Abstract
Purpose of review
This review explores the comprehensive management and treatment strategies for pediatric chronic rhinosinusitis with nasal polyps (CRSwNP). It addresses questions regarding the efficacy and safety of both current treatments and emerging therapies. Additionally, this paper examines the diagnostic challenges in pediatric CRSwNP, particularly its distinct presentations and characteristics compared to those in adults.
Recent findings
Current research highlights various approaches for treating pediatric CRSwNP. Intranasal corticosteroids are found to be effective in managing symptoms, while oral corticosteroids are used to manage severe cases. Antibiotic therapy is recommended for acute exacerbations of CRSwNP when a bacterial cause is suspected. Surgical interventions such as adenoidectomy and endoscopic sinus surgery are considered when medical therapy fails. Emerging biologic therapies show promise but require further investigation regarding safety and cost-effectiveness in the pediatric population.
Summary
The findings suggest that a multimodal approach is essential for treating pediatric CRSwNP. Future research should aim to develop targeted therapies and refine treatment guidelines specifically for the pediatric population.
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Introduction
Chronic rhinosinusitis (CRS) is a persistent inflammation of the sinonasal mucosa lasting at least 12 weeks, marked by nasal congestion, rhinorrhea, facial pressure or pain, and hyposmia [1••]. There are two primary CRS phenotypes: CRS without nasal polyposis (CRSsNP) and CRS with nasal polyposis (CRSwNP), with CRSwNP affecting about 25-30% of CRS patients [2, 3]. Although the nasal polyps in CRSwNP are benign, this condition leads to significant morbidity and reduced quality of life (QoL) [4, 5]. The pathophysiology of CRSwNP, often involving a type 2 eosinophilic inflammatory response, is complex and not fully understood. Moreover, histopathological differences are noted in the sinonasal tissue of adults and children with CRS; adults typically exhibit lymphoplasmacytic inflammation whereas children show a lymphocyte-dominant inflammatory background [6]. Ongoing research is exploring the inflammatory markers and variations across CRS phenotypes and endotypes [7].
Additional factors such as genetic predisposition, fungal colonization, and epithelial barrier dysfunction may also contribute to nasal polyp development [8, 9•, 10, 11]. Environmental factors, such as exposure to tobacco smoke, exacerbate the severity of CRS, leading to worse clinical scores and higher rates of revision surgery [12]. Diagnosing CRSwNP involves clinical assessment, imaging studies, and nasal endoscopy [13]. Treatment typically includes intranasal and systemic corticosteroids, nasal saline irrigations (NSI), antibiotics, surgery, and biologic therapies [14,15,16,17,18,19] (Table 1).
Despite efforts in understanding CRSwNP in adults, CRSwNP in pediatric patients is not as well understood. CRS in pediatric patients under 18 years of age is defined by having at least two symptoms of nasal congestion, nasal discharge, facial pressure and pain, or cough, with confirmation through endoscopic signs of mucosal edema, purulent nasal discharge, or characteristic imaging findings [20]. CRS is identified in approximately 2-4% of pediatric patients, while CRSwNP is found in only 0.1% of the general pediatric population [21]. However, even with a relatively low prevalence, pediatric CRS imposes a significant economic burden, with 3.7–7.5 million annual visits in the United States and considerable healthcare expenditures of $1.8 billion per year. Furthermore, CRS significantly impacts QoL in children, leading to impaired general health, physical limitations, and increased body pain [22,23,24].
As evidenced by lack of expert agreement, diagnosing pediatric CRS can be challenging due to unique clinical presentations, difficulties in performing nasal endoscopy, and concerns about radiation exposure with CT imaging [25•]. While sinus CT scans are the standard imaging modality for evaluating CRS, magnetic resonance imaging (MRI) may be considered in the pediatric population to avoid radiation exposure [26]. Children with CRS often present with distinct symptoms, such as persistent cough, nasal drainage, low-grade fever, and irritability. Furthermore, many children show non-specific and subtle symptoms, leading to unremarkable physical exam findings [27, 28].
