Host-response biomarker MxA for etiological discrimination of pediatric lower respiratory tract infections: implications for diagnostic study design

Introduction

Lower respiratory tract infections (LRTIs) remain a leading cause of pediatric morbidity, mortality, and antibiotic exposure worldwide (1,2). In high-density populations such as China, seasonal epidemics further increase healthcare burden and complicate clinical decision-making (3). Accurate discrimination between viral and bacterial etiologies is therefore central to effective LRTI management and antibiotic stewardship. However, in children, clinical manifestations are frequently nonspecific, with substantial overlap across etiologies, limiting the reliability of symptom-based assessment alone (4,5).

Conventional microbiological diagnostics face important constraints in pediatric practice. Blood cultures have low sensitivity in childhood pneumonia (6), while respiratory samples are prone to contamination and may reflect colonization rather than true infection. Although molecular multiplex panels have improved detection rates, they often identify multiple agents, leaving causal attribution—particularly in the context of viral-bacterial coinfection—uncertain (7,8). This diagnostic uncertainty directly contributes to antibiotic overuse, accelerating antimicrobial resistance and exposing children to avoidable treatment-related risks (9,10).

Common inflammatory biomarkers, including C-reactive protein (CRP) and procalcitonin (PCT), are widely used but lack sufficient etiological specificity. Considerable overlap between viral and bacterial infections is observed, especially during early disease stages and in mixed infections (11-16). These limitations highlight the need for biomarkers that more directly reflect host-pathogen interactions rather than nonspecific inflammation.

Host-response biomarkers offer a mechanistically grounded alternative. Myxovirus resistance protein A (MxA) is a cytoplasmic dynamin-like GTPase strongly induced by type I and type III interferons (IFNs) during viral infection (Figure 1) (17-20). In contrast, its expression remains low in most isolated bacterial infections, providing a clear biological rationale for its role as an antiviral-specific marker (18,21). Early studies in both adult and pediatric populations have demonstrated promising diagnostic performance of MxA for distinguishing viral from bacterial respiratory infections (20,22-24).

Figure 1 Innate immune signaling pathways leading to MxA induction and antiviral activity in respiratory epithelial cells. Step 1: viral recognition via PRRs viruses carry unique PAMPs. In infected cells, specialized PRRs—such as RIG-I, TLR3/7, and MDA5—detect these PAMPs. Step 2: activation of transcription factors & interferon production. This detection triggers the activation of transcription factors IRF3/IRF7. Once activated, they drive the production and secretion of type I IFNs (key antiviral signaling molecules). Step 3: IFN signaling & JAK-STAT pathway activation. Secreted type I interferons (IFN-I), together with type III interferons (IFN-III, IFN-λ), bind to their respective receptors (IFNAR1/IFNAR2 and IFNLR1/IL10R2) on infected and neighboring epithelial cells. This binding activates the JAK-STAT signaling pathway: receptor-associated kinases phosphorylate STAT1 and STAT2; Phosphorylated STAT1/STAT2 associate with IRF9 to form the ISGF3 complex. Step 4: nuclear translocation & antiviral gene induction. The ISGF3 complex enters the nucleus and binds to ISREs in the promoter regions of ISGs (e.g., MxA). Step 5: antiviral effector function. Expression of ISGs (such as MxA) generates antiviral proteins that block viral replication and assembly within infected cells, ultimately limiting viral spread in the respiratory epithelium. This flowchart details how the innate immune system detects viral invasion and mounts a coordinated response to suppress viral infection. Each step—from PRR activation to ISG-mediated viral inhibition—highlights the complexity of host-virus interactions in innate immunity. IFNs, interferons; ISGF3, interferon-stimulated gene factor 3; ISGs, interferon-stimulated genes; ISREs, interferon-stimulated response elements; MxA, myxovirus resistance protein A; PAMPs, pathogen-associated molecular patterns; PRRs, pattern recognition receptors.

Importantly, beyond its role as a general antiviral marker, MxA expression has been reported across a wide spectrum of specific viral infections, including respiratory syncytial virus (RSV), influenza virus, and other RNA viruses. While MxA does not provide pathogen-specific identification, its consistent induction across these viral diseases reflects a conserved IFN-driven antiviral state. This feature supports its utility as a universal host-response biomarker, particularly in settings where multiplex pathogen detection yields multiple candidates but lacks etiological attribution. Recent studies [2024–2026] have further expanded this field, examining MxA across etiological subtypes (25), evaluating point-of-care platforms combining MxA and CRP (26,27), and extending its application to upper respiratory tract infections (28). Nevertheless, the pediatric evidence base remains fragmented. Key unresolved issues include heterogeneous study designs, inconsistent classification of mixed infections, and the absence of robust, age-specific reference ranges for MxA in healthy children (23,24,29).

