Eosinophilic Cationic Protein in Chronic Pediatric Cough

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1		Tsvetelina Veselinova Velikova	--	1920	2024-03-07 10:29:34	\|
2	Reference format revised.	Lindsay Dong	+ 3 word(s)	1923	2024-03-08 02:22:17	\|

This entry is adapted from the peer-reviewed paper 10.3390/sinusitis8010001

Although the cough reflex is one of the essential protective mechanisms in the respiratory tract, it is considered a considerable health problem in adults and children when it becomes chronic and hypersensitive. However, the need for biomarkers for chronic cough in children and adults is critical. The problem with cough is also a severe symptom in hypersensitivity children. Respiratory infections are a considerable challenge for pediatricians, especially in allergic children. The term cough hypersensitivity syndrome, although introduced in adults, was questioned for children. Eosinophil cationic protein (ECP) is a promising marker for chronic cough but still needs to be validated and proved in clinical settings.

chronic cough chronic cough in children eosinophilic cation protein

1. Eosinophil Cationic Protein

Eosinophil cationic protein (ECP) is a heterogenous molecule presented in the granules of activated eosinophilic granulocytes, along with major basic protein (MBP), eosinophil peroxidase, and eosinophil-derived neurotoxin/eosinophil protein X. ECP secretion by eosinophils is stimulated via antibody-dependent (IgG, IgA) or antibody-independent manner (C3, C5 complement components) ^[1]. Additionally, it is encouraged by IL-3, IL-5, and granulocyte–monocyte colony-stimulating factor (GM-SCF). This molecule, ribonuclease 3 (RNase 3), is involved in the host immune response to parasites and some Gram-positive and Gram-negative bacteria and viruses ^[1].

Cytotoxic biologic activities of ECP could also be directed against the host. The most common damages of ECP are observed on neurons and respiratory epithelial cells. The latter is clinically associated with allergic asthma and allergic rhinitis, atopic eczema ^[2], inflammatory gastrointestinal and respiratory disorders, malignancies, and eosinophilia ^[3].

However, ECP exerts also non-toxic properties, such as immunomodulatory ones. ECP can inhibit T cell proliferation, activation, and histamine release by basophils and downregulating epithelial cells’ receptors and adhesion molecules ^[4]. ECP also regulates tissue remodeling by stimulating the secretion of TGFβ, which alters the fibroblasts’ metabolism and inhibits proteoglycan degradation ^[5].

It was further demonstrated that ECP does not alter mediators and airway hypersensitivity but correlates positively with the eosinophils’ activity in asthma pathophysiology. However, ECP failed to be a suitable asthma diagnostic marker and could only be applied to allergic asthma ^[1].

Although ECP was investigated mainly in eosinophilic conditions (i.e., asthma, rhinitis, atopic diseases, etc.), it was demonstrated that ECP could have a role in other conditions, such as bacterial sinusitis. ECP concentrations in the systemic bloodstream and locally usually correlate with disease activity. Also, increased ECP during asthma exacerbations could be used to monitor and assess a new therapeutic regimen or follow-up patients.

2. Immunological Mechanisms of ECP, IgE, and Chronic Cough

2.1. Immunological Mechanisms of ECP

The molecular mechanisms and genetic factors contributing to the suppression of innate antiviral immune responses by allergens have been the subject of recent research. Atopy-related allergen–virus interactions include intricate cellular and tissue processes. Potential treatment targets may be found in future investigations, elucidating the processes underlying these interactions. The information indicates that treatments designed to restore particular antiviral responses will probably enhance clinical results in allergic illnesses ^[6].

In line with this, it is well known that allergic inflammation in asthma patients is regulated by Th2 and Th1 cells and related cytokines (i.e., IL-4, IL-5, and GM-CSF, which exerted positive regulation, and IFNγ and IL-10, which are negative regulators, respectively). However, cytokines have little or no effect on eosinophils to produce ECP.

