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OBM Genetics

(ISSN 2577-5790)

OBM Genetics is an international Open Access journal published quarterly online by LIDSEN Publishing Inc. It accepts papers addressing basic and medical aspects of genetics and epigenetics and also ethical, legal and social issues. Coverage includes clinical, developmental, diagnostic, evolutionary, genomic, mitochondrial, molecular, oncological, population and reproductive aspects. It publishes a variety of article types (Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.). There is no restriction on the length of the papers and we encourage scientists to publish their results in as much detail as possible.

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Open Access Review

The Roles of IL-6, IL-8, and TNF-α in Pediatric Immune Defense and Infection Severity

Monday Uchenna Obaji , Angus Nnamdi Oli *, Malachy C Ugwu

  1. Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Agulu, Nigeria

* Correspondence: Angus Nnamdi Oli

Academic Editor: Lunawati L Bennett

Received: December 12, 2024 | Accepted: April 13, 2025 | Published: April 23, 2025

OBM Genetics 2025, Volume 9, Issue 2, doi:10.21926/obm.genet.2502293

Recommended citation: Obaji MU, Oli AN, Ugwu MC. The Roles of IL-6, IL-8, and TNF-α in Pediatric Immune Defense and Infection Severity. OBM Genetics 2025; 9(2): 293; doi:10.21926/obm.genet.2502293.

© 2025 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Cytokines are pivotal regulators of immune responses. They are critical in mediating inflammation, recruiting immune cells, and driving pathogen clearance. Among these, interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α) stand out as key players in pediatric immunity, as they exhibit unique expression patterns that reflect the dynamic nature of the developing immune system. This review explores the dual roles of these cytokines in orchestrating immune defense and their potential as diagnostic biomarkers for infection severity in children. It highlights how elevated IL-6, IL-8, and TNF-α levels correlate with the severity of bacterial, viral, and fungal infections and discusses their utility in distinguishing between these etiologies. The article pinpoints current technologies for cytokine detection and their impact on early diagnosis and risk stratification. The relevance of cytokine-targeted therapies in managing hyperinflammatory states is highlighted and argued that integrating cytokine profiling with other diagnostics and personalized medicine has transformative potential in pediatric healthcare. These would pave the way for more precise, timely, and effective management of pediatric infections.

Keywords

Cytokines; children; infection; immune responses

1. Introduction

The immune system is a cornerstone of host defense against pathogenic microorganisms. Among the key players in immune regulation are cytokines, which are small signaling proteins that mediate and modulate inflammatory responses. Interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α) serve as critical mediators of the immune response to infections [1,2,3]. These cytokines ar vital for immune defense and hold significant potential as biomarkers for assessing the severity of infections in pediatric populations. IL-6 is a pleiotropic cytokine with pro-inflammatory and anti-inflammatory roles [4]. It is rapidly produced in response to infections and tissue injury, initiating the acute-phase reaction by stimulating the production of C-reactive protein (CRP) and other inflammatory mediators in the liver [5]. In children, IL-6 is particularly crucial in early immune responses because it helps to mobilize leukocytes and enhance pathogen clearance [6]. Elevated IL-6 levels have been observed in severe bacterial infections, sepsis, and inflammatory syndromes.

IL-8 is a chemokine primarily responsible for recruiting neutrophils to sites of infection. This cytokine plays a pivotal role in the first line of defense against bacterial pathogens by directing neutrophils to areas of inflammation where they perform phagocytosis and degranulation [7]. In pediatric infections, elevated IL-8 levels are mostly linked to conditions such as pneumonia, neonatal sepsis, and meningitis. The unique patterns of its expression during various infections in children could serve as a valuable diagnostic tool for distinguishing between bacterial and viral infections and assessing infection severity [8].

TNF-α is a pro-inflammatory cytokine central in mediating immune responses against infections. It promotes the activation of macrophages, the recruitment of immune cells, and the induction of apoptosis in infected cells. In children, it is often a marker of severe infection and systemic inflammation [9]. High levels of TNF-α have been implicated in pediatric sepsis and other hyperinflammatory states, where its dysregulated expression can exacerbate tissue damage and organ dysfunction. This dual role, both as a protector and a potential driver of pathology, forms the basis of its clinical importance in managing and diagnosing severe infections [10,11,12].

