Recent Advances in Targeted Therapeutics and highlights on Biomarker in Asthma Management: A Review

Abstract

A diverse, long-term inflammatory condition of the airways, asthma has a major influence on world health Characterized by reversible airway obstruction, bronchial hyperresponsiveness, and persistent inflammation, its pathophysiology involves a complex interplay of genetic, environmental, and immunological factors particularly a Th2 skewed immune response. The disease manifests in various phenotypes, with T2-high asthma being the most thoroughly characterized due to identifiable biomarkers and therapeutic targets. This review explores key inflammatory pathways and highlights current and emerging biomarkers including blood and sputum eosinophils, serum IgE, periostin, fractional exhaled nitric oxide (FeNO), exhaled breath condensates, cytokines, and urine metabolites. The role of transcription factors such as NF-?B, AP-1, and NF-AT in the regulation of inflammatory genes is also examined. Recent advancements in biologic therapies—such as omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab—have significantly improved disease control in severe eosinophilic asthma by targeting specific immunological pathways. However, challenges remain in pediatric management, treatment personalization, and non-T2 asthma phenotyping. This review emphasizes the importance of integrating biomarker-driven diagnostics with precision medicine approaches to enhance the management and prognosis of asthma..

Keywords

Asthma Management, reversible airway obstruction, bronchial hyperresponsiveness, and persistent inflammation, its pathophysiology involves a complex interplay of genetic, environmental, and immunological factors.

Introduction

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 Fig.1 Pathophysiology of asthma: sensitization phase and challenge phase.

Diagnostic Biomarker

Blood eosinophils

The pathophysiology of many inflammatory diseases is significantly influenced by eosinophils and the mediators they release. Interleukin-5 (IL-5) is the main factor that drives their differentiation and maturation in the bone marrow in response to infectious, inflammatory, and allergy stimuli. Increased eosinophil counts in the blood and/or tissues, with or without activation indicators, are indicative of eosinophil-associated illnesses. Eosinophils usually circulate in the blood for a few hours and are recruited into tissues by chemokines, especially those belonging to the eotaxin family. They can, however, remain in tissues for weeks at a time, where they become activated, cause tissue damage and inflammation, and avoid apoptosis(14).

Blood neutrophile

In asthma, neutrophilia is more common in patients with a history of smoking and persistent airflow limitation than in non-smoking asthma patients, implying that neutrophilia may serve as a distinguishing factor between asthma and asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACO). Furthermore, severe asthma patients have altered expression of genes involved in immune cell regulation, such as B lymphocytes, T lymphocytes, and granulocytes, which are either elevated or downregulated when compared to healthy controls(15).  

Sputum cells and mediators  

The quantitative analysis of sputum cells is considered the benchmark for evaluating airway inflammation in asthma. Eosinophilic airway inflammation is a prominent characteristic, affecting roughly 40–60% of patients with severe asthma. Measuring eosinophil levels in induced sputum is a common approach for identifying T2-high asthma, with sputum eosinophil percentage recognized as the gold standard biomarker for type 2 inflammation. However, this method may not be ideal for routine clinical application due to its invasive procedure and operational challenges. Sputum neutrophilia has been proposed as a potential predictive biomarker for non-T2 asthma. Previous studies assessing sputum inflammatory profiles in asthma patients reported that approximately 20% exhibited neutrophil levels exceeding 61%. Elevated sputum neutrophil counts are correlated with increased asthma severity and a diminished therapeutic response to corticosteroid treatment. Various sputum-derived mediators have been investigated as potential biomarkers. For identifying inflammatory phenotypes, sputum eosinophil peroxidase levels have been shown to correlate with eosinophilic inflammation, while specific microRNAs can distinguish between neutrophilic and eosinophilic asthma. Additionally, neutrophil myeloperoxidase may serve as a marker for differentiating asthma–COPD overlap syndrome (ACOS) from asthma. As a prognostic biomarker, elevated sputum expression of human tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been associated with greater disease severity, poor asthma control, and reduced lung function in pediatric patients with non-eosinophilic asthma(16),(17).