Moreover, the expression of IgE receptors was also shown in neutrophils ^[7]. Previously, the authors reported several neutrophil activities, such as generating inflammatory mediators, respiratory burst, and degranulation, in response to allergens through an IgE-dependent mechanism ^[8]. Additionally, encountering surface-bound IgE with anti-IgE antibodies or allergens leads to stimulation of neutrophils and secretion of ECP ^[9].

However, glucocorticoids could regulate histamine production by neutrophils in allergic patients in an IgE-dependent manner ^[10]. Thus, inhibition of ECP production could be exerted by corticosteroid treatment through neutrophil inhibition.

Furthermore, immunotherapy augments the secretion of immunosuppressive cytokines IFNγ and IL-10. Thus, these cytokines may enhance the effect of allergen immunotherapy ^[11].

A very significant result reported by Vega-Rioja et al. is the correlation between ECP levels and airway obstruction and eosinophilic inflammation. Still, most importantly, FEV1 inversely correlates with the in vitro ECP secretion by peripheral neutrophils after an allergen challenge. The authors conclude that the in vitro production of neutrophil ECP could predict the severity of allergic asthma, and future strategies must consider the molecular pathways that offer potential therapeutic targets ^[12].

2.2. Connection of ECP with Chronic Cough

It is well established that the most common symptoms of childhood asthma are wheezing, dyspnea, and cough. However, a single sign could not adequately predict asthma ^[13].

One can speculate that cough alone could be the only sign of an ongoing lower respiratory tract problem. A population-based study by Skaaby et al. demonstrated that one in four children with asthma had a chronic cough for more than 3 months. Furthermore, they observed that 19.9% of children had a dry cough at night in the past 12 months. The authors found a connection between IgE sensitization to respiratory allergens and the risk of infection and disease, taking into account the T helper type 2 (Th2) lymphocytes skewed immune response and IgE antibody development. Almost 15,000 participants were included in the study, where IgE sensitization correlated with asthma, other chronic lower airway diseases, and pneumonia ^[14].

2.3. Connection between ECP and IgE

The role of ECP, total IgE, and eosinophilia in children with bronchial hyperresponsiveness is well established ^[15].

In the pediatric population, ECP is not only a non-invasive marker of bronchial hyperresponsiveness but may also predict asthma sensitivity and severity ^[16]. Moreover, total and specific IgE levels correlated with ECP levels in asthmatic children.

Dodig et al. assess the usefulness of ECP measurement in children with respiratory diseases (n = 156) and healthy controls (n = 55). Although the levels of ECP were higher in children with respiratory diseases than in healthy children, ECP could be used in assessing airway inflammation, allergic disease severity, treatment efficacy, and compliance ^[17].

However, Cetinkaya and Cakir found increased serum ECP and total IgE levels in children with acute laryngotracheobronchitis. Additionally, after treatment with nebulized budesonide, ECP and IgE levels dropped significantly, emphasizing that these two parameters are unsuitable for diagnosing and following up allergic conditions in children with recent acute laryngotracheitis ^[18].

3. ECP and Chronic Cough in Children

Cetinkaya and Cakir, based on their results for the ECP and IgG levels during the acute phase of laryngotracheitis, suggested that because of their increase, these markers should not be used in diagnosing and follow-up of allergic children who experienced recent acute inflammation of the larynx for a few weeks ^[17]. Additionally, they pay attention to the limitations of clinical use of ECP based on the pre-analytical factors. Among them were using appropriate samples, gel and clot activator tubes, ensuring temperature and proper time of blood clotting tracking, etc. Therefore, since determining serum ECP concentration is a complex process that depends on numerous pre-analytical factors, this raises the question of external validity and generalizability. However, if all factors that could potentially limit the reliability of the determination are considered, the results could be useful for objectively assessing eosinophil degranulation in allergic inflammation and tracking the efficacy of anti-inflammatory treatment.

Managing chronic cough in children is also challenging. Tang et al. created their protocol for meta-analysis on using montelukast combined with budesonide in children with cough variant asthma based on the recommendations of The American College of Clinical Pharmacy, British Thoracic Society, and Chinese guidelines. The study would assess the efficacy and safety of combining leukotriene receptor antagonists with inhaled corticosteroids ^[19].

