Integrating the Wei–Qi–Ying–Blood Theory with Modern Pathophysiology: A Multitarget Translational Framework for Dengue Management

Introduction

Dengue is a mosquito-borne viral disease caused by four distinct dengue virus serotypes (DENV-1 to DENV-4) and is an increasingly important global public health problem.^1,2 Climate-driven vector expansion and greater human mobility continue to extend the geographic range of DENV transmission, including into Europe and the Eastern Mediterranean.^1,2 The World Health Organization (WHO) reported more than 4 million reported cases and 3000 deaths in the first half of 2025 alone, underscoring the need for effective interventions.²

Clinical management remains largely supportive despite this growing burden. Fluid therapy during the critical phase requires careful balance: inadequate replacement can lead to hypovolemic shock, whereas excessive administration can cause life-threatening respiratory distress.^3,4 Achieving this balance is especially difficult in resource-limited settings.³ Prevention is also limited by safety concerns about the CYD-TDV vaccine in individuals who are seronegative at baseline.⁵

Targeted therapies are difficult to develop because the main processes involved in dengue pathogenesis are closely connected.^6,7 Severe disease develops through a dynamic cascade of viral replication, dysregulated inflammation, endothelial dysfunction, plasma leakage, thrombocytopenia, and coagulation abnormalities.^6–9 These processes interact rather than occur separately, so single-target interventions may be insufficient. Host-directed multitarget strategies have therefore received increasing attention.^3,7,8

Against this background, TCM offers pharmacological and theoretical resources for studying stage-specific, multitarget interventions.^10,11 TCM formulations have long been used for acute febrile infectious diseases and are intended to regulate multiple physiological networks.^10,11 From a systems-biology perspective, the Wei–Qi–Ying–Blood theory may help connect traditional pattern differentiation with modern dengue staging. This review examines the links between Wei–Qi–Ying–Blood patterns, stage-specific dengue pathophysiology, and biomarkers, together with the available evidence, current limitations, and future directions for TCM-based dengue management. Figure 1 shows the overall pathological cascade and possible intervention points.

Figure 1 Pathological cascade of the virus–inflammation–vascular–coagulation axis in dengue and corresponding intervention points. The upper arrow indicates pathological progression. The yellow, blue, green, and purple boxes represent antiviral, anti-inflammatory/immunomodulatory, endothelial-protective, and coagulation-stabilizing/platelet-recovery interventions, respectively. Arrows from the boxes indicate the principal intervention points. Abbreviations: DENV, dengue virus; E protein, envelope protein; NS5, nonstructural protein 5; RNA, ribonucleic acid; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin-6; IFN-γ, interferon-gamma.

Theoretical Bridging: From the Wei–Qi–Ying–Blood Theory to Modern Pathophysiological Staging

A Quantifiable Correspondence Framework Between TCM Patterns and Modern Pathophysiology

In traditional Chinese medicine (TCM), dengue has historically been classified as wenbing yidu (epidemic warm-toxic disease).^12,13 Traditional pathophysiology describes its progression in terms of accumulating “dampness” (fluid dysregulation and edema), “heat” (fever and hyperinflammation), and “toxic pathogens” (viral burden).^12,13 Although metaphorical, these terms broadly parallel the modern clinical course of dengue.^7,14,15 More specifically, progression from the Wei–Qi co-involvement pattern to the Qi–Ying blazing pattern resembles the shift from the acute febrile phase to the critical phase, when severe endothelial barrier disruption, plasma leakage, and progressive coagulopathy may occur.^7,14,15

To make this empirical knowledge more usable, we relate TCM pathodynamic terms to modern pathological processes and measurable biological indicators, providing a shared interdisciplinary language (Table 1). This is not meant to be a simple translation of terminology. Rather, it links traditional pattern manifestations with specific pathological biomarkers.^7,13,15 Grounding these concepts in association analyses may help bridge TCM and contemporary biomedicine and provide a testable, mechanism-based approach to identifying and validating multitarget TCM interventions.^13–15 In resource-limited settings, the approach can rely on clinical warning signs and routine tests; advanced biomarkers remain supplementary rather than essential.^16–18