Serum IgE

Serum immunoglobulin E (IgE) is responsible for mediating type I hypersensitivity reactions and anaphylaxis. As previously discussed, IgE also plays a crucial role in the development of allergic asthma. Elevated serum IgE levels are commonly observed in individuals with asthma and are associated with allergen sensitization, skin test reactivity, and impaired lung function. Clinical evidence demonstrates an inverse correlation between serum IgE concentrations and the FEV1/FVC ratio in asthmatic patients. Several clinical trials have utilized IgE as a biomarker to identify Th2-high asthma phenotypes. Omalizumab, a recombinant humanized monoclonal antibody targeting the IgE receptor binding site, inhibits the activation of mast cells and basophils. A large phase III clinical trial involving over 500 asthma patients reported baseline serum IgE levels ranging from 30 to 700 IU/mL. Treatment with omalizumab significantly reduced the frequency of exacerbations and improved quality-of-life measures. However, a 2014 Cochrane review highlighted uncertainty regarding an optimal serum IgE threshold for maximal therapeutic efficacy, citing considerable variability in mean IgE levels across different studies, ranging from 141.5 to 508.1 IU/mL(18).  

Periostin

Periostin is an extracellular matrix protein synthesized by eosinophils, epithelial cells, and fibroblasts, and it plays a significant role in Th2-mediated allergic diseases. The cytokines IL-4 and IL-13 stimulate eosinophils to secrete periostin, which in turn enhances eosinophil proliferation through a positive feedback mechanism. Additionally, IL-4, IL-13, and TGF-β induce periostin production in fibroblasts and epithelial cells. Periostin subsequently activates these cells to express NF-κB, contributing to fibrosis and airway remodeling. Elevated periostin levels have been identified as a biomarker associated with asthma characterized by frequent exacerbations. However, its clinical application in pediatric populations is complicated by physiologically higher periostin concentrations during early childhood due to active bone turnover(19).  

Fractional exhaled nitric oxide

Fractional exhaled nitric oxide (FeNO) is currently the most commonly utilized exhaled biomarker for assessing airway inflammation in asthma. Its measurement offers the advantage of being rapid, noninvasive, and standardized. Nitric oxide (NO) is synthesized by airway epithelial cells, eosinophils, and macrophages through the enzymatic conversion of L-arginine to L-citrulline, mediated by nitric oxide synthase (NOS). In healthy individuals, NOS is constitutively expressed in two isoforms: neuronal NOS (nNOS) and endothelial NOS (eNOS). However, during airway inflammation in asthma, both isoforms are upregulated. Clinical studies have demonstrated that FeNO can serve as a noninvasive biomarker to predict responsiveness to corticosteroid therapy. In steroid-naïve individuals, FeNO levels can guide therapeutic decisions, where a low FeNO value (<25 parts per billion) suggests a low likelihood of eosinophilic airway inflammation and a reduced probability of steroid responsiveness. Conversely, elevated FeNO levels (≥50 parts per billion) are strongly associated with airway eosinophilia and favorable responses to corticosteroids. In patients with difficult-to-treat asthma who are already receiving inhaled corticosteroids, FeNO measurements can help differentiate between persistent eosinophilic inflammation and non-inflammatory causes of poor disease control, thereby informing adjustments in corticosteroid dosing(20).

