pediatric encephalitis (Feng et al., 2020; Rebecca et al., 2024; Ngan et al., 2024).

Our study demonstrated that XYPI effectively alleviates clinical symptoms and improves patient prognosis, an effect likely attributable to its multifaceted pharmacological activities, including anti-inflammatory, antiviral, and neuroregulatory properties. Previous studies have shown that AS, the principal active component of XYPI, not only directly inhibits adenovirus replication but also enhances host immunity by modulating neutrophil and T-cell function and promoting macrophage phagocytic activity. These immunomodulatory actions facilitate viral clearance and the release of antiviral factors, thereby suppressing viral replication (Zhang J et al., 2021; Li et al., 2025). Moreover, XYPI mitigates cytokine storm through four key mechanisms: inhibition of p38 phosphorylation, suppression of MAPK phosphorylation, reduction of NF-κB phosphorylation, and negative regulation of STAT3 activation (Li et al., 2025).

The neuroprotective potential of XYPI has been demonstrated across diverse preclinical models, confirming its target-organ specificity for the central nervous system. Permeability–surface area product analyses by Zhou et al. revealed that XYPI stabilizes the blood–brain barrier by modulating paracellular transport and attenuating neuroinflammatory cascades (Zhou et al., 2024). Emerging evidence further highlights the dual therapeutic efficacy of XYPI in promoting neurological recovery and exerting neuro-oncological effects, particularly through the modulation of glioma stem cell plasticity (Zhang L et al., 2021; Othman and Mohd, 2022).

Our study also identified a notable finding: the duration of fever was significantly longer in patients who did not receive XYPI. This observation is consistent with the report by Yang et al., which demonstrated that prolonged fever is a risk factor for poor prognosis in VE (Yang et al., 2024). The antipyretic effect of XYPI may be explained by its ability to suppress the release of pyro-inflammatory mediators such as interleukin-1 and tumor necrosis factor-α, while simultaneously reducing the production of positive regulatory factors, including prostaglandin E2 and 5-hydroxytryptamine, within the hypothalamic fever center (Liu et al., 2014; Guo et al., 2012; Peng et al., 2016a; Peng et al., 2016b). By modulating these key mediators, XYPI may attenuate the febrile response, thereby shortening fever duration and potentially improving clinical outcomes in VE.

The precise causal relationships between VE and the development of complex systemic infections, respiratory diseases, and gastrointestinal disorders warrant further investigation (Bohmwald et al., 2018). Notably, our results demonstrated that XYPI significantly reduced the incidence of respiratory tract infections, an effect that may be attributable to its capacity to ameliorate pathological lung changes, alleviate pulmonary edema, and suppress inflammatory cytokine production (Peng et al., 2016a; Christie et al., 2007; Glaser and Bloch, 2020). Moreover, XYPI administration was associated with a lower rate of myocardial injury. Supporting this finding, Zhang et al. reported the efficacy of XYPI in children with myocardial damage based on real-world data from 39 hospitals across China (Zhang X. Y et al., 2021). Preclinical studies further suggest that these cardioprotective effects may involve activation of the peroxisome proliferator-activated receptor-α signaling pathway (Zhang et al., 2024).

VE imposes a substantial economic burden worldwide. Wang et al. reported that encephalitis caused by Chinese flavivirus in children continues to exhibit a high prevalence of severe cases, particularly in rural regions (Wang et al., 2022). Similarly, Tarantola et al. demonstrated that in the Mekong region—a hotspot for VE—the financial burden associated with this disease exceeds the average income of the general population by nearly tenfol (Tarantola et al., 2014). In the United States, the average cost of encephalitis treatment doubled between 1998 and 2010 (Vora et al., 2014). Consistent with these observations, our findings further highlighted the potential of XYPI to alleviate the economic burden of inpatient care.

Although the incidence of sequelae was relatively low in our cohort, VE remains a life-threatening condition in children. Viruses can invade the central nervous system via three primary routes: peripheral nerves connecting to the brain, olfactory neurons within the nasal epithelium, or direct penetration across the blood–brain barrierr (Sun et al., 2024). Such infections can cause irreversible neural injury, resulting in long-lasting neurological sequelae. Notably, XYPI has been reported to reduce the risk of virus-related sequelae, potentially by inhibiting hemagglutinin adsorption and enhancing immune cell activity, thereby strengthening host antiviral defenses (Wen et al., 2015).

The present study, although retrospective in design, provides valuable evidence supporting the potential therapeutic benefits of XYPI in mitigating VE-related sequelae. Nevertheless, high-quality prospective trials are warranted to conclusively establish its efficacy. In addition, the absence of adult VE data limits the generalizability of our findings. Another limitation is the lack of proteomic profiling and dynamic cytokine analyses of cerebrospinal fluid, which precludes a deeper understanding of the mechanisms underlying XYPI’s effects in pediatric VE. Future studies incorporating these molecular approaches are needed to validate the current findings and elucidate the pathways mediating XYPI’s therapeutic action.

This study demonstrates that XYPI effectively reduces adverse outcomes, alleviates clinical symptoms, and lessens the economic burden in pediatric patients with VE. However, larger prospective, multicenter trials are warranted to definitively confirm its efficacy and safety.