There are anatomical and mechanistic differences between adult and pediatric CRS. For instance, pediatric CRS often involves the adenoids serving as a bacterial reservoir [29]. Evaluating potential comorbidities, such as asthma, allergies, cystic fibrosis (CF), primary ciliary dyskinesia (PCD), immunodeficiency, and gastroesophageal reflux disease (GERD) is crucial in pediatric CRSwNP patients, who are more likely to have comorbidities related to their CRSwNP [16, 30•]. A high index of suspicion for CF is warranted in children with nasal polyps, sinus disease, poor weight gain, respiratory diseases, and gastrointestinal abnormalities [31]. CRSwNP associated with CF is treated with transmembrane conductance modulator therapies such as elexacaftor/tezacaftor/ivacaftor [32]. Moreover, PCD should be considered in children with refractory CRS and associated pulmonary conditions, such as bronchiectasis, especially when accompanied by situs inversus or spermatozoid abnormalities [33]. Children with refractory CRS should also be evaluated for humoral immune deficiency, as immunodeficiencies can significantly impact the management of the condition as well [34]. One study also pointed out the possibility of GERD contributing to more proximal airway diseases such as CRS [35].
Given the distinct presentations and substantial impact of CRSwNP on the pediatric population, it is imperative to advance our understanding this condition [36, 37]. This review aims to comprehensively address the management and treatment strategies for pediatric CRSwNP, underscoring the need for tailored approaches in children.
Treatment
Pharmacologic treatment
Intranasal corticosteroids (INCS)
Intranasal corticosteroids (INCS) exert anti-inflammatory effects on the sinonasal mucosa. The use of INCS has been shown to improve QoL for children with CRS, with a significant impact on increasing sinonasal biodiversity [38•]. In CRSwNP, INCS treatment has demonstrated the ability to decrease polyp size and reduce sinonasal symptoms after 12 weeks of treatment [38•].
Commonly used INCS include fluticasone, mometasone, and budesonide. The dosage is tailored based on the child's age, weight, and the severity of symptoms [39•]. For children ≥2 years of age, flonase propionate (50 mcg/spray) is typically administered as one spray per nostril once daily and can be increased to two sprays per nostril once daily if needed. For children ≥2 years of age, mometasone (50 mcg/spray) is administered as one spray per nostril once daily. Moreover, short term budesonide transnasal nebulization was shown to be an effective and safe treatment option in patients with eosinophilic CRSwNP [40]. Budesonide (32 mcg/spray) is given to children ≥6 years of age as one to two sprays once daily.
The main side effects of INCS are usually mild and localized, including nasal irritation, epistaxis, and headaches. Long-term systemic side effects, such as growth retardation, are rare due to the topical administration of INCS [41]. To minimize systemic absorption, children should be instructed to aim the nasal spray away from the nasal septum [42].
Contraindications to using INCS in pediatric CRSwNP are generally minimal, except when there are known hypersensitivity or allergic reactions to corticosteroids. Additionally, INCS generally have a low risk of significant drug interactions [43].
INCS are generally cost-effective for patients without severe to extreme anatomical nasal obstruction, especially when there is no need for invasive treatments such as surgery. However, the cost can vary depending on the specific medication, dosage, and regional costs [44].
Oral corticosteroids (OCS)
For individuals with severe symptoms of CRSwNP such as complete nasal obstruction, a short course of oral corticosteroids (OCS) can be effective [45]. This is particularly relevant in cases where nasal polyposis is extensive and fills the nasal cavity and paranasal sinuses, making it difficult for INCS to reach the affected tissues [46]. In these cases, combining OCS with INCS is beneficial for reducing the size of nasal polyps, improving olfactory function, and alleviating overall sinonasal symptoms [47, 48].