The ability to measure cytokine levels accurately is a potential opportunity for diagnosing infections and measuring their severity. In pediatric patients, where clinical symptoms may overlap between bacterial and viral infections, they provide objective biomarkers that can guide treatment decisions. For instance, elevated IL-6 levels can indicate the need for aggressive treatment in sepsis, while high IL-8 levels may signal bacterial etiology [13,14,15,16]. Similarly, TNF-α levels could help identify patients at risk of progressing to severe systemic inflammation or multi-organ dysfunction [17]. Despite their numerous clinical potential, the translation of cytokine data into routine clinical practice faces challenges, including variability in cytokine expression due to age, genetic factors, and comorbidities [18]. There are no standardized protocols for measuring and interpreting cytokine levels in children. This review addresses these gaps by synthesizing current evidence on IL-6, IL-8, and TNF-α in pediatric immune responses and their diagnostic utility.

2. Biological Functions of IL-6, IL-8, and TNF-α

IL-6 is a multifunctional cytokine with critical roles in regulating immune and inflammatory responses. It is produced by various cell types in response to infections, trauma, or tissue injury. It is a primary mediator of the acute-phase response. It stimulates hepatocytes in the liver to produce acute-phase proteins such as C-reactive protein (CRP), fibrinogen, and serum amyloid A. These proteins enhance pathogen clearance and limit tissue damage [19,20,21,22]. It acts as both a pro-inflammatory and anti-inflammatory mediator [23]. As a pro-inflammatory mediator, it promotes the activation of T cells and B cells, contributing to adaptive immunity. As an anti-inflammatory mediator, it can inhibit the effects of TNF-α and interleukin-1 (IL-1) by inducing the production of interleukin-10 (IL-10). It is responsible for systemic manifestations of inflammation, including fever and the mobilization of neutrophils from the bone marrow [24,25]. In pediatric infections, IL-6 levels often correlate with disease severity, making it a critical cytokine in diagnosing and managing severe inflammatory states [26].

IL-8 is primarily involved in the recruitment and activation of neutrophils. It plays a vital role in the innate immune response. It is a potent chemotactic factor that directs neutrophils to sites of infection or injury. This targeted migration ensures a robust and localized response to pathogens [27]. Once at the site, IL-8 activates neutrophils, enhancing their phagocytic activity and degranulation to eliminate pathogens. It also promotes the release of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) to combat infections [28]. It contributes to tissue repair and healing by promoting the formation of new blood vessels in response to injury or illness. In children, it plays a key role in conditions such as bacterial pneumonia and neonatal sepsis. Elevated IL-8 levels can indicate bacterial infections and help differentiate them from viral infections [29,30].

TNF-α is a pro-inflammatory cytokine produced by macrophages, dendritic cells, and other immune cells in response to infections and tissue damage. It is a key mediator of inflammation and immune responses. It binds to TNF receptors (TNFR1 and TNFR2) on target cells, initiating apoptotic pathways [31,32]. This controlled cell death eliminates infected or damaged cells, preventing pathogen replication and aiding tissue repair. It activates the nuclear factor kappa B (NF-κB) pathway that leads to the production of other inflammatory cytokines and chemokines [33]. It enhances the recruitment of immune cells to infection sites and amplifies the inflammatory response. It promotes macrophage activation, increases their ability to phagocytose pathogens, and presents antigens to T cells. It also stimulates endothelial cells to express adhesion molecules and facilitate leukocyte migration [34]. Although essential for host defense, dysregulated TNF-α production can lead to excessive inflammation and tissue damage. In children, elevated TNF-α levels are associated with severe infections like sepsis, severe dengue, and septic shock [35].

Different infections trigger distinct cytokine response patterns due to variations in host-pathogen interactions and immune activation pathways. For instance, bacterial infections are characterized by high IL-6, IL-8, and TNF-α levels, which drive a robust neutrophil-mediated response and promote inflammation and pathogen clearance [36]. In contrast, viral infections typically induce high IFN-γ and IL-10 levels, which reflect antiviral immunity and immune regulation, with IFN-γ enhancing viral clearance and IL-10 helping to prevent excessive immune activation. Meanwhile, fungal infections elicit elevated IL-6, IL-8, and IL-10, which lead to chronic inflammation and immune evasion, as fungi can persist in host tissues by modulating immune responses [37]. To provide a clearer comparison, Table 1 below presents a comparative overview of cytokine responses in bacterial, viral, and fungal infections.

