Immunity‐targeted approaches to the management of chronic and recurrent upper respiratory tract disorders in children

Background Upper respiratory tract infections (URTIs), including rhinitis, nasopharyngitis, tonsillitis and otitis media (OM), comprise of 88% of total respiratory infections, especially in children. Therefore effective prevention and treatment of RTIs remain a high priority worldwide. Preclinical and clinical data highlight the rationale for the use and effectiveness of immunity‐targeted approaches, including targeted immunisations and non‐specific immunomodulation in the prevention and management of recurrent upper RTIs. Objective of review The idea of this review was to summarise the current evidence and address key questions concerning the use of conservative and immunity‐targeted approaches to recurrent and chronic URTIs, with a focus on the paediatric population. Search strategy/Evaluation method Literature searches were conducted in March 2017 and updated in September 2017 using: Academic Search Complete; CENTRAL; Health Source: Nursing/Academic Edition; MEDLINE; clinicaltrials.gov; and Cochrane databases. In total, 84 articles were retrieved and reviewed. Two independent researchers focused on primary and secondary endpoints in systematic reviews, meta‐analyses and randomised, controlled trials, using immunity‐directed strategies as the control group or within a subpopulation of larger studies. Existing guidelines and interventional/observational studies on novel applications were also included. Results Children are particularly susceptible to RTIs due to the relative immaturity of their immune systems, as well as other potential predisposing factors such as day care attendance and/or toxic environmental factors (eg increased pathogenic microbial exposure and air pollutants). Recurrent URTIs can affect otherwise healthy children, leading to clinical sequelae and complications, including the development of chronic conditions or the need for surgery. Available pre‐clinical and clinical data highlight the rationale for the use and effectiveness of immunity‐targeted approaches, including targeted immunisations (flu and pneumococcal vaccines) and non‐specific immunomodulation (bacterial lysates), in the prevention and management of recurrent croup, tonsillitis, otitis media, recurrent acute rhinosinusitis and chronic rhinosinusitis. Conclusions In this review, we summarise the current evidence and provide data demonstrating that some immunity‐targeted strategies, including vaccination and immunomodulation, have proved effective in the treatment and prevention of recurrent and chronic URTIs in children.


| Introduction
Upper respiratory tract infections (URTIs; also known as ENT infections), including rhinitis, nasopharyngitis, tonsillitis and otitis media (OM), comprise 88% of total respiratory infections. 1 The aetiology of URTIs is mostly viral, being primarily caused by rhinovirus (HRV), parainfluenza, respiratory syncytial virus (RSV), influenza, adenovirus and coronavirus. Upper respiratory tract infections are more common in the autumn/winter in Europe and North America, and during the rainy season in tropical countries. 2 Children are prone to developing RTIs because their immune system has yet to fully mature. [3][4][5] Increased exposure to viral infections during day care attendance, as well as other social and environmental factors, can increase the risk of RTI. 4 The respiratory system is a primary target for key air pollutants, which can increase the risk of acute and recurrent RTIs. 6 Most of these pollutants disrupt local mucosal innate immunity mechanisms, leading to bacterial colonisation, impaired killing and increased allergen permeability.

| Burden and management of RTIs
URTIs are associated with sequelae and complications, including severe lower RTIs (LRTIs), the development of chronic conditions or the need for surgery when recurrent. Owing to the high morbidity, mortality and healthcare costs, effective prevention and treatment of RTIs are a high priority worldwide. 7,8 Treatment is focused on symptom relief, such as antihistamines and decongestants for nasal congestion 9 and antitussives for cough. 10,11 Although antibiotics are only indicated in a minority of patients, they are often unnecessarily prescribed for viral infections against which they have no effect. A recent US report highlighted that ~30% of outpatient, oral antibiotic prescriptions were inappropriately written. 12 Antibiotic misuse has led to the emergence of resistant bacteria, meaning that higher doses and more advanced generations of drugs are required, and at present, some infected patients cannot be treated adequately. 13 Owing to the current unmet need for effective, alternative conservative therapies, efforts are being refocused towards preventative strategies including 5 behavioural intervention; avoidance of environmental risk factors such as passive smoking 14 and highly polluted city areas; vaccination, such as active targeted immunisation; targeted medical intervention; non-specific immunostimulation or immunomodulation (eg bacterial lysates) [15][16][17][18] ; nutrition, including vitamins (eg C or D) and microelements; and regular physical activity ( Table 1). Parents of children with recurrent RTIs may also discuss "immune-stimulating" therapies that they have seen advertised, such as herbal (eg Echinacea) and homoeopathic remedies, and animalderived products (eg cod liver oil and thymus extracts). 5 Owing to significant heterogeneity and a lack of high-quality clinical evidence supporting many of these therapies, 19 here we reviewed existing immunity-targeted therapies available for ENT infections in children, with an emphasis on non-specific immunomodulation administered together with the standard of care. which is not only based on an increase in non-specific immunoglobulin A response against pathogens at mucosal surfaces, but also on activation of mucosal dendritic cells by pattern recognition receptor-dependent signalling. 26  In this review, we want to highlight emerging, evidence-based approaches for conservative management of the most common recurrent and chronic URTIs in children, with an emphasis on the role of immunomodulation.