In adults, the typical OCS regimen involves a 10-14 day course of prednisone, usually beginning with a dosage of 40-60mg followed by a taper [49]. In the case of pediatrics, the safety and efficacy of OCS for CRSwNP is less clearly defined. However, for pediatric patients experiencing severe symptoms from CRSwNP, a common approach is to administer prednisone at a dose of 1 mg/kg/day for 5-7 days, followed by a taper [50, 51].
The side effects of OCS are typically associated with long-term or repeated use such as psychiatric events, infections, adrenal suppression, osteoporosis, and growth suppression in children [52]. However, even short-term courses can lead to adverse effects, such as hyperglycemia, mood changes, insomnia, and gastrointestinal disturbances, among others [53].
OCS are contraindicated in patients with conditions that could be exacerbated by steroid use, such as diabetes, glaucoma, or osteoporosis [54]. Therefore, the use of OCS, particularly in pediatric patients, requires careful consideration and monitoring.
While OCS are cost-effective, the indirect costs due to adverse events, particularly with long-term use, can be expensive [55]. However, the current evidence is not specific to CRSwNP, indicating a need for more focused research in this area [56].
Antibiotics
Individuals with CRSwNP are prone to experiencing acute exacerbations or infections. When an acute infection is suspected, as indicated by purulent nasal drainage, fevers, or a sudden worsening of sinonasal symptoms, antibiotics are recommended [57]. In such cases, amoxicillin/clavulanate is generally the first-line treatment for adults with acute bacterial rhinosinusitis (ABRS), while for children, amoxicillin with or without clavulanate is usually prescribed. The choice of antibiotics can be adjusted based on the patient's previous culture results and any known allergies [58, 59]. However, it is important to note that there is no supportive evidence for either short or long term antibiotic regimens in pediatric CRS, indicating that antibiotics should be used with caution and primarily focused on treating complications associated with ABRS [30•].
In adults with CRSwNP, prolonged courses of low-dose azithromycin or doxycycline can be considered for their anti-inflammatory effects; however, these are not currently recommended in treating pediatric patients given a lack of clinical evidence [60, 61].
Common side effects of antibiotics include gastrointestinal issues such as nausea, vomiting, or diarrhea. Long-term or frequent use may cause antibiotic resistance or disrupt gut flora, potentially leading to C. diff infection [62].
It is important for patients to complete the full antibiotic course to avoid bacterial resistance and recurrence. Furthermore, antibiotics should be avoided in suspected cases of viral ARS to improve cost-effectiveness and reduce the risk of antibiotic resistance [63]. Short courses of antibiotics are generally considered to be cost-effective when used in the appropriate clinical setting.
Surgery
Surgical management of CRSwNP is indicated when medical therapy fails to adequately control the patient’s symptoms. Surgery plays an important role in managing pediatric CRSwNP, with adenoidectomy as the initial choice and endoscopic sinus surgery reserved for cases in which adenoidectomy is ineffective [64].
Adenoidectomy
The adenoids are prominent in childhood and regress as individuals get older. In pediatric patients, especially those under 13 years of age, the adenoids can act as a bacterial reservoir and exacerbate CRS. For children whose CRS is refractory to medical treatment, adenoidectomy is often the first-line surgical option [25, 65•]. A meta-analysis of eight studies revealed a significant improvement in CRS symptoms in about 69.3% of pediatric patients following adenoidectomy [65•]. For pediatric patients with CRS, adenoidectomy alone or in combination with sinus lavage is the most common initial surgical intervention chosen by otolaryngologists in the United States [66, 67].
While potential complications such as postoperative bleeding, infection, changes in voice quality, and the rare occurrence of velopharyngeal insufficiency are relatively uncommon, a comprehensive risk-benefit analysis is necessary before undergoing the procedure [68]. Adenoidectomy has been shown to result in high parental satisfaction, although the costs and cost-effectiveness of the procedure can vary [69].