Table 1 TCM Pathogenesis, Clinical Stage, and Biomarker Framework in Dengue

Dynamic Correspondence Between Stage-Based Treatment and Core Pathophysiological Processes

Dengue usually progresses through three clinical stages: febrile, critical, and recovery, each with its own pathophysiological features and clinical risks.^16–18 Based on the Wei–Qi–Ying–Blood theory, we propose a matching model that aligns each stage with TCM patterns, underlying mechanisms, measurable indicators, and representative herbal formulations (Table 2).^18,26 In this way, traditional pattern identification is considered together with modern clinical risk stratification across the disease course.^18,27

Table 2 Stage-Specific TCM Patterns, Pathological Focus, Representative Formulas, and References in Dengue

The model is not a fixed step-by-step treatment pathway. Patients may first present at any stage, including the late febrile or critical phase. Initial treatment should be chosen according to the stage at presentation, warning signs, hemodynamic status, organ involvement, and readily available laboratory findings, including platelet count, hematocrit trend, coagulation parameters, liver function, and evidence of plasma leakage. Treatment should be reassessed and adjusted as the clinical picture changes.^16–18

This model may also help guide target discovery and pharmacological research. Multicomponent TCM formulations are chemically complex, and conventional single-compound models may not be sufficient. Combining chemical profiling, network pharmacology, target prediction, molecular docking, and multi-omics analysis may help identify candidate active constituents and pathway interactions.^35,36 These computational findings should be treated as hypotheses and tested in DENV-specific experimental models and well-designed clinical studies. Figure 2 shows the stage-based model.

Figure 2 Stage-based management framework integrating dengue phase, TCM pattern, clinical risk, and Western supportive and TCM management strategies. The horizontal arrow indicates progression from the febrile phase through the critical phase to the recovery phase. The yellow, blue, and purple panels distinguish the three phases, respectively. Abbreviations: TCM, traditional Chinese medicine; WBC, white blood cell count; PLT, platelet count; Hct, hematocrit. Symbols: ↑, increase; ↓, decrease; ↓↓, marked decrease.

Pharmacological Mechanisms: Molecular Basis of Pleiotropic Regulation

Figure 3 brings together the multitarget pharmacological network proposed for representative TCM interventions against DENV. Some host-directed mechanisms, particularly endothelial barrier protection, are extrapolated from non-dengue models and should be regarded as hypothesis-generating evidence.

Figure 3 Multitarget mechanistic network of representative natural products and TCM-related interventions against DENV infection. The blue, pink, green, and yellow sectors represent direct antiviral activity, attenuation of hyperinflammation, endothelial barrier protection, and modulation of thrombocytopenia, respectively. Arrows indicate activation or positive regulation, blunt-ended lines indicate inhibition, and dashed boxes group related mechanisms or outcomes. Symbols: ↑, increase; ↓, decrease. Abbreviations: TCM, traditional Chinese medicine; DENV, dengue virus; E protein, envelope protein; NS2B–NS3, nonstructural protein 2B–nonstructural protein 3 protease; RM-1, Rhododendron mariae extract; MTase, methyltransferase; SAM, S-adenosylmethionine; RdRp, RNA-dependent RNA polymerase; RNA, ribonucleic acid; PN-1, a dammarane-type triterpenoid saponin from Panax notoginseng; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin-6; CXCL10, C-X-C motif chemokine ligand 10; ALOX12, arachidonate 12-lipoxygenase; 12-HETE, 12-hydroxyeicosatetraenoic acid; Syndecan-1, syndecan-1; TEER, transepithelial electrical resistance; ZO-1, zonula occludens-1.