| Ethical considerations
As no human participants were involved in the development of this review, no ethics committee (Institutional Review Board) approval was sought or obtained, and it was not necessary to obtain informed consent from patients.

| Introduction
Children with recurrent or severe croup are commonly referred to a paediatric otolaryngologist or ENT specialist for further assessment and exclusion of an underlying anatomical or congenital upper airway disorder.

| Epidemiology
Croup occurs at a rate of ~5/100 in the second year of life, with a peak incidence between 6 months and 3 years of age. 35 Around 15% of annual clinic and emergency department visits for paediatric RTIs are due to croup. 35 Recurrent croup in children is typically defined as more than three episodes. 36

| Aetiology
Croup is primarily caused by parainfluenza viruses 1, 2 and 3, as well as RSVs. The viruses are generally spread by direct inhalation from a cough or sneeze, or by contamination of the hands following contact with fomites, with subsequent transference to the mucosa of the eyes, nose or mouth.

| Treatment of acute or recurrent episodes
The treatment of croup is dependent on the severity of the upper airway obstruction and the risk for rapid deterioration of the patient's condition. Mild-to-moderate croup is typically treated with anti-inflammatory agents (nebulised or oral steroids), while adrenaline is required urgently in cases of severe croup. 37 The use of systemic corticosteroids early in the disease process reduces hospitalisation rates, 38 although 6-10% of patients still require hospitalisation. 39

| Epidemiology
Tonsillitis is more common among children than adults. 49,50 In the USA, sore throat accounts for 2.1% of outpatient visits, 51 with a prevalence of bacterial tonsillitis of 15-30% among affected children. [52][53][54] Recurrent tonsillitis in children is defined as multiple episodes of acute tonsillitis in a year. 55 The burden of recurrent tonsillitis is substantial and it may lead to peritonsillitis. However, the overall frequency and magnitude of the problem of recurrent tonsillitis remains unclear.

| Treatment of acute and recurrent episodes
The treatment of tonsillitis in children focuses on reducing symptoms, avoiding complications, decreasing the number of disease-related school absences and improving quality of life. According to clinical practice guidelines, the first-line treatment for bacterial tonsillitis should be a narrow-spectrum antibiotic (eg penicillin). 16,49,50 However, some European countries, including Germany, the UK and the Netherlands, only recommend antibiotics in certain high-risk patients. 56 The widely accepted indications for tonsillectomy in children are at least seven well-documented, clinically significant, adequately treated sore throat (defined as "acute pharyngitis, tonsillitis or acute exudative tonsillitis") in the preceding year, or at least five such episodes in each of the preceding 2 years, or at least three such episodes in each of the preceding 3 years. 49,50 Surgery should also be considered if the episodes are disabling and prevent normal functioning.  62 Approximately 50% of children aged less than 2 years treated for AOM experience a recurrence within 6 months. 62 Symptoms that last for more than 10 days may also predict recurrence. 63