Exhaled breath condensate

Exhaled breath condensate (EBC) analysis is a relatively recent technique that has enhanced the understanding of asthma pathophysiology. This method enables the identification of a wide range of biomarkers in a simple, noninvasive, and reproducible manner, making it particularly suitable for use in pediatric populations. EBC is collected by having the subject exhale warm air into a cooled tube (maintained at 0°C), which captures both volatile and non-volatile molecules from the respiratory tract. Subsequent analysis of the condensate allows for the evaluation of inflammatory mediators and biomarkers present in the airways. Multiple biomarkers have been identified in the exhaled breath condensate (EBC) of individuals with asthma, including pH, hydrogen peroxide (H?O?), nitric oxide derivatives, leukotrienes, isoprostanes, cytokines, and others. Asthmatic patients typically exhibit a lower mean EBC pH, which tends to normalize following anti-inflammatory treatment. EBC pH has been shown to reflect acute asthma exacerbations and is associated with markers such as sputum eosinophilia, total nitrite/nitrate concentrations, and oxidative stress. Furthermore, total nitrite/nitrate levels are elevated in asthmatic patients compared to healthy controls and are reduced after administration of inhaled corticosteroids(21).  Hydrogen peroxide (H?O?) is a reactive oxygen species (ROS) that contributes to oxidative stress within the airways. Elevated concentrations of H?O? in exhaled breath condensate (EBC) have been reported in both adults and children with severe asthma compared to healthy controls. Factors such as cigarette smoking and disease severity can influence H?O? levels, with smoker asthmatics exhibiting approximately fivefold higher concentrations than non-smokers. The activation of inflammatory cells, including neutrophils, macrophages, and eosinophils, promotes the generation of superoxide anions (O??), which subsequently undergo spontaneous or enzymatic dismutation to form H?O?. Due to its relatively lower reactivity compared to other ROS, H?O? can diffuse across biological membranes and reach other tissue compartments. Being water-soluble, increased airway H?O? can equilibrate with the airways' extracellular environment. However, the extracellular space and respiratory tract possess limited antioxidant defenses relative to intracellular systems. Catalase, the primary enzyme responsible for the degradation of H?O?, is present at low levels in the respiratory tract. Consequently, elevated exhaled H?O? serves as a potential noninvasive biomarker for oxidative stress in the lungs(22).

Urine metabolites

Bromotyrosine is a product of the post-translational modification of tyrosine residues in proteins, catalyzed by hypobromous acid generated by activated eosinophils during a respiratory burst. It offers several advantages as a potential biomarker due to its stability and the ability to be noninvasively detected in urine. Elevated urinary bromotyrosine levels have been shown to predict a more favorable response to corticosteroid treatment. However, the correlation between sputum eosinophil counts, fractional exhaled nitric oxide (FeNO) levels, and urinary bromotyrosine concentration is limited, suggesting that its clinical utility may be more effective when evaluated as part of a broader panel of inflammatory biomarkers. Leukotriene E4 (LTE4) is a stable product of cysteinyl leukotriene metabolism, which can be measured noninvasively in urine samples. Urinary LTE4 (uLTE4) concentrations are significantly elevated in children with allergic asthma and adults with aspirin-exacerbated respiratory disease (AERD). Several studies have indicated that uLTE4 could serve as a valuable biomarker for guiding asthma treatment selection(23).

Cytokines 

A major factor in defining the type of inflammatory response, cytokines are becoming more well acknowledged as important mediators of chronic inflammation. These proteins can be made and released by a variety of inflammatory cells, such as mast cells, eosinophils, lymphocytes, and macrophages. Furthermore, a variety of cytokines can be secreted by structural cells, including endothelial and epithelial cells, which contribute to the chronic inflammatory process. When used to treat patients with severe airway illnesses, a number of cytokines that support type 2 immunity, including IL-4, IL-5, and IL-13, have shown encouraging outcomes in properly chosen subjects(24).