Direct Antiviral Strategies Targeting the Viral Life Cycle

Natural products may act at several points in the DENV life cycle.³⁷ At the entry stage, several botanical extracts interfere with binding between the viral envelope (E) protein and host receptors.³⁷ Extracts from Glycyrrhiza uralensis, Rhododendron mariae (designated RM-1), and Ampelopsis japonica, for example, have shown early-stage inhibitory activity against multiple DENV serotypes by targeting E protein domain III or blocking viral adsorption.^38–40

During viral replication, the highly conserved NS2B–NS3 protease and NS5 proteins are major therapeutic targets, as shown in Figure 3.^37,41 Myricetin and quercetin have been reported to inhibit the NS2B–NS3 protease complex at micromolar concentrations.^42,43 The quercetin findings, however, need cautious interpretation. Quercetin is prone to aggregation and may produce nonspecific or false-positive signals in biochemical assays.^44,45 Its apparent antiviral activity should therefore be confirmed with aggregation controls, orthogonal assays, and cellular target-engagement studies. Translation to clinical use is also limited by poor aqueous solubility, low and variable oral bioavailability, and extensive first-pass metabolism.⁴⁶ Liposomes, lipid nanoparticles, polymeric nanoparticles, micelles, and nanoemulsions may improve quercetin stability and systemic exposure.⁴⁶ Even so, their pharmacokinetics, cytotoxicity, target specificity, and anti-DENV efficacy still require validation in DENV-specific experimental models.

NS5 is another important target for natural compounds because it has both methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) activities.^41,47,48 PN-1, a dammarane-type triterpenoid saponin from Panax notoginseng, acts as a non-nucleoside RdRp inhibitor and has shown in vivo efficacy in AG129 mouse models.⁴⁷ Computational and in vitro findings also suggest that isoquercitrin may target the S-adenosylmethionine-binding and RNA-capping sites of the NS5 MTase.⁴⁸ These compounds provide preliminary structural scaffolds for anti-DENV drug development, although further pharmacological optimization and clinical validation are still needed.^47,48

Attenuation of the Hyperinflammatory Cascade

The hyperinflammatory response triggered by DENV, often described as a cytokine storm, is a primary driver of severe disease.⁸ Higher serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-X-C motif chemokine ligand 10 (CXCL10) are strongly associated with more severe vascular leakage, organ failure, and adverse clinical outcomes.^8,49 Bioactive TCM constituents may reduce this abnormal immune response by regulating key inflammatory mediators, as illustrated in Figure 3.^50–52 In murine models, quercetin and the alkaloid sinococuline reduce viral burden and markedly downregulate TNF-α and IL-6 expression, thereby mitigating vascular leakage.^50,51 A randomized, double-blind, placebo-controlled trial in patients with dengue hemorrhagic fever also found that Propoelix accelerated platelet recovery, shortened hospitalization, and reduced serum TNF-α levels.⁵² Two mechanisms may be involved and are not mutually exclusive: direct antiviral activity together with independent modulation of host inflammatory pathways, and an indirect anti-inflammatory effect caused by lower viral burden and reduced antigen-driven immune activation. Current clinical evidence does not clearly separate their relative contributions. Future studies should therefore measure viral kinetics and inflammatory biomarkers together to determine whether the anti-inflammatory effects are independent of viral-load reduction.^50–52

Endothelial Stabilization and Barrier Protection

Disruption of the vascular endothelial barrier is a pathological hallmark of severe dengue. It is driven largely by DENV nonstructural protein 1 (NS1)-mediated degradation of the endothelial glycocalyx and tight junctions.^9,22 Clinically, shedding of syndecan-1, a core glycocalyx component, is a robust biomarker of plasma leakage severity.⁹

Some TCM-derived compounds appear to have broad barrier-stabilizing properties. In several vascular injury models, ginsenoside Rg1 and astragaloside IV preserve glycocalyx structure by inhibiting heparanase expression and upregulating syndecan-1.^53,54 Under inflammatory stress, berberine and puerarin can also restore transepithelial electrical resistance (TEER) and the expression of tight junction proteins, including ZO-1, occludin, and claudin-1.^55,56 Most of these barrier-protective effects were reported in non-dengue models, so their relevance to dengue remains inferential and requires confirmation in DENV NS1-specific endothelial models.^22,53,55