Accordingly, this review synthesizes current evidence on MxA in pediatric LRTIs with a specific focus on diagnostic study design. Beyond summarizing diagnostic accuracy, we propose a conceptual shift from inflammation-based inference toward IFN-driven host-response profiling. In this framework, MxA represents a distinct antiviral signaling axis that complements conventional inflammatory biomarkers. Building on this mechanistic basis, the temporal dynamics of MxA in relation to CRP and PCT further clarify its diagnostic role (Figure 2). We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0128/rc).

Figure 2 Temporal kinetics of MxA compared with CRP and PCT following infection onset. Schematic curves illustrate the dynamic changes of MxA and commonly used inflammatory biomarkers after the onset of infection. PCT rises rapidly within 3–6 hours, reflecting an early systemic response to bacterial infection, and declines with an approximate half-life of 24 hours. In contrast, CRP shows delayed kinetics, typically increasing after 12 hours and peaking around 36–50 hours. Lactate elevation occurs later in the disease course and is associated with tissue hypoperfusion and severity of sepsis. WBC, shown as a schematic dashed curve, exhibits variable and non-specific changes with limited temporal diagnostic value. MxA is shown as a schematic early-response curve, rising within approximately 4–6 hours after viral stimulation, reaching peak levels at approximately 12–24 hours, and then gradually declining. Unlike CRP and PCT, whose kinetics are more extensively characterized in clinical settings, the temporal pattern of MxA is illustrated schematically based on interferon-stimulated gene expression dynamics and experimental observations from viral infection studies, as no standardized clinical time-course curve is currently available. These distinct kinetic profiles highlight two complementary host-response axes: interferon-driven antiviral signaling represented by MxA, and inflammation-driven bacterial response reflected by CRP and PCT. This temporal divergence provides a biological rationale for multi-marker strategies in etiological discrimination of pediatric lower respiratory tract infections. This temporal divergence positions MxA as an early virus-specific marker, complementing CRP and PCT in bacterial inflammation, thereby supporting a dual-axis diagnostic framework. CRP, C-reactive protein; MxA, myxovirus resistance protein A; PCT, procalcitonin; WBC, white blood cell count.

Methods

Study design

This review does not aim to provide pooled quantitative estimates but to inform study design. The work constitutes a structured, pre-trial evidence synthesis designed to inform the protocol development for a prospective diagnostic accuracy study evaluating MxA in pediatric LRTI. It adopts a narrative review methodology focused on integrating clinically and methodologically relevant data rather than conducting a formal systematic review with meta-analysis.

Literature search strategy

A comprehensive search of electronic databases (PubMed, Embase, Web of Science) was performed for literature published up to January 2026. The search strategy combined Medical Subject Headings (MeSH) and free-text terms: (“Myxovirus Resistance Protein A” OR “MxA” OR “MX1”) AND (“child” OR “pediatric” OR “infant”) AND (“lower respiratory tract infection” OR “pneumonia” OR “bronchiolitis”) AND (“biomarker” OR “diagnos*” OR “sensitivity and specificity”). References of identified articles and relevant reviews were manually screened. Searches were limited to English and Chinese languages.

Eligibility criteria

Inclusion criteria were: (I) pediatric population (age ≤18 years); (II) measurement of quantitative MxA levels in blood or whole-blood-derived samples; (III) enrollment of participants with clinically or microbiologically defined LRTI (viral, bacterial, or mixed) or healthy controls; (IV) reporting of data relevant to diagnostic discrimination (e.g., intergroup comparisons, sensitivity, specificity, AUC). Exclusion criteria were: (I) studies exclusively in adults; (II) lack of etiological classification; (III) focus on non-respiratory infections; (IV) non-primary research (e.g., editorials, case reports without datasets).

Data extraction and synthesis

Data were extracted using a standardized form capturing study characteristics (design, setting, population), etiological definitions, MxA assay details (platform, sample type), timing of sampling, and diagnostic performance metrics. Given the anticipated and observed heterogeneity in reference standards and methodologies, a quantitative meta-analysis was deemed inappropriate. Instead, a qualitative descriptive synthesis was performed, organized around predefined etiological subgroups: viral LRTI, bacterial LRTI, mixed viral-bacterial LRTI, and healthy controls.