Interleukin -4

The B cell growth factor interleukin-4 (IL-4) was first identified as enhancing the best possible B cell stimulation by antigens. In a broader sense, IL-4 is thought to be the main cytokine implicated in the pathophysiology of allergic reactions. It has an important role in airway remodeling by affecting T cell differentiation, which in turn promotes the formation of type 2 helper (TH2) responses. In addition to being necessary for the differentiation of TH2 cells from precursor T cells, IL-4 and IL-13 also stimulate B cells to produce IgE, drive eosinophilic inflammation by causing airway epithelial cells to secrete the eosinophil chemoattractant CCL26, and contribute to mucus hypersecretion, airway fibrosis, and remodeling(25). The ability of IL-4 to stimulate the expression of vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells is another significant role of IL-4 in allergic inflammation. This increases the endothelium's adhesiveness for T cells, eosinophils, basophils, and monocytes—all of which are essential components of allergic reactions. Owing to these characteristics, IL-4 has long been thought of as a possible therapeutic target for the management of asthma and allergies. Though its function in the generation of IgE is widely known, research has revealed that its participation in airway hyperreactivity, a defining feature of asthma, is more intricate and cannot be well described by its effects on IgE alone(26).

Interleukin -5

It is well established that eosinophils play a central role as effector cells in the pathogenesis of allergic inflammation. Interleukin-5 (IL-5) is considered the primary cytokine involved in the production, differentiation, maturation, and activation of eosinophils within the airways. As such, IL-5 has been a major therapeutic target in the treatment of refractory eosinophilic asthma, with strategies including the blockade of IL-5 or its receptor using monoclonal antibodies. Mepolizumab, a humanized monoclonal antibody that targets IL-5, has demonstrated a dose-dependent and rapid reduction in circulating eosinophil counts following a single intravenous dose, with effects lasting up to three months. Sputum eosinophils also decreased as a result of this treatment. However, despite a significant decrease in blood and sputum eosinophils, no discernible improvements in symptoms, lung function, or quality of life were observed in a study where mepolizumab was given monthly for six months to patients with moderate persistent asthma who continued to experience symptoms despite inhaled corticosteroid (ICS) therapy. Additionally, there was no decrease in exacerbation rates. Similarly, patients with late-onset asthma experienced a 75% decrease in exacerbations when using reslizumab, another monoclonal antibody that targets IL-5, compared to less than 50% for patients with sensitization sthma(27).

Interleukin-13

Interleukin-13 is produced by activated T and B-lymphocytes, and mast cells. Th2 cells in asthmatic patients release IL-13, a cytokine that is closely linked to IL-4 and interacts to the IL-4 receptor α (IL-4Rα). IL-13 has anti-inflammatory and pro-inflammatory properties. It shares several biological actions with IL-4 and is found in asthmatic people's airways in higher amounts. Both atopic and nonatopic asthma patients have shown increased expression of IL-13 mRNA in their airway mucosa(28). Activated T-lymphocytes, B-lymphocytes, and mast cells all produce interleukin-13 (IL-13). Th2 cells in asthmatic patients release IL-13, a cytokine that is closely linked to IL-4 and interacts to the IL-4 receptor α (IL-4Rα). IL-13 has anti-inflammatory and pro-inflammatory properties. It shares several biological actions with IL-4 and is found in asthmatic people's airways in higher amounts. Both atopic and nonatopic asthma patients have shown increased expression of IL-13 mRNA in their airway mucosa(29).

Interleukin -10

It has been demonstrated that in whole blood cultures activated by lipopolysaccharide (LPS), histamine increases the release of the Th2 cytokine IL-10 via activating the H2 receptor, which raises the levels of cyclic AMP (cAMP). Furthermore, histamine increases the release of IL-10 from alveolar macrophages that are not stimulated and those that are triggered by LPS(30). We have shown that histamine causes cloned murine T helper type 2 (Th2) cells to upregulate IL-10 in a dose-dependent manner. By inhibiting the generation of Th1 cytokines, IL-10 plays a crucial part in regulating the cellular immune response and affecting how viral infections turn out. IL-10 decreases allergen-induced IL-5 production and prevents eosinophil activation and buildup in animal models of asthma. Mice with IL-10 deletion exhibit increased levels of proinflammatory cytokines and worsened airway inflammation (31).