Table 1 Comparative cytokine profiles in bacterial, viral, and fungal infections.

3. Cytokine Expression Patterns in Children

The immune system in children undergoes significant development after birth, adapting to a world filled with diverse antigens. Cytokines, as key mediators of immune responses, play a crucial role in this adaptation process. Their expression patterns in pediatric populations differ markedly from those in adults, influencing both immunity and the ability to regulate inflammation. Newborns have an underdeveloped immune system characterized by limited innate immunity and an immature adaptive immune response. At birth, cytokine production is skewed toward anti-inflammatory pathways to avoid overreaction to environmental antigens. This is partly driven by maternal regulatory factors during gestation [51,52].

In neonates and infants, the immune system is predominantly Th2-biased, producing cytokines like interleukin-4 (IL-4) and IL-10 [11]. This helps protect against overactive Th1 responses, which could damage tissue. This bias also means lower production of Th1-associated cytokines like TNF-α and interferon-gamma (IFN-γ), potentially reducing the ability to respond robustly to intracellular pathogens. As children grow, their immune system matures, cytokine production shifts toward a balance between pro-inflammatory and anti-inflammatory responses [31]. IL-6 and TNF-α levels become more responsive to infections as the innate immune system matures, while IL-8 production supports neutrophil recruitment, which is critical in bacterial infection defense [53]. In pediatric infections, IL-6, IL-8, and TNF-α are often overproduced in response to pathogens, reflecting the immune system's vigorous attempt to compensate for immaturity. However, this overproduction can lead to excessive inflammation, as seen in conditions like pediatric sepsis or hyperinflammatory syndromes [54,55,56]. Cytokine production in children is also influenced by genetic factors, epigenetic modifications, and environmental exposures, which include infections, vaccinations, and nutrition. Regulatory mechanisms, such as the activity of T regulatory (Treg) cells, are still developing, which can contribute to dysregulated cytokine responses in some instances [57].

In adults, innate immune cells like macrophages and neutrophils produce higher baseline levels of pro-inflammatory cytokines (e.g., TNF-α and IL-6) than children. This reflects a more robust first-line defense in adults. Children exhibit delayed and lower IL-6 and TNF-α responses during early life, potentially making them more vulnerable to severe infections. Adults have a well-established adaptive immune response with a balanced Th1/Th2 cytokine profile [58]. In children, the predominance of Th2 cytokines such as IL-4 and IL-10 contributes to weaker cell-mediated immunity but protects against excessive inflammation. In adults, cytokine dysregulation often leads to chronic inflammatory diseases such as rheumatoid arthritis, which are driven by persistent production of cytokines [59]. In children, cytokine dysregulation is more commonly associated with acute inflammatory syndromes, such as MIS-C or pediatric sepsis, where cytokines like IL-6 and IL-8 surge dramatically. Adults are more likely to develop long-lasting immune memory and regulate cytokine expression post-infection [60]. Children may experience prolonged or exaggerated cytokine responses due to the slower resolution of inflammation, which increases the risk of complications like multi-organ dysfunction in severe infections. Studies have shown that cytokine thresholds for diagnostics (e.g., IL-6 levels in sepsis) differ significantly between children and adults. These variations necessitate age-specific reference ranges for cytokine-based diagnostics [61]. Table 2 shows clinical trial data on cytokine-targeted therapies in pediatric patients.

Table 2 Clinical trial data on cytokine-targeted therapies in pediatric patients.

4. Multisystem Inflammatory Syndrome in Children (MIS-C)

MIS-C is a hyper-inflammatory condition associated with SARS-CoV-2 infection, resembling Kawasaki disease (KD) but with systemic involvement. IL-6 is a key driver of the cytokine storm in MIS-C, contributing to fever, vascular inflammation, and multi-organ involvement [65]. Elevated levels of IL-8 are linked to neutrophil activation and endothelial damage, exacerbating the inflammatory state. TNF-α amplifies inflammation and promotes cardiac dysfunction, a common complication in MIS-C. Cytokine panels, including IL-6 and TNF-α, differentiate MIS-C from other inflammatory conditions and guide treatment. IL-6 receptor inhibitors e.g., tocilizumab and TNF-α blockers are emerging therapeutic options [66,67,68,69].