Systemic Modulation of Dengue-Associated Thrombocytopenia

Thrombocytopenia is common in DENV infection and results from both suppression of bone marrow megakaryopoiesis and accelerated peripheral platelet clearance.⁵⁷ Because prophylactic platelet transfusion does not improve outcomes and may increase the risk of fluid overload, promoting endogenous thrombopoiesis pharmacologically is important.⁵⁸

Carica papaya leaf extracts have emerged as a clinically validated intervention.^59–61 Papaya extract strongly upregulates ALOX12 expression and enhances megakaryopoiesis through 12-HETE-related pathways.⁵⁹ A multicenter randomized controlled trial confirmed that papaya leaf extract significantly accelerated platelet recovery and shortened the critical phase in patients with severe dengue compared with placebo.^60,61 Euphorbia hirta has also shown viral inhibition and hematological restoration.⁶² Clinical observations indicate that it rapidly increases platelet and leukocyte counts.²⁶ The effect of TCM on thrombocytopenia may therefore extend beyond simply raising platelet counts and may involve coordinated regulation of viral replication, bone marrow hematopoiesis, and immune-mediated clearance. This provides a modern pharmacological basis for its clinical use.^57,59

Pattern Identification and Stage-Based Treatment of Dengue

TCM management of dengue generally follows a stage-based approach, with treatment adjusted to the changing pathophysiological features of the disease.^26,28

Febrile Phase: Early Viral Control and Inflammation Modulation

During the acute febrile phase, treatment mainly aims to limit viral replication and excessive early immune activation. In TCM, this is described as “clearing heat, resolving dampness, and detoxifying”. Representative formulations include modified Ganlu Xiaodu Dan and Shufeng Jiedu Capsules. In a clinical observation of patients with dengue, Shufeng Jiedu Capsules were associated with faster defervescence, shorter hospitalization, and fewer early hemorrhagic manifestations.⁶³

Evidence from influenza A and SARS-CoV-2 models may help explain the potential host-directed effects of these formulations. Modified Ganlu Xiaodu Dan has been reported to regulate PI3K/Akt signaling in an influenza A model, while Lianhua Qingwen Capsules showed antiviral and anti-inflammatory activity against SARS-CoV-2.^64–66 Because these viruses differ substantially from DENV in their biology, tissue tropism, and clinical features, the findings should be interpreted cautiously and confirmed in DENV-specific models.

Critical Phase: Rescuing the Cytokine Storm and Coagulopathy

The critical phase of severe dengue is marked by a life-threatening triad of cytokine storm, plasma leakage, and coagulation dysfunction.⁸ In TCM, this severe systemic decompensation is described as the Qi–Ying blazing pattern with toxin accumulation and blood stasis. Treatment therefore shifts toward systemic rescue through “cooling the blood, detoxifying, and resolving blood stasis”. Modified Qingwen Baidu Decoction is a representative intervention for severe inflammatory states. Evidence from LPS-induced acute lung injury and sepsis models suggests that it may reduce systemic inflammation and preserve barrier integrity, as indicated by improved pulmonary oxygenation, reduced alveolar permeability, and lower inflammatory mediator levels.^67,68 Alveolar barrier injury is not the same as the systemic vascular endothelial dysfunction seen in severe dengue, although both involve inflammation-related barrier disruption and increased vascular permeability. The findings therefore offer indirect mechanistic support for possible effects on inflammation and vascular barrier dysfunction, not direct evidence of efficacy in DENV infection.

In patients with sepsis-associated coagulation dysfunction, adding modified Qingwen Baidu Decoction to standard therapy was reported to improve platelet counts and D-dimer levels and reduce Acute Physiology and Chronic Health Evaluation II scores.⁶⁹ Because these findings were obtained outside dengue, they require confirmation in DENV-specific endothelial, hepatic, and clinical studies.