Tumour necrosis factor-α (TNF-α) 

A new insight into asthma pathogenesis has emerged from the discovery that mast cells are found within the airway smooth muscle (ASM) bundles of asthmatic patients. Mast cells are the primary source of tumor necrosis factor-alpha (TNF-α) in the airways. As a result, the proximity of these cells to the ASM may promote TNF-α-driven activation of ASM, potentially contributing to the development of airway hyperresponsiveness (AHR). While the exact mechanisms by which TNF-α affects ASM contractility are not fully understood, potential pathways include alterations in receptor expression, changes in the affinity for bronchoconstrictors, reduced responsiveness to bronchodilators, or modifications in calcium influx and sensitivity. Calcium plays a critical role in regulating ASM contractile function, so disruptions in Ca regulation by TNF-α are likely to impair ASM contractility. Several therapeutic strategies targeting the TNF-α pathway are currently available. Preliminary studies involving small patient cohorts have shown improvements in lung function, AHR, asthma-related quality of life, and exacerbation rates following treatment with anti-TNF therapies(32).  interferon-gamma (IFN-γ) Th1 cytokine interferon-gamma and the monokine interleukin-12 (IL-12) induce the development of naïve T helper cells into Th1 cells. It has been demonstrated that histamine inhibits the production of IFN-γ in polyclonally activated human blood mononuclear cells; this effect may be reversed by adding recombinant IL-2, a Th1 cytokine. Forty percent of T cell clones made from the blood and bronchoalveolar lavage fluid of asthmatic patients had their IFN-γ production blocked by histamine, whereas only fifteen percent had their secretion boosted (33). Histamine dose-dependently suppresses IFN-γ in cloned murine Th1 lymphocytes, according to additional research conducted on cultured human peripheral blood mononuclear cells. IFN-γ contributes to the suppression of certain Th2 cytokine production. Aerosolized recombinant IFN-γ administered locally to mice was able to restore normal airway function and stop antigen-induced eosinophil infiltration into the trachea. However, in steroid-dependent asthma, subcutaneous injection of recombinant IFN-γ did not demonstrate any therapeutic advantage(34).

Transforming growth factor β (TGF-ß)(35).

Numerous biological processes in the airways, including alveolarization, immune cell recruitment, platelet aggregation, apoptosis, cell differentiation, and proliferation, are regulated by the multifunctional ligands that make up the TGF-ß superfamily. TGF-ß1, TGF-ß2, and TGF-ß3 are the three mammalian isoforms that belong to this family. In controlling airway inflammation and the remodeling process, each isoform plays unique and overlapping roles. Despite being encoded by distinct genes, some isoforms have traits in common, such as comparable biological targets and cell surface receptors(36). The term "airway remodeling" describes the pathological alterations in the structure of the airway wall, which include a complicated rearrangement of its cellular and molecular constituents. Although this process includes mechanisms for repairing damage, the dysregulated inflammation that results causes structural alterations like thickening of the basement membrane, subepithelial fibrosis, loss of epithelial integrity, hyperplasia of mucus glands and goblet cells, smooth muscle hypertrophy, and increased airway vascularity.(37). Being a strong chemotactic factor and activator for different inflammatory cells, TGF-ß1 is essential to inflammation. TGF-ß1 is produced by both structural and inflammatory cells, which helps explain why asthmatic patients' bronchoalveolar lavage (BAL) fluid has higher levels of this protein. After being exposed to allergens, higher TGF-ß1 levels are linked to higher concentrations of macrophages, which greatly increases inflammation by activating Th17 cells. Increases in BAL macrophages and elevated levels of lipid peroxidation markers such as malondialdehyde and 8-isoprostanes are correlated with the upregulation of TGF-ß1 in the airways, indicating that oxidative stress mediates the effects of TGF-ß1 and plays a role in airway remodeling in children with severe asthma(38). According to studies, smoking cigarettes strongly stimulates the release of IL-18 from pulmonary macrophages. Activated macrophages and airway epithelial cells then release IL-18 as well, exacerbating asthmatic inflammation. IL-18 promotes remodeling in asthma mice models by inducing the synthesis of TGF-ß1, IL-13, and IFN-γ. All of this data points to the involvement of both inflammatory and allergy processes in the TGF-ß pathway, and more investigation is required to determine the effects of cigarette smoking on the release of TGF-ß1 from different cells (39).