Endoscopic Sinus Surgery (ESS)
In adult patients, endoscopic sinus surgery (ESS) is often the first-line surgical treatment for individuals with medically-refractory CRS. However, in pediatric patients, ESS is typically reserved for patients who fail to improve with adenoidectomy [64]. The primary goal of ESS for CRS is to relieve obstruction of the paranasal sinus outflow tracts and to allow for more effective topical medication delivery. In cases of CRSwNP, ESS is particularly effective in removing nasal polyps, but it is critical to incorporate medical therapy postoperatively to reduce the risk of nasal polyp regrowth [70].
In terms of outcomes, ESS has proven to be successful in pediatric patients, often achieving higher levels of parent satisfaction and overall success rates compared to adenoidectomy [71•, 72,73,74,75]. One study suggests that a limited, disease-driven approach to ESS, focusing on drainage over an extirpation procedure, may offer potential benefits in treating pediatric patients [76].
While some studies report minimal clinical differences between ESS and balloon sinuplasty [77], solid evidence for using balloon sinuplasty in pediatric CRS is limited. Notably, patient-reported acute exacerbations were higher, and reductions in thick nasal discharge were less significant in the balloon sinuplasty group [78]. Moreover, ESS has proven to be more cost-effective than dupilumab, a biologic medication, for medically-refractory CRSwNP, providing higher quality-adjusted life years (QALYs) at a lower cost [79].
Complications, though infrequent, can include postoperative hemorrhage, orbital complications, and cerebrospinal fluid (CSF) leaks [80]. Prior animal studies raised concerns that ESS might affect midface growth and development; however, human studies found no impact on facial development among children who underwent ESS [81,82,83,84]. Furthermore, the use of image-guided navigation systems can be helpful in the surgical management of complex sinus and skull base surgery in pediatric patients [85].
Prognostic factors for ESS revision, such as younger age, nasal allergies, and higher Lund-Mackay scores on preoperative CT scans, are associated with poorer outcomes after ESS. For pediatric patients with these factors, it is crucial to discuss recurrence risks, ensure longer post-operative follow-ups, and consider biologic therapy options [86].
Other Treatments
Nasal Saline Irrigation (NSI)
Nasal saline irrigation (NSI) involves the mechanical clearance of thick mucus and inflammatory mediators, along with improving mucociliary function [87•]. NSI has shown significant improvements in QoL for adult patients with CRS. In the pediatric patients with CRS, three randomized controlled trials have demonstrated the benefits of NSI treatment, both as a sole modality and as an adjunct treatment [88,89,90].
Complications associated with NSI are rare, but may include discomfort from improper irrigation techniques, transient burning or stinging sensations, and irritation of the nasal passages. Rarely, contamination of the saline solution may lead to infections, highlighting the importance of keeping solutions and irrigation devices clean. Moreover, NSI is generally considered cost-effective due to the affordability and widespread availability of saline solutions and irrigation tools [91, 92].
Emerging therapies
Biologic medications
CRSwNP is classically considered to be a type 2 eosinophilic inflammatory response [93•]. As such, biologic agents that target the type 2 inflammatory pathway have been developed for use in CRSwNP [14]. The three biologic medications that are currently approved by the United States Federal Drug Administration (FDA) for the treatment of CRSwNP include omalizumab, dupilumab, and mepolizumab [94]. The effectiveness of these treatments in the adult population has been demonstrated in randomized controlled trials (RCTs) such as POLYP1/2 for omalizumab, SYNAPSE for mepolizumab, and LIBERTY NP SINUS 24/52 for dupilumab. Although these biologic medications are only approved for use in adults with CRSwNP, they are approved for use in pediatric patients with other type 2 inflammatory conditions, such as asthma and atopic dermatitis [95]. Moreover, emerging biologics such as Benralizumab, Tezepelumab, Etokimab, and Depemokimab are under study and pending FDA approval for their potential in CRSwNP management [96, 97].