KD is an acute vasculitis of unknown etiology that primarily affects children under 5 years old, with cytokine dysregulation playing a central role. Elevated levels of IL-6 contribute to systemic inflammation and coronary artery involvement. IL-8 is involved in neutrophil activation and vascular damage, which are hallmark features of KD. TNF-α Plays a role in the progression of coronary artery aneurysms, a severe complication of KD. Monitoring cytokine levels can help identify children at risk for severe cardiac complications. Anti-inflammatory treatments, including IV immunoglobulin (IVIG) and corticosteroids, target cytokine-driven pathways [70,71]. Acute Respiratory Distress Syndrome (ARDS) in children is characterized by severe lung inflammation and hypoxia, often triggered by infections or trauma. IL-6 contributes to the acute-phase response and lung inflammation, which leads to fluid accumulation and reduced oxygen exchange. IL-8 drives neutrophil infiltration into the lungs, exacerbating lung damage and inflammation. TNF-α promotes endothelial dysfunction and increases vascular permeability, thereby worsening respiratory distress. Cytokine levels can stratify ARDS severity and inform ventilatory support strategies [72,73,74].

Cytokine dysregulation is a hallmark of autoimmune conditions such as juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE). IL-6 drives chronic inflammation and contributes to joint damage in JIA and systemic inflammation in SLE. IL-8 promotes neutrophil activation, which leads to tissue damage in autoimmune conditions. TNF-α plays a central role in inflammatory cascades, exacerbating symptoms in autoinflammatory disorders. Cytokine profiling helps tailor immunosuppressive therapies to individual patients [75,76].

5. Cytokine-Based Diagnostic Tools

Enzyme-linked immunosorbent Assay (ELISA) is widely used for measuring individual cytokines in blood or serum samples. ELISA offers high specificity and sensitivity that makes it suitable for detecting cytokine elevations in infections [77]. Elevated IL-6 levels are reliable biomarkers for bacterial infections, sepsis, and severe inflammation. High IL-6 correlates with organ dysfunction, which makes it an essential marker for stratifying infection severity. IL-8 can differentiate bacterial from viral infections, particularly in febrile infants and children. Elevated levels also predict poor outcomes in conditions like sepsis and pneumonia. High TNF-α levels predict septic shock and mortality in severe bacterial infections. Monitoring TNF-α can aid in the early identification of hyperinflammatory conditions. Combining cytokine data with clinical features, imaging results, and other biomarkers e.g., procalcitonin, can enhance the accuracy of diagnosis. For example, high IL-6 + CRP equals likely bacterial sepsis. Meanwhile, moderate IL-6 + IL-8 + mild CRP elevation equals viral or bacterial infection [78,79].

Targeting cytokines directly through immunomodulatory agents is a veritable option in treating severe pediatric infections, especially those associated with cytokine storms. For instance, tocilizumab is a monoclonal antibody that blocks the IL-6 receptor and reduces inflammation. It has been approved for conditions like MIS-C and has shown efficacy in severe COVID-19 cases [80]. Sarilumab is another IL-6 receptor antagonist under investigation for pediatric hyperinflammatory conditions. Infliximab is a monoclonal antibody that inhibits TNF-α. These drugs are already used in autoimmune diseases and are being explored for sepsis and severe inflammatory infections [81]. Technologies like Cytosorb are used to physically remove IL-6 and TNF-α from the bloodstream in critically ill children with sepsis or severe inflammatory states. While plasmapheresis removes excess cytokines along with pathogenic components from the blood and helps reduce inflammation. Corticosteroids are used to suppress cytokine production in severe inflammatory states. For instance, dexamethasone is effective in reducing mortality in pediatric sepsis and ARDS. It is also used as an adjunct in conditions like bacterial meningitis to reduce inflammation-induced damage. IVIG has immunomodulatory effects that can reduce cytokine production. It is widely used in conditions like MIS-C, Kawasaki disease, and severe viral infections in children [82].

Proteomics and transcriptomics have uncovered novel cytokine-related biomarkers, which have improved infection severity stratification. Metabolomics integration has provided insights into how cytokines influence metabolic pathways during infections [83]. Portable cytokine assays (e.g., IL-6 lateral flow devices) are being integrated into mobile health platforms for real-time patient monitoring. Wearable biosensors measuring IL-6 and TNF-α fluctuations could revolutionize early sepsis detection and home-based infection monitoring [84]. Table 3 shows methods for detecting cytokines, their advantages, and challenges.

Table 3 Methods of cytokine detection, their advantages and challenges.