Results

MxA in viral LRTIs

Consistently across pediatric studies, blood MxA concentrations are significantly elevated in children with viral LRTI compared to those with bacterial infections or healthy controls (22-24). This elevation reflects the activation of the type I/III IFN pathway. Early foundational studies demonstrated marked MxA upregulation during acute viral respiratory infections with minimal overlap with uninfected controls (23,24). The TREND study, a large prospective cohort, reported strong discriminatory ability of MxA for viral LRTI, with area under the receiver operating characteristic curve (AUC) values approaching or exceeding 0.90 in a setting of high pneumococcal vaccine coverage (22). This performance appears robust across common respiratory viruses (e.g., RSV, influenza), underscoring that MxA signals a general antiviral state rather than pathogen-specific detection (22,25).

MxA in bacterial LRTIs

In contrast, MxA levels in bacterial LRTI remain low, primarily because most extracellular bacteria do not strongly activate type I/III IFN pathways. Unlike viral pathogens, which trigger intracellular nucleic acid sensing (e.g., RIG-I, MDA5), bacterial infections predominantly activate NF-κB-mediated inflammatory pathways rather than IFN-driven antiviral responses. This fundamental difference in host immune activation constitutes the biological basis for the discriminatory capacity of MxA.

MxA in mixed viral-bacterial infections

Mixed infections represent a critical and common clinical challenge.Mixed infections should be distinguished from simple viral carriage with concurrent bacterial infection. True mixed infection refers to the simultaneous pathogenic contribution of both viral and bacterial agents to disease manifestation, supported by clinical, microbiological, and host-response evidence. In contrast, viral detection alone (e.g., by PCR) may represent asymptomatic carriage or residual shedding. Failure to distinguish these entities contributes to heterogeneity across studies and may partially explain the intermediate MxA levels observed in this group. Data specific to this subgroup are limited, as many studies have either excluded such cases or not analyzed them separately (7,22). Available evidence indicates that MxA levels in mixed infections often occupy an intermediate range between purely viral and purely bacterial cases, leading to substantial overlap and reduced diagnostic classification accuracy (25,30). A 2025 cohort study explicitly highlighted this limitation, showing that while MxA effectively discriminated viral from bacterial infections, its performance significantly declined in the mixed infection subgroup (25).

Comparative performance of MxA, CRP, and PCT

The differential diagnostic performance of MxA, CRP, and PCT is fundamentally rooted in their distinct biological pathways and temporal response kinetics. While CRP and PCT primarily reflect systemic inflammation and bacterial burden, MxA specifically captures IFN-mediated antiviral responses, representing a mechanistically distinct dimension of host-pathogen interaction.

As illustrated in Figure 2, MxA and conventional inflammatory biomarkers exhibit markedly different temporal dynamics following infectious insult, reflecting divergent host-response pathways. PCT rises rapidly within 3–6 hours, indicating early systemic responses to bacterial infection, whereas CRP demonstrates delayed kinetics, typically increasing after 12 hours and peaking at approximately 36–50 hours. In contrast, MxA, as an IFN-stimulated gene product, is induced early during viral infection, generally within 4–6 hours following IFN activation, reaching peak levels around 12–24 hours before gradually declining. These temporal differences highlight a critical limitation of CRP and PCT in early disease stages, where delayed or non-specific inflammatory responses may obscure etiological discrimination.

Across studies, MxA consistently demonstrates higher specificity for viral infections, with minimal elevation in most isolated bacterial infections. In contrast, CRP and PCT exhibit substantial overlap between viral and bacterial etiologies, particularly in early disease phases and in mixed infections. For example, CRP may be elevated in severe viral infections due to secondary inflammatory activation, while PCT may remain low in localized or early bacterial infections, reducing their standalone diagnostic reliability. These patterns underscore the intrinsic limitations of inflammation-based biomarkers when used in isolation.

Importantly, MxA exhibits superior ability to “rule in” viral infection, whereas CRP and PCT are more effective in identifying bacterial inflammation. Rather than representing competing biomarkers, these markers reflect complementary biological processes. This complementarity can be conceptualized as a dual-axis host-response model, integrating IFN-driven antiviral signaling (MxA) and inflammation-driven bacterial response (CRP/PCT).

Together, these findings suggest that single-marker approaches are inherently limited, as they capture only one dimension of host response. Integrating MxA with CRP and/or PCT provides a more biologically coherent and clinically informative strategy for etiological discrimination in pediatric LRTIs, particularly in early disease stages and diagnostically ambiguous presentations.