Transcription factors

The genesis and progression of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD) are significantly influenced by transcription factors, which are important regulatory proteins that alter the expression of a broad range of inflammatory genes. In order to either promote or repress transcription, they bind to certain regulatory elements, which are typically found in the 5' upstream promoter regions of target genes. In the end, this control affects protein production and modifies cellular processes(40).

key transcription factors that are involved in the etiology of respiratory diseases.

Nuclear Factor-Kappa B (NF-κB)

One essential transcription factor that controls many cellular functions, especially those connected to immunological and inflammatory reactions, is nuclear factor-kappa B. It controls the transcription of several genes linked to inflammation, such as adhesion molecules like ICAM-1 and VCAM-1, chemokines like interleukin-8 (IL-8) and eotaxin, cyclooxygenase-2, and inducible nitric oxide synthase (iNOS). These genes all play a crucial role in encouraging the recruitment of inflammatory cells(41). Because it binds to an inhibitory protein called IκB, NF-κB is trapped in the cytoplasm when at rest. IκB kinase-2 (IKK2) phosphorylates IκB upon cellular activation, which causes it to get ubiquitinated and be broken down by the proteasome, which releases NF-κB. Following its release, NF-κB moves into the nucleus and attaches itself to particular κB consensus sequences found in the target inflammatory genes' promoter regions(41). Furthermore, NF-κB is a transcription factor that reacts to oxidative stress because it can be activated by oxidative stressors such as hydrogen peroxide (H2O?). This oxidative activation pathway may be crucial to the maintenance of chronic inflammation through the generation of reactive oxygen species, such as superoxide anions, by inflammatory cells or in asthma, where environmental oxidants, such as ozone, exacerbate inflammatory responses(42).

Activator Protein-1 (AP-1)

Activator protein-1 is a group of transcription factors that include members of the Jun (c-Jun, JunB, JunD) and Fos (c-Fos, FosB) families. These transcription factors can form dimers in different combinations using their leucine zipper domains. The most prevalent AP-1 complexes in the majority of cell types are Fos/Jun heterodimers, which have a high binding affinity, while Jun/Jun homodimers, which have a lower binding affinity, are less frequently seen. Numerous cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), trigger AP-1 activation. These cytokines mainly do this by activating protein tyrosine kinases (PTKs) and mitogen-activated protein (MAP) kinases, especially Jun-N-terminal kinase (JNK), which trigger a series of intracellular signaling events. The bronchial epithelial cells of asthmatic patients have been shown to express c-Fos at elevated levels; in patients with severe, therapy-resistant asthma, this elevation is even more pronounced. Furthermore, a variety of events that trigger NF-κB in asthma can also trigger AP-1 activation(43).

Nuclear Factor of Activated T-Cells (NF-AT)

The transcription factor known as nuclear factor of activated T-cells (NF-AT) is mostly expressed in T lymphocytes, where it is essential for regulating the synthesis of interleukin-2 (IL-2) and possibly additional cytokines derived from T cells, such as IL-4 and IL-5. The phosphatase calcineurin is active when T cells are stimulated, which in turn causes cytoplasmic NF-AT to be activated. It is commonly known that NF-AT and AP-1 work together to enhance the transcription of the IL-2 gene. Immunosuppressive drugs such tacrolimus and cyclosporin A, which reduce calcineurin activity, or corticosteroids, which disrupt AP-1 function, can also block this route. Notably, when used to treat asthma, calcineurin inhibitors have demonstrated anti-inflammatory benefits(44).