The detection and quantification of cytokines have historically relied on ELISA and multiplex bead-based immunoassays [85,90]. Although these methods provide accurate and detailed cytokine profiling, they are also time-consuming and expensive. As a result, their use is often impractical in low-resource areas and emergencies. To address these limitations, recent advancements in point-of-care cytokine assays (POC-CAs) are transforming the field by enabling real-time, bedside cytokine measurement for early infection diagnosis and severity stratification [94]. One of the significant advantages of POC-CAs is their ability to provide faster turnaround times and improved accessibility in low-income settings. For instance, microfluidic immunoassays allow rapid multiplex detection of cytokines such as IL-6, IL-8, and TNF-α using just a single droplet of blood. In addition, electrochemical biosensors offer high sensitivity and specificity in cytokine detection and are being integrated into wearable health monitoring devices. Similarly, lateral flow cytokine assays, which function in the same way as rapid antigen tests, have been developed to detect IL-6 in patients with suspected sepsis, thus enabling early intervention [95,96].

While these technological advances enhance cytokine detection, it is crucial to recognize that cytokines do not act in isolation. Instead, the immune response is a complex and dynamic network where cytokines interact in highly coordinated ways [97]. For example, IL-6, IL-8, and TNF-α function as part of a broader inflammatory cascade, which can either amplify or suppress immune activity depending on the type and severity of infection. A key example of this interplay is the relationship between IL-6 and TNF-α. Conversely, TNF-α stimulates IL-6 production, contributing to systemic inflammation, as observed in cytokine storm syndromes. On the other hand, IL-8 plays a crucial role as a chemotactic cytokine. Still, when present in excessive amounts alongside high TNF-α levels, it correlates with neutrophil exhaustion and immune paralysis, particularly in severe infections [98,99]. Furthermore, anti-inflammatory cytokines such as IL-10 are vital in regulating IL-6 and TNF-α activity. However, dysregulation of this balance is a hallmark of sepsis progression. Cytokine interactions are illustrated in Table 4 below.

Table 4 Cytokine interactions in infectious diseases.

6. Clinical Utility and Challenges of Cytokine-Based Diagnostics

Cytokines play a pivotal role in diagnosing and determining the prognosis of pediatric infections, offering valuable insights into disease type and severity. For example, IL-6 and IL-8 are early markers of infection, often rising before conventional indicators such as CRP. In neonatal sepsis, elevated IL-6 levels can detect infections before symptoms appear, which enables timely antibiotic administration. Similarly, IL-8 can distinguish bacterial from viral infections in febrile children, reducing unnecessary antibiotic use [103]. Beyond bacterial and viral infections, cytokine profiles are crucial in managing fungal infections by guiding treatment choice and duration. Decreasing IL-6 levels in sepsis suggests effective infection control, while persistently high cytokine levels may indicate inadequate response. Additionally, cytokine panels help differentiate between infection types. For instance, bacterial infections typically present with high IL-6, IL-8, and TNF-α, while viral infections exhibit moderate IL-6, low IL-8, and variable TNF-α levels. Fungal infections, on the other hand, are characterized by elevated IL-6 and TNF-α, with moderate IL-8 levels [104].

Cytokines are also key indicators in severe inflammatory conditions, such as MIS-C and Kawasaki disease. Elevated IL-6 and TNF-α levels can predict multi-organ dysfunction risk, while in pediatric ARDS, persistently high cytokines correlate with poor prognosis and prolonged ventilation requirements [105]. Despite their diagnostic potential, several challenges limit the widespread clinical implementation of cytokines. One key limitation is the variability in cytokine levels, which fluctuate throughout the infection course, with different cytokines peaking at various times. Moreover, differences in detection methods (e.g., ELISA vs. multiplex assays) can lead to inconsistent results. At the same time, the lack of standardized cytokine thresholds makes it challenging to generalize findings across patient populations [106].