Combined biomarker strategies

To improve diagnostic accuracy, several studies have evaluated algorithms combining MxA with bacterial-associated inflammatory markers like CRP. These strategies aim to leverage complementary biological signals. Evidence suggests that combined MxA-CRP approaches can achieve better discrimination than either marker alone for differentiating viral from bacterial etiologies (31-33). Point-of-care tests integrating both biomarkers (e.g., FebriDx^®) have shown promise in feasibility studies for reducing antibiotic prescribing in primary care (27,32). However, similar to MxA alone, the accuracy of combined strategies is also attenuated in mixed infections (25). Rather than a limitation, the intermediate MxA signal in mixed infections may reflect biologically meaningful host-response dominance, suggesting a shift from pathogen-centric to host-centric etiological classification. Mechanistically, combined biomarker strategies integrate two distinct host-response axes: MxA reflects IFN-driven antiviral signaling, whereas CRP/PCT capture bacterial-induced inflammatory responses. This dual-axis framework enables a more nuanced interpretation of infection etiology, particularly in borderline or mixed presentations, where reliance on a single biomarker may be insufficient.

Reference values of MxA in healthy children

Establishing reliable pediatric reference ranges is a prerequisite for the clinical implementation of MxA-based diagnostics. Rather than relying on a universal diagnostic cut-off, emerging evidence supports the use of assay-specific reference distributions, reflecting biological and technical variability across platforms and populations (22-24,29).

Available studies consistently report low baseline MxA concentrations in healthy children; however, substantial inter-study variability exists, driven by differences in assay methodology (e.g., ELISA versus point-of-care immunoassays), sample matrices (plasma versus whole blood), and age composition of study cohorts. Importantly, few studies have incorporated prospectively enrolled, age-stratified healthy control groups, limiting the interpretability and generalizability of proposed thresholds.

From a methodological perspective, future diagnostic studies should adopt a percentile-based framework, reporting age- and assay-specific reference distributions rather than fixed cut-offs. Healthy control cohorts should be embedded within each study, matched for age and analyzed using the same analytical platform as clinical samples. Reporting of upper reference limits (e.g., 95th or 97.5th percentiles) would allow context-dependent interpretation while accounting for biological heterogeneity during immune maturation in childhood (17-19).

Recent studies [2024–2026] increasingly emphasize the need for assay- and context-specific baseline calibration rather than reliance on universal cut-off values (25,28). Accordingly, the establishment of pediatric MxA reference values should be considered a core design element, not a secondary analysis, in future prospective diagnostic investigations.

Discussion

This synthesis supports a conceptual reframing of infection diagnostics in pediatric LRTI. Rather than relying solely on inflammation-based biomarkers, which provide indirect and often overlapping signals, MxA introduces an IFN-driven antiviral axis that directly reflects host-virus interaction. This dual-axis framework—comprising antiviral (MxA) and inflammatory (CRP/PCT) responses—offers a more biologically coherent approach to etiological discrimination.

Addressing the challenge of mixed infections

The suboptimal performance in mixed infections—a prevalent phenotype (7) —remains a key limitation. Future studies should prospectively define mixed infection as a core analytical subgroup, report diagnostic accuracy separately, and ensure sufficient statistical power for subgroup analyses rather than treating coinfection as an exclusion or secondary outcome.Future studies should adopt a rigorous framework for defining mixed infections, integrating longitudinal clinical follow-up, quantitative pathogen load assessment, and host-response profiling. Dynamic evaluation—such as serial biomarker measurements—may help distinguish true co-pathogenic infection from incidental viral carriage. In addition, predefined diagnostic criteria combining molecular detection, clinical severity, and expert adjudication should be incorporated to improve classification accuracy.

Harmonizing etiological reference standards

Substantial heterogeneity in how “viral”, “bacterial”, and “mixed” infections are defined across studies complicates evidence synthesis and threshold derivation. Future prospective studies should employ standardized, multi-modal reference standards combining molecular pathogen detection, clinical criteria, and expert adjudication where possible. Sensitivity analyses using different reference standard definitions should be planned to assess robustness.

Establishing pediatric reference ranges

The lack of standardized pediatric MxA reference values is a critical barrier to clinical implementation. Variability driven by assay and population factors precludes the adoption of a single diagnostic threshold. Therefore, prospective diagnostic studies must incorporate adequately sized healthy control groups, matched for key factors like age, to establish internal reference distributions. Reporting should include age-stratified percentiles (e.g., 95th, 97.5th percentiles).