Some critical complications require targeted formulations. Jiedu Huayu Granules mitigate vascular endothelial inflammation and hepatic injury by suppressing chemokines such as monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules such as soluble vascular cell adhesion molecule-1 (sVCAM-1).^70,71 In patients with severe central nervous system involvement, such as encephalopathy or seizures, traditional emergency remedies including Angong Niuhuang Pill and Zixue Powder show marked neuroprotective and anticonvulsant effects.^72,73 Mechanistic studies indicate that these effects involve modulation of cerebral calcium influx, reduction of nitric oxide, and rebalancing of glutamate/GABA neurotransmission, thereby significantly prolonging seizure latency and improving neurological outcomes.^72,73

Recovery Phase: Tissue Repair and Immune Homeostasis

In the recovery phase, attention shifts to residual inflammation, tissue repair, and post-viral fatigue. In TCM, this corresponds to the Qi–Yin deficiency pattern.

Modified Zhuye Shigao Decoction and Shengmai Drink are used to clear residual heat, nourish Qi and Yin, and restore homeostasis.⁷⁴ Modified Zhuye Shigao Decoction is classically used to clear residual heat. Its relevance to dengue remains indirect because the available mechanistic evidence mainly comes from non-DENV models, including radiation esophagitis, gouty arthritis, and COPD. These studies suggest that the formula may inhibit TLR/NF-κB and IL-6/JAK/STAT3 signaling and strengthen antioxidant defenses, thereby reducing inflammatory and oxidative tissue injury.^75,76 The findings provide a mechanistic rationale for its use in the recovery phase but do not constitute direct dengue-specific evidence. A dengue-specific clinical reference comes from Propoelix™, a standardized propolis extract. In a randomized, double-blind, placebo-controlled trial of patients with dengue hemorrhagic fever, Propoelix™ reduced serum TNF-α levels, accelerated platelet recovery, and shortened hospitalization.⁵² This supports inflammatory modulation as a relevant therapeutic direction during dengue recovery and highlights the need for direct validation of modified Zhuye Shigao Decoction in DENV infection.

Shengmai Drink also acts as a broad modulator of the host response. Transcriptomic analysis in DENV-infected cellular models shows widespread changes in gene networks related to the cell cycle, DNA replication, and PI3K-Akt/FoxO signaling.⁷⁴ By combining low-toxicity viral clearance with restoration of immune and metabolic homeostasis, these recovery-phase interventions provide a broad pharmacological approach to promoting functional recovery and reducing post-dengue sequelae.^74,77

Representative Clinical Preparations and Intravenous Therapeutics

Clinical Evidence for Institutional Formulations

Several institutional TCM formulations were developed empirically during major regional dengue outbreaks and were subsequently evaluated in clinical practice. Chaishi Jiedu Granules have mainly been assessed in a real-world observational study, whereas Dengue Formula No. 1 was evaluated in a small clinical study involving 41 patients.^28,78 The reported herbal compositions of Chaishi Jiedu Granules and Dengue Formula No. 1 are summarized in Table 3. These findings should therefore be regarded as preliminary clinical evidence rather than confirmation from large, rigorously designed randomized controlled trials.

Table 3 Reported Raw Herbal Components of Chaishi Jiedu Granules and Dengue Formula No. 1

Preclinical evidence is available for Chaishi Jiedu Granules. In an interferon-receptor-blockaded C57BL/6 mouse model, the formulation was reported to limit early viremia, reduce the expression of the pro-inflammatory cytokines TNF-α and IL-6, and lessen virus-associated cerebral and renal injury.⁷⁹

Across the available clinical reports, adding these formulations to standard supportive care was associated with faster defervescence, relief of symptoms such as headache, myalgia, and rash, and recovery of leukocyte, lymphocyte, and platelet counts.^28,78 Because one study was observational and the other involved a small clinical sample, these findings do not establish causal efficacy. Standard supportive care included appropriate oral or intravenous fluid therapy, acetaminophen/paracetamol-based management of fever and pain, serial clinical and hematological monitoring, and additional rescue measures when clinically indicated.^18,80 Larger, multicenter, rigorously designed randomized controlled trials are required to confirm the efficacy and safety of these formulations.