Another primary concern is the overlap of cytokine elevations with non-infectious conditions. Inflammatory diseases, autoimmune disorders, and even trauma can elevate cytokine levels, complicating diagnosis. For instance, while IL-6 is a known sepsis marker, it is also elevated in autoimmune diseases, reducing specificity. Furthermore, advanced cytokine detection methods are costly and require specialized equipment, limiting their accessibility in resource-constrained settings [107]. Given these challenges, cytokine measurements alone are insufficient for definitive diagnosis. A more reliable approach integrates cytokine data with other biomarkers, such as CRP and procalcitonin (PCT), alongside clinical assessments. This approach enhances diagnostic accuracy and reduces the risk of misclassification. To improve the accuracy and clinical applicability of cytokine-based diagnostics, several strategies must be implemented. Genetic variability is a key factor, as polymorphisms in cytokine genes (e.g., IL-6, TNF-α) can result in individual differences in cytokine levels, making universal reference values unreliable [108]. Developing personalized cytokine reference ranges based on genetic studies could improve precision.

Comorbidities further complicate cytokine interpretation, as chronic conditions such as diabetes, cancer, and autoimmune diseases can alter baseline cytokine levels, potentially leading to misdiagnoses. Combining biomarker panels (e.g., CRP with cytokines) can improve specificity, thereby helping to distinguish infection-related inflammation from pre-existing inflammatory conditions [109]. Additionally, disease severity itself influences cytokine profiles. In severe infections, excessive cytokine elevation may obscure the underlying cause. Introducing severity-adjusted biomarker thresholds can improve diagnostic clarity in critically ill patients. Moreover, standardizing the timing of cytokine measurement would ensure more consistent and reliable readings, mitigating the impact of fluctuations in cytokine levels.

A multi-biomarker approach significantly enhances diagnostic accuracy by leveraging the complementary strengths of different biomarkers [109]. For instance, combining IL-6 and PCT effectively differentiates bacterial from viral infections by integrating systemic inflammation (IL-6) with bacterial specificity (PCT). Similarly, pairing IL-10 with IFN-γ improves the ability to distinguish viral from bacterial infections, as elevated IL-10 levels indicate viral persistence, whereas IFN-γ plays a critical role in bacterial clearance. Moreover, using IL-8, CRP, and D-Dimer together provides valuable insights into sepsis progression and coagulation abnormalities, since IL-8 acts as a neutrophil chemoattractant, CRP reflects systemic inflammation, and D-Dimer serves as an indicator of coagulopathy risk [110]. While IL-6 and TNF-α inhibitors remain critical immunotherapeutic strategies, emerging approaches offer more precise cytokine modulation in infectious diseases. For instance, next-generation JAK-STAT inhibitors (e.g., Ruxolitinib, Baricitinib) expand the scope of IL-6 signaling modulation. Unlike traditional IL-6 inhibitors, these drugs offer broader immune regulation, which makes them highly effective in treating severe COVID-19 and bacterial sepsis [111].

Beyond pharmacological inhibitors, gene-editing technologies have introduced novel avenues for cytokine modulation. CRISPR interference (CRISPRi) has been successfully used in preclinical models to suppress IL-6 and TNF-α expression, which reduces inflammation without completely shutting down immune function [112]. Similarly, gene-silencing RNA therapies are being actively explored to selectively modulate cytokine expression in acute infections, offering an additional level of precision in cytokine regulation. Dual-cytokine targeting therapies are another promising innovation. For example, simultaneous inhibition of IL-6 and TNF-α has been proposed as a more balanced approach to treating pediatric infections. Additionally, combining cytokine inhibitors with traditional antibiotics is emerging as a synergistic strategy to manage sepsis-associated immune dysregulation [113].

7. Discussion

Cytokines are integral to the immune response in pediatric infections, playing pivotal roles in regulating inflammation, immune cell recruitment, and pathogen clearance. They both orchestrate immune responses and serve as valuable biomarkers for diagnosing and determining the prognosis of infections [114]. Their dynamic expression patterns and unique roles in pediatric immunity provide opportunities for targeted diagnostics and therapies, especially in managing severe infections and hyperinflammatory conditions. IL-6 acts as a central regulator of the acute-phase response and systemic inflammation. It is rapidly produced in response to infections, thereby triggering the release of acute-phase proteins [115,116]. Its dual role as a pro-inflammatory and anti-inflammatory cytokine makes it crucial for modulating immune responses during infections. Elevated IL-6 levels are consistently associated with severe bacterial infections, sepsis, and hyperinflammatory syndromes. In pediatric sepsis, its levels rise earlier than CRP, making it a reliable early diagnostic marker. However, its role is not limited to diagnosis; IL-6 levels correlate with infection severity and organ dysfunction [117].