Omalizumab is a monoclonal antibody that targets immunoglobulin E (IgE) and was approved by the FDA in 2020 for the treatment of CRSwNP. The POLYP 1 and POLYP 2 multicenter RCTs demonstrated these positive outcomes after 24 weeks of treatment, marking omalizumab as a promising option for refractory CRSwNP [98, 99]. Omalizumab has been shown to reduce endoscopic nasal polyp scores (NPS), nasal congestion, and Sinonasal Outcome Test (SNOT-22) scores as well as increase sleep and self-reported health status in patients [100, 101]. A recent study also highlighted its economic benefits compared to revision surgery for CRSwNP [102].
Mepolizumab, an anti-interleukin-5 (IL-5) monoclonal antibody, was approved in 2021. Mepolizumab was shown to improve endoscopic NPS and alleviate nasal obstruction in the SYNAPSE trial, a multicenter RCT for 52 weeks [18, 103, 104]. It was further highlighted that mepolizumab can improve olfaction in severe cases of CRSwNP [105].
Dupilumab is a monoclonal antibody that targets the α subunit of the interleukin-4 (IL-4) receptor and gained FDA approval for CRSwNP in 2017. The LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 multicenter RCTs demonstrated the efficacy of dupilumab in improving various clinical scores, including NPS, nasal congestion, sinonasal QoL, and Lund-Mackay scores after 24 and 52 weeks of treatment, respectively. Compared to omalizumab, dupilumab appears more effective, demonstrating superior outcomes in NPS, congestion, olfactory function, and total symptom scores [106,107,108]. Moreover, patients with poorly controlled CRSwNP have been shown to have significant improvements in radiologic, endoscopic, and clinical disease severity with dupilumab [109]. However, it is important to note the rare but severe adverse reactions reported with dupilumab, such as eosinophilic granulomatosis with polyangiitis and chronic T-cell lymphoma exacerbation, underscoring the importance of careful monitoring [110, 111].
Biologic medications pose several challenges, including short-term and long-term side effects, potential concerns about antidrug antibodies, and high costs [15, 16, 112]. A systematic review of biologics’ side effects in CRSwNP patients found that dupilumab often causes pharyngitis, erythema, and headaches. Similarly, omalizumab is linked to headaches, pharyngitis, and injection-site reactions, while mepolizumab is associated with nasal polyps, congestion, pharyngitis, and infections [113]. As previously mentioned, studies indicate that ESS is more cost-effective than biologics [114,115,116,117]. Therefore, biologic medications are generally reserved for patients who previously underwent ESS and have recurrent symptoms, or for poor surgical candidates or those who have co-morbidities that can be simultaneously treated with biologics [118••].
Ongoing research is focused on identifying new biologic agents and alternative targets, underscoring the need for reliable biomarkers and expanded clinical trials, especially for specific groups such as pediatric patients [119]. For further research, it is important to address the regulatory hurdles facing pediatric clinical trials. These include concerns over exposing children to uncertain treatment effects, challenges in obtaining parental consent, and questions about cost-effectiveness [120]. Therefore, further studies are necessary to determine the safety and efficacy of biologic medications in pediatric CRSwNP treatment.
Conclusion
The management of CRSwNP in the pediatric population poses a significant challenge, requiring a comprehensive approach that includes a combination of corticosteroids, antibiotics, nasal saline irrigations, and surgery. Given the limited data on CRSwNP in pediatric patients, there is a need for continued research on this topic and for the development of specialized treatment strategies tailored to the pediatric population. Moreover, factors such as patient goals, treatment efficacy and safety-profile, and the cost of treatment options must be considered in a shared decision-making process between patients, caregivers, and physicians when discussing treatment options. To reduce the overall health burden and enhance QoL in pediatric CRSwNP, further research should focus on advancing knowledge and refining treatments, especially for the emerging therapies.
Data availability
No datasets were generated or analysed during the current study.
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Oh, E., Miller, J.E. & Lee, J.T. Multidisciplinary Management of Pediatric Chronic Rhinosinusitis with Nasal Polyposis. Curr Treat Options Allergy 11, 34–48 (2024). https://doi.org/10.1007/s40521-024-00362-z
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DOI: https://doi.org/10.1007/s40521-024-00362-z