Emerging Trends in Targeted Therapy for Asthma Control

Omalizumab

As the first humanized monoclonal anti-IgE antibody authorized for use in children six years of age and up, omalizumab is a well-established therapeutic strategy for treating severe asthma by blocking immunoglobulin E (IgE). Patients with documented sensitization to at least one aeroallergen and blood IgE values between 30 and 1500 IU/mL are advised to use it as an adjuvant treatment for severe allergic asthma(45). Omalizumab is injected subcutaneously, and the dosage is based on the patient's body weight and initial IgE levels. It works by lowering the amount of free IgE in the blood, suppressing the expression of IgE receptors, and preventing the release of pro-inflammatory mediators. Omalizumab effectively reduces hospitalizations, oral corticosteroid (OCS) use, and asthma exacerbations while improving asthma control and patient quality of life, according to both clinical studies and empirical data. It has also been demonstrated to strengthen type I interferon responses, which restore antiviral immunity(46). Omalizumab has a good safety record, is generally well tolerated, and has not been shown to raise the risk of cancer. Age over 12, a recent history of exacerbations, a lower forced expiratory volume in one second (FEV1), and the presence of allergic comorbidities, which are defined by elevated eosinophil counts, high serum IgE, and increased fractional exhaled nitric oxide (FeNO), are all factors linked to a better therapeutic response. Its usage in children under six years old, those with non-allergic asthma, and patients whose serum IgE levels are higher than 1500 IU/mL are among the remaining restrictions, nevertheless. Clinical trials are still being conducted to determine the best length of treatment and its long-term effectiveness(47).

Anti?Interleukin?5 (IL?5)

Mepolizumab

With indications that varies by location, mepolizumab, a humanized IgG1 monoclonal antibody that targets interleukin-5 (IL-5), has been authorized as an adjuvant treatment for severe eosinophilic asthma. Patients 12 years of age and older with blood eosinophil counts greater than 150 cells/μL are eligible for it in the US and the EU (but not the UK) and a history of flare-ups of asthma. Under stricter criteria, such as eosinophil counts greater than 300 cells/μL, reliance on oral corticosteroids (OCS), or four or more exacerbations annually, its use is expanded to children aged 6 to 11 in the United Kingdom. Mepolizumab is applied subcutaneously and comes in lyophilized powder form in doses of 40 mg for younger children and 100 mg for adults over the age of twelve. Improvements in clinical symptoms, quality of life, exacerbation rates, and FEV1 are frequently used to gauge efficacy, despite the lack of widely recognized response criteria. After a year, if there is a ≥50% decrease in exacerbations, the National Institute for Health and Care Excellence (NICE) recommends continuing medication. Mepolizumab has been shown in clinical trials including DREAM, MENSA, SIRIUS, COSMOS, and COLUMBA to effectively lower the frequency of exacerbations, lower the need for OCS, and improve lung function. The majority of reported side effects are minimal, and the medication is generally well tolerated. However, there is currently a lack of information regarding its use in juvenile populations, and research is being conducted to better assess its efficacy and safety in kids(48),(49),(50).

Reslizumab

With a dosage of 3.0 mg/kg every four weeks, reslizumab, an IgG4 kappa monoclonal antibody that targets interleukin-5 (IL-5), was authorized in 2016 as an additional intravenous treatment for people (≥18 years) with severe eosinophilic asthma. Patients with blood eosinophil counts ≥400 cells/μL, a history of at least three exacerbations in the past year, and continuous treatment with high-dose inhaled corticosteroids (ICS) in addition to another controller medication are advised to use it, according to the National Institute for Health and Care Excellence (NICE)(51). Particularly for individuals with late-onset asthma, phase III BREATH studies have demonstrated notable improvements in lung function, symptom control, exacerbation frequency, and quality of life that last for up to 24 months(52). Within days of the first dosage, there were noticeable improvements in the early symptoms. Reslizumab also decreased eosinophilic inflammation and decreased the need of oral corticosteroids (OCS). The medicine is generally well tolerated, with common adverse effects including minor infections, headaches, and occasional infusion-related problems. There were no reports of allergy or elevated cancer risk. Its effectiveness in adolescents (ages 12–17) is not well-documented, and there is also a dearth of pediatric data for children ages 0–11. Although the cause is yet unknown, reported adverse outcomes in children, including eosinophilic esophagitis and chronic cholecystitis, have been noted. Confirming long-term safety and efficacy requires more research, especially in pediatric populations(53).