IL-8 primarily functions as a chemokine, recruiting and activating neutrophils at infection sites. This activity enhances the innate immune response, facilitating pathogen clearance. Elevated IL-8 levels are most commonly associated with bacterial infections where neutrophil recruitment is crucial. It also distinguishes bacterial infections from viral ones and serves as a diagnostic marker in febrile children. However, excessive IL-8 activity can contribute to tissue damage and poor outcomes in conditions like severe pneumonia and respiratory syncytial virus (RSV) infection. In addition to its diagnostic utility, its levels provide prognostic information, with persistently high levels indicating severe inflammation and an increased risk of complications [118,119,120]. TNF-α is a pro-inflammatory cytokine critical in driving systemic inflammation, apoptosis, and macrophage activation. It acts early in infections and enhances pathogen clearance and immune cell recruitment. However, excessive production of TNF-α can lead to immunopathology, including vascular leakage and organ dysfunction. In pediatric sepsis and severe dengue, high TNF-α levels are associated with septic shock and mortality. Its pivotal role in hyperinflammatory states also makes it a target for therapeutic interventions. Anti-TNF-α therapy, infliximab has shown promise in managing severe inflammatory responses in infections and other conditions [121,122].

Despite their numerous potentials, cytokine-based diagnostics face challenges in clinical application. Current detection methods, such as ELISA and multiplex assays, are highly sensitive and specific but require laboratory facilities and trained personnel, which limit their accessibility in low-income settings. Nevertheless, variability in cytokine responses due to age, genetics, and comorbidities necessitates the development of pediatric-specific thresholds and diagnostic algorithms. Moreover, cytokine elevations are not exclusive to infections, as inflammatory and autoimmune diseases can also increase their levels, which could complicate diagnosis. To address these limitations, integrating cytokine data with other biomarkers enhances specificity and reduces misclassification risks [123,124,125]. Furthermore, strategies such as developing personalized cytokine reference ranges based on genetic studies, using severity-adjusted thresholds, and standardizing timing protocols can improve diagnostic precision [126]. A multi-biomarker approach enhances accuracy, with combinations like IL-6 + PCT distinguishing bacterial from viral infections, IL-10 + IFN-γ differentiating viral from bacterial infections, and IL-8 + CRP + D-Dimer providing insights into sepsis progression and coagulopathy risk [127,128,129]. Meanwhile, advancements in cytokine-targeted therapies are expanding treatment options, with next-generation JAK-STAT inhibitors broadening IL-6 signaling modulation. Additionally, gene-editing technologies such as CRISPRi and RNA-silencing therapies offer precise cytokine modulation without compromising immune function. Emerging dual-cytokine targeting strategies and combining cytokine inhibitors with antibiotics present a synergistic approach to managing sepsis-associated immune dysregulation [130,131,132].

The therapeutic potential of targeting cytokines to manage hyperinflammatory states is another critical area of exploration. IL-6 blockers have demonstrated efficacy in conditions like MIS-C and severe COVID-19 by mitigating inflammation and preventing organ damage. Similarly, TNF-α inhibitors, widely used in autoimmune diseases, are being evaluated for their role in severe bacterial infections and septic shock [133,134].

8. Conclusion

The cytokines are pivotal biomarkers and therapeutic targets in pediatric infections, which offer significant potential for improving diagnostic precision, risk stratification, and personalized treatment strategies.

Acknowledgments

Acknowledge the people or organization(s) that have technically supported this work, excluding fund provider.

Author Contributions

All the authors contributed equally in conceptualizing the theme of the review and the manuscript's design and structure. While Monday Uchenna Obaji conducted an extensive literature review focusing on IL-6, IL-8, and TNF-α, their biological functions, and diagnostic and therapeutic implications in pediatric infections, Angus Nnamdi Oli contributed to writing the sections on diagnostic innovations and Malachy C Ugwu focused on therapeutic strategies involving cytokine modulation.

Funding

The authors declare that this review was conducted independently and did not receive any specific grant or financial support from funding agencies in the public, commercial, or not-for-profit sectors.

Competing Interests

The authors declare no competing interest related to this research.

Data Availability Statement

This review is based on data and information sourced from publicly available literature and databases, including PubMed, PubMed Central, Scopus, Elsevier, and other academic repositories. All referenced studies and articles used in this review are cited appropriately within the manuscript. Readers can access these resources through the provided references and links. No primary datasets were generated or analyzed for this study. If specific assistance in accessing any referenced material is required, readers are encouraged to contact the corresponding author.

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