Intravenous Therapeutics for Acute and Severe Intervention

In integrative clinical practice, Reduning Injection, Xiyanping Injection, and Tanreqing Injection have been used as intravenous TCM treatments for dengue. The Diagnosis and Treatment Protocol for Dengue (2024 Edition) lists them among the recommended TCM patent medicines for the febrile and critical stages.¹⁸ The following sections summarize their clinical effects, safety profiles, and possible mechanisms based on relevant clinical and experimental studies.

The intravenous route makes safety and tolerability especially important. Post-marketing and clinical safety data indicate that Reduning Injection generally has a low incidence of adverse drug reactions, whereas Xiyanping Injection and Tanreqing Injection are mainly associated with infusion-related or hypersensitivity reactions, including rash, pruritus, fever, and, rarely, anaphylaxis.^81–83 These agents should therefore be used according to approved indications and dosing instructions. Inappropriate drug combinations and rapid infusion should be avoided, and patients should be monitored closely during and shortly after administration, especially those with a history of allergy, hepatic or renal dysfunction, or other high-risk conditions.

Clinical trials show that adding Reduning Injection to standard therapy markedly shortens fever duration, accelerates normalization of hematological parameters, and improves overall clinical recovery rates.⁸⁴ Standard therapy included fluid replacement, symptomatic antipyretic treatment, routine clinical and hematological monitoring, and other supportive measures.⁸⁴ Network pharmacology suggests that Reduning may act on multiple targets through regulation of hypoxia-inducible factor-1 (HIF-1) and NF-κB signaling, with possible involvement of leukocyte transendothelial migration and apoptosis-related processes.⁸⁵

Xiyanping Injection contains andrographolide sulfonate as its main active pharmaceutical ingredient and has potent direct antiviral activity.^86,87 In severe infection models, including SCID-HepG2 xenograft mice, it significantly reduces viral genome replication and the proportion of virus-positive cells in the spleen, liver, and serum. These effects are accompanied by markedly longer survival and higher overall survival rates.⁸⁶

Tanreqing Injection has also shown marked anti-inflammatory and endothelial-protective effects.^88–90 In vitro and in vivo studies show that it inhibits progeny virion release and strongly suppresses the hyperinflammatory cascade.^88,89 It also inhibits activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, markedly reduces IL-1β cleavage, and attenuates leukocyte transendothelial migration by downregulating the ICAM-1/VCAM-1 axis.^88,89 In AG129 mouse models, these effects are associated with reduced multiorgan injury and prolonged survival.⁸⁸

Available clinical studies suggest that selected intravenous TCM preparations may improve fever control and hematological recovery.^84,90 Experimental and computational studies point to possible mechanisms involving antiviral activity, inflammasome suppression, and endothelial protection.^85,86,88,89

Challenges and Future Directions of Traditional Chinese Medicine in Dengue Treatment