The meta-analysis by Koh et al. (2006) investigated the clinical usefulness of ECP in children with different respiratory disorders ^[2]. The authors confirmed that ECP could be useful in assessing airway inflammation independently of the causing agent or type of virus but does not correlate well with airway hyperresponsiveness. Additionally, ECP could not be useful as a diagnostic tool in children with asthma (including cough variant asthma) because there are too many other atopic diseases associated with elevated ECP. ECP could be an assessment and management tool—ECP is more sensitive than eosinophil counts in evaluating asthma severity, with sputum ECP overweighting serum ECP.

4. ECP and Chronic Cough in Adults

The differential diagnosis of chronic cough is a long-standing clinical–diagnostic problem. It is still a challenge for clinical specialists due to the diverse etiology, various factors, and the increased cough reflex. Several diagnostic algorithms have been developed, but they still lack prognostic markers. However, chronic cough’s most common etiological causes, such as obstructive airway diseases and other pulmonary and extrapulmonary conditions, are known. Speaking of the most common causes of chronic cough in non-smoking adult patients with a normal chest radiograph, they are bronchial asthma and its subtypes (such as cough variant asthma, non-asthmatic eosinophilic bronchitis, rhinitis and rhinosinusitis (considered a cough syndrome by upper respiratory tract), and gastroesophageal reflux disease ^[20].

In contrast, respiratory infections, asthma, and environmental factors are the predominant triggers for chronic cough in children. Additionally, variations in the immune response, airway anatomy, and environmental exposures contribute to age-specific differences in chronic cough.

The presence of biomarkers for eosinophilic airway inflammation observed in 30% to 50% of patients with a chronic cough could facilitate the diagnosis. It is often found in asthma and cough syndrome by the upper respiratory tract and is essential in diagnosing non-asthmatic eosinophilic bronchitis ^[21]. ECP is a known marker studied for many years for distinguishing bronchial asthma from other diseases ^[22]. However, eosinophilia is not a diagnostic criterion for asthma but can be found in patients with early allergic and late nonallergic asthma.

Additionally, eosinophilic inflammation can be assessed in peripheral blood and the airways by sputum induction or bronchoscopy. As a mediator in eosinophilic granules, ECP can be used as an additional biomarker in diagnosing chronic cough with eosinophilic involvement. The involvement of eosinophils and ECP in patients with classical bronchial asthma and cough variant asthma is known, and there is a correlation with the severity of their course ^[23]. High levels of ECP have been measured in the blood and sputum of patients with severe asthma (predominantly atopic) compared to milder asthma ^[24]. It is assumed that ECP can be used as a marker for administering and dosing corticosteroids, but further studies are needed in this direction ^[25].

In the simultaneous course of diseases with eosinophilic inflammation and accompanying chronic cough, eosinophilic infiltrates in the tissues and eosinophilia in the blood can be characteristics of several processes that would increase the values of serum ECP, but the result of which would not help distinguish the origin of the disease.

5. Conclusions

Complexities tied to chronic cough in sensitive children and infections and allergies underscore the necessity for individualized diagnostics and treatments. While “cough hypersensitivity syndrome” originated in adults, its relevance to children remains uncertain, prompting tailored approaches.

ECP emerges as a promising chronic cough biomarker, though further pediatric validation is essential. Examining ECP-IgE interplay deepens insight into a chronic cough, laying the groundwork for future pediatric respiratory studies. Well-designed prospective studies are required to better understand the relationship between changes in ECP and IgE levels and the onset and resolution of chronic cough in children. Additionally, investigations into the effects of age, gender, and geographic variations on ECP and IgE levels in pediatric populations are necessary. Longitudinal studies that track the trajectory of ECP and IgE levels from childhood into adolescence and adulthood may shed light on the continuity or evolution of these biomarkers over time. Interventional studies that evaluate the efficaciousness of targeted treatments based on ECP and IgE levels in managing chronic pediatric cough could also be helpful. Nevertheless, integrating cutting-edge technology, such as omics methods, may provide a thorough molecular knowledge of the complex pathways linking IgE and ECP in the pathophysiology of persistent childhood cough.

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