| Treatment of acute and recurrent episodes
The treatment approach in AOM depends on factors such as patient age and the severity of signs and symptoms. 62  malformations, cystic fibrosis and ciliary dyskinesia need to be excluded); greater patient/parent education, such as highlighting the importance of avoiding passive smoking, as this is a significant factor impairing mucosal immunity; and breastfeeding for children aged less than 1 year. 64 More invasive interventions, such as the insertion of tympanostomy tubes, may be required for children with recurrent AOM and one or more of the following: aged less than 2 years; underlying medical conditions that predispose the patient to recurrence; or comorbid conditions associated with developmental or language delays. However, there is generally a lack of consensus regarding the role of surgery in AOM. 65 The parents of children with recurrent AOM are usually anxious about pursuing a surgical treatment option and often seek complementary remedies. 66

| Epidemiology
The EPOS group defined acute rhinosinusitis (ARS) as "the sudden onset of two or more symptoms that last for <12 weeks." 32 However, in older classifications the term "subacute sinusitis" was proposed, which represents a temporal progression of symptoms for 4-12 weeks (contemporarily defined as "post-viral ARS"). Although chronic rhinosinusitis (CRS) is defined as persistence of sinus inflammation for at least 12 weeks, the EPOS group did not feel a separate term to describe patients with prolonged ARS was necessary, and that "exacerbation of CRS" was more appropriate. In Europe, 0.5-5% of children with URTIs progress to post-viral ARS 77,78 and many experience recurrences (point prevalence of 0.035%). 79 Estimates of CRS prevalence vary significantly worldwide, partly related to differences in the diagnostic criteria used (eg symptom-based diagnosis vs inclusion of objective rhinoscopy or imaging findings). In the USA, the prevalence of CRS ranges from 2% to 16%, while in various EU countries, it is 7-27% (average 11%). 77 Estimates from South America and the Caribbean are in a similar range. 80,81 Differentiation between recurrent ARS and CRS is difficult, but relies on the complete resolution of symptoms between episodes. 82 Some patients have recurrent episodes of ARS and may represent a distinct clinical phenotype 83 ; these patients should be assessed for underlying risk factors such as allergy, immunodeficiency, cystic fibrosis and anatomical abnormalities, 84 with consideration of imaging or endoscopic evaluation. As the nasal/paranasal mucosa is the first interface with inhaled toxins and pollutants, environmental factors are thought to be an important cause of transition from ARS to CRS, as well as the trigger for symptom exacerbation in CRS. 85 For example, there is a significant association between passive smoking and sinusitis. 86

| Treatment of acute and recurrent episodes
Careful analysis of the underlying defect should be performed, for example anatomical abnormalities and immunodeficiency. 87 Cochrane meta-analysis evaluating intranasal steroids for CRS in children, there was no effect on disease severity, although symptomatic improvement (nasal blockage, rhinorrhoea, loss of sense of smell and facial pain) was observed. 89 Based on these observations, we recommend intranasal steroids as a category Ia/A option for children with recurrent ARS and/or CRS. 89

| Prevention of recurrent episodes and role of immunomodulation
Immunisation leads to an increase in the host's resistance capabilities and a decrease in the incidence of acute respiratory disease. 93   The rapid emergence of resistant bacteria is jeopardising the efficacy of antibiotics; indeed, decreasing the use of antibiotics is considered a top priority for healthcare authorities around the world to avoid the consequent effects of overuse such as an increase in antibiotic resistance and mucosa microbiome impairment. 103 As such, new treatments and preventative modalities for respiratory infections are expected and welcomed. Modulation of the human immune systems is becoming increasingly relevant, not only in general infectious diseases, allergy or gastroenterology, but also in disciplines such as oncology and ENT-related disorders. In this review, we have discussed the clinical evidence that supports the use of selected immunomodulatory strategies in children with specific ENT conditions.

| Implications for clinical practice
However, there remain some barriers to the widespread use of these therapies. For example, the availability of data on specific ENT infections remain sparse, although evidence around the prevention of general RTIs is more robust. Ideally, new studies will be performed in specific ENT infections in children, in order to increase the evidence base and support treatment recommendations. In addition, according to the available meta-analysis, many of the commercially available products demonstrate a moderate effect.

| Future directions
As such, it is important that we generate high-quality research data on the use of immunomodulatory strategies in patients with specific URTIs and other upper respiratory tract diseases.

ACK N OWLED G EM ENTS
The authors would like to thank Andrew Jones, PhD (Mudskipper Business Ltd) for his excellent editorial assistance and Dr. Stefania Ballarini for coordinating initial discussions during the preparation of the manuscript.