Major Limitations and Strategic Perspectives

Traditional Chinese medicine (TCM) has an established theoretical basis for dengue treatment, but the field is still moving from experience-based practice toward rigorous evidence-based medicine (EBM).^10,11 The main limitation is the shortage of high-quality clinical data. Many available studies have small sample sizes (typically n < 72), single-center designs, and limited randomization or blinding.^{28,71,78,84,90} Several TCM interventions have been evaluated clinically, but the evidence remains limited. For this reason, this review distinguishes clinical findings from preclinical and computational mechanistic support. There is also a gap between the traditional Wei–Qi–Ying–Blood theory and modern clinical staging. Given the rapid 19- to 37-hour critical window of dengue progression, subjective traditional pattern identification (“Zheng”) should be combined with a three-part dynamic monitoring model.^16–18,91 Such a model should integrate traditional pattern assessment with objective biomarkers, particularly DENV RNA, NS1, IL-6, and the Ang-2/Ang-1 ratio, to improve risk stratification.^15,20,92 Mechanistic research remains fragmented, and in vitro studies of isolated compounds often progress faster than in vivo evaluation of complex formulas. Correlative findings therefore often come before clear causal evidence.^35,37,93,94 The pharmacological “material basis” of these multi-herb interventions, especially synergistic or antagonistic interactions among constituents, still needs to be defined across viral replication, systemic inflammation, and endothelial protection.^36,93 Current animal models, including AG129 mice and SCID-HepG2 xenograft systems, do not fully reproduce human-specific features such as antibody-dependent enhancement (ADE) and plasma leakage.^95,96 This limits clinical translatability.^95,96 International adoption is also hindered by the lack of standardized manufacturing and quality control for empirical formulas and in-hospital preparations.³⁶ Multicenter trials and standardized pharmacological evaluation are needed to define the role of TCM, especially injectable formulations, alongside modern supportive care in global dengue management.^11,36

Future Research Directions

Structure-based studies of highly conserved dengue proteins, including the NS2B-NS3 protease and NS5 polymerase, are important for drug development.^93,94 Co-crystal studies are needed to define binding modes and structure-activity relationships and support the design of anti-dengue therapeutics with high affinity and selectivity.⁹⁴ It is also important to examine whether multiple formula components bind cooperatively to viral or host targets. This approach may help clarify the scientific basis of molecular interactions and multicomponent synergy.

A rigorous safety framework is also needed when TCM is combined with Western medicine.^80,97,98 Prospective and retrospective studies should monitor drug-drug interactions and adverse events when TCM is used with antiviral agents, analgesics, or fluid therapy.^80,98 Real-world data platforms can support systematic collection of safety information across different populations.^81–83 Particular attention should be given to children, pregnant women, older adults, patients with chronic comorbidities, and those with hepatic or renal insufficiency.⁸⁰ This work can provide the evidence base needed for standardized integrative treatment protocols.^36,80,98

International validation also depends on a full-chain quality-control system covering botanical authentication, chemical fingerprinting, and pharmacodynamic consistency.³⁶ Multinational trials should be conducted in endemic regions, including Southeast Asia and South America, to evaluate formulations such as Chaishi Jiedu Granules across different ethnic populations and DENV serotypes. Nanodelivery systems and liposomal formulations should also be studied as ways to improve the bioavailability of compounds such as quercetin and berberine. Because these approaches alter pharmacokinetic profiles, cytotoxicity, dose-dependent toxicity, biodistribution, and safety limits should be evaluated alongside antiviral efficacy.^46,99 Progress in standardization and modernization could support the integration of TCM into the global framework for dengue prevention and treatment.³⁶

Conclusion

This review links the Wei–Qi–Ying–Blood theory and pattern identification with contemporary dengue staging and proposes a dynamic framework for stage-specific intervention. Current evidence suggests that TCM formulations and bioactive compounds, including Chaishi Jiedu Granules and Reduning Injection, have potential translational applications based on their proposed effects on viral replication, inflammation, vascular dysfunction, and coagulation abnormalities. Clinical use remains limited, however, by the lack of large, high-quality randomized controlled trials, insufficient systems-level mechanistic validation, and the absence of standardized manufacturing and quality-control frameworks. Future research should prioritize DENV-specific mechanistic validation, standardized quality control of TCM preparations, and adequately powered multicenter randomized controlled trials with clinically meaningful endpoints. Network pharmacology, multi-omics analysis, and chemical fingerprinting may help address current gaps in mechanism and standardization. This work could improve the reproducibility of TCM-based interventions, support international evaluation and wider scientific communication, and contribute to a modern interpretation of classical theory in dengue management.