From diagnostic accuracy to clinical impact

Diagnostic accuracy alone is an intermediate outcome. MxA-based strategies may be best positioned as antibiotic rule-out tools rather than standalone etiological classifiers. The ultimate value of MxA lies in its capacity to improve clinical decision-making and antibiotic stewardship. Future investigations should therefore adopt pragmatic or pathway-embedded designs to evaluate patient-centered and system-level outcomes, including antibiotic exposure, length of stay, and safety endpoints.

Evaluating combined biomarker strategies

Although combined MxA-CRP strategies appear promising, their real-world feasibility and cost-effectiveness remain insufficiently studied. Prospective evaluations should test multi-marker algorithms within routine workflows and incorporate health-economic analyses to quantify effects on resource utilization and healthcare costs.

Integration of reference range establishment within the conceptual framework

As illustrated in Figure 3, the establishment of pediatric MxA reference ranges constitutes a foundational component of MxA-based diagnostic study design. Within the proposed framework, healthy control cohorts are embedded alongside clinical enrollment to generate age- and assay-specific reference distributions, which serve as the interpretative baseline for subsequent diagnostic analyses.

Figure 3 Conceptual framework for the design and evaluation of MxA-based diagnostic studies in pediatric lower respiratory tract infections. The framework summarizes key methodological challenges and corresponding design recommendations across four core domains: population definition, etiological reference standards, index biomarkers, and clinical impact. Major challenges include the high prevalence of mixed viral-bacterial infections, heterogeneous etiological definitions, assay- and age-dependent MxA thresholds, and uncertain real-world feasibility. To address these issues, future studies should prospectively define and power mixed-infection subgroups, adopt standardized multi-modal reference standards, establish age- and assay-specific reference ranges using healthy controls, and evaluate combined biomarkers strategies (e.g., MxA-CRP) within pragmatic clinical pathways. The ultimate endpoints extend beyond diagnostic accuracy to include antibiotic use, length of hospital stay, safety, and healthcare costs, thereby facilitating the translation of MxA-based diagnostics into routine pediatric practice. CRP, C-reactive protein; LOS, length of stay; MxA, myxovirus resistance protein A.

Rather than applying fixed thresholds across heterogeneous populations, reference distributions inform probabilistic interpretation of MxA values in viral, bacterial, and mixed infection phenotypes. This approach enables context-dependent classification, improves robustness in mixed infections, and facilitates integration with additional biomarkers such as CRP within multi-marker decision algorithms.

By positioning reference range establishment upstream of diagnostic accuracy assessment and downstream clinical impact evaluation, the framework emphasizes that reference calibration is not a secondary analytical step but a core methodological prerequisite for reliable translation of host-response biomarkers into pediatric clinical practice.

Conceptually, MxA reframes infection diagnostics from inflammation-based inference to IFN-driven host-response profiling, representing a shift toward mechanism-informed clinical decision-making.

Conclusions

MxA represents a biologically grounded host-response biomarker with strong potential for distinguishing viral from bacterial infections in pediatric LRTI. Current evidence supports its high specificity for viral infections and its complementary role alongside traditional inflammatory markers. However, key challenges—including heterogeneous study designs, unclear definitions of mixed infection, and the absence of standardized pediatric reference ranges—limit clinical implementation. Future research should prioritize standardized etiological frameworks, robust subgroup analysis, integration of multi-marker strategies, and evaluation within real-world clinical pathways. Addressing these gaps will be essential for translating MxA into routine clinical practice and improving antibiotic stewardship in children.

Strengths and limitations

The key strength of this review lies in its design-oriented perspective, which synthesizes existing evidence to identify critical methodological gaps and inform future diagnostic study design rather than merely summarizing diagnostic accuracy. By explicitly addressing real-world complexities—such as the high prevalence of mixed infections and heterogeneity in etiological reference standards—it highlights issues often underemphasized in prior reviews but central to clinical translation. A narrative, non-quantitative approach represents a limitation; however, this strategy was intentionally adopted given the substantial heterogeneity in study designs, assay platforms, and outcome definitions, under which pooled quantitative estimates would risk oversimplification and potentially misleading conclusions. Instead, this approach preserves methodological nuance and real-world complexity, which are essential for guiding the development of robust and clinically meaningful MxA-based diagnostic strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0128/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0128/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0128/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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