Benralizumab

Eosinophils are nearly completely depleted by benralizumab, a humanized monoclonal antibody that targets the interleukin-5 receptor alpha (IL-5Rα) and modifies associated immunological pathways. In Europe, it is licensed for adults with severe eosinophilic asthma that is still uncontrolled after using long-acting beta-agonists (LABA) and high-dose inhaled corticosteroids (ICS). In the United States, it is approved for individuals 12 years of age and older. According to Matera et al. (2017), the medication is given subcutaneously in three doses of 30 mg every four weeks, then every eight weeks. Benralizumab dramatically decreased exacerbations, improved forced expiratory volume in one second (FEV1), and improved symptom control, especially in patients with eosinophil counts ≥300 cells/μL, according to phase III clinical trials like SIROCCO and CALIMA. According to the BORA trial's safety statistics, the medication is well tolerated over a two-year period and does not increase the risk of infections or cancer. Benralizumab's long-term effectiveness, effects on lung function, quality of life, and comorbidities connected to asthma are all being further assessed by ongoing trials like MELTEMI, ANDHI, MIRACLE, and SOLANA(54),(55).

Dupilumab

A fully human IgG4 monoclonal antibody called dupilumab blocks the signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13), two molecules essential to type 2 inflammation. Since its approval in the United States in March 2017, it has been prescribed for adults with moderate-to-severe asthma and eosinophilia (≥300 cells/μL), as well as adolescents 12 years of age and older. Initial dosages of dupilumab are given subcutaneously as 400 mg followed by 200 mg every two weeks or 600 mg followed by 300 mg every two weeks (56). It was found to be effective in lowering severe asthma exacerbations, increasing forced expiratory volume in one second (FEV1), and decreasing the need for oral corticosteroids, especially in patients with elevated eosinophil counts and fractional exhaled nitric oxide (FeNO), according to the results of two-Phase III trials, QUEST and VENTURE. The most frequent side effect was injection-site responses, and while temporary eosinophilia was noted, it was not linked to any negative clinical outcomes. Results from the VOYAGE trial in children aged 6 to 12 have not yet been released, and pediatric data are still forthcoming(57), (58).

CONCLUSION

The biology, immunological response, and clinical symptoms of asthma, a chronic inflammatory disease of the airways, are all diverse. Our knowledge of asthma phenotypes, especially T2-high asthma, has improved thanks to the discovery and application of certain biomarkers, such as blood and sputum eosinophils, serum IgE, periostin, FeNO, and cytokine profiles. These biomarkers have also made it possible to develop more specialized treatment strategies. Biologic therapy advancements such as omalizumab (anti-IgE), mepolizumab and reslizumab (anti-IL-5), benralizumab (anti-IL-5Rα), and dupilumab (anti-IL-4/IL-13) have improved lung function and quality of life while lowering exacerbation rates and corticosteroid dependence in patients with severe eosinophilic asthma. However, due to a lack of safety and efficacy data, restrictions still exist in pediatric groups. Furthermore, not all patients react to existing biologics in the same way, which emphasizes the necessity of predictive biomarkers to tailor care. Our knowledge of the long-term safety, effectiveness, and best usage of these medications is still being improved by ongoing clinical research. In summary, combining tailored biologic therapy with biomarker-driven diagnosis presents a bright future for treating severe asthma; however, more study is required to maximize precision medicine approaches and extend these advantages to larger